Safety Assessment of Saccharide Esters As Used in Cosmetics

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Safety Assessment of Saccharide Esters as Used in Cosmetics

Status: Draft Final Report for Panel Review Release Date: November 11, 2016 Panel Meeting Date: December 5-6, 2016

The 2016 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D., Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This safety assessment was prepared by Laura N. Scott, Scientific Writer/Analyst.

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Memorandum

To: CIR Expert Panel Members and Liaisons From: Laura N. Scott Senior Scientific Writer Date: November 11, 2016 Subject: Draft Final Report of the Safety Assessment of Saccharide Esters as Used in Cosmetics

At the June 6-7, 2016 CIR Expert Panel meeting, the Panel issued a Tentative Report for public comment on the Safety Assessment of Saccharide Esters with the conclusion of safe as used in cosmetics in the present practices of use and concentrations described in this safety assessment. Sucrose Disinapate was removed from the report because it is structurally dissimilar and read-across is not applicable; the current ingredient count for this report is 40.

Enclosed is the Draft Final Report of the Safety Assessment of Saccharide Esters as Used in Cosmetics (identified as SACEST122016rep in the PDF document). Additionally, the CIR report history (SACEST122016hist), literature search strategy (SACEST122016strat), ingredient data profile (SACEST122016prof), process flow chart (SACEST122016flow), 2016 FDA VCRP data (SACEST122016FDA), and minutes from the June 2016 Panel Meeting (SACEST122016min) are included for the Panel’s review. There were no reported concentrations of use for Sucrose Dipalmitate, Sucrose Palmitate/Stearate, and Sucrose Stearate-Palmitate Ester following a Council industry survey; the report has been updated to reflect this.

The following are the main changes made to this Draft Final Report following the June Meeting:

1. The 2-year chronic study, which also evaluated carcinogenicity, was added to the Chronic Toxicity Section, to Table 11, and mentioned in the Summary. The applicable portions of this study were also mentioned briefly in the Carcinogenicity section. Two, 4-week range-finding studies were moved from the Chronic Toxicity and Carcinogenicity sections to Short-term Toxicity. Some 90-day studies were moved from Short-Term Toxicity to Subchronic Toxicity.

2. The anonymous submission of Wave 2 data presented to the Panel for the June meeting was added (highlighted in Tables and │bracketed│in text) to the Genotoxicity Section (Maltitol Laurate; negative Ames test, added to Table 13), to the Dermal Irritation Section (Sucrose Pentahydroxystearate and Sucrose Tetraisostearate; negative Human Patch Tests, added to Table 15), and to the Summary.

3. Clarifications were made to the Toxicokinetics Section-ADME (including Table 9 and the Summary) concerning dosed radioactivity and the location of radiolabels when that information was provided by the source.

Council comments on the Draft Report (SACEST1262016pcpc_1) and on the Tentative Report (SACEST122016pcpc_2) were received and have been addressed. In their comments (SACEST122016pcpc_2) on the Discussion section, the Council asked how a structural activity relationship was determined for read-

______1620 L Street, NW Suite 1200, Washington, DC 20036 (Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org Distributed for Comment Only -- Do Not Cite or Quote across (i.e., the safety data for Sucrose Acetate Isobutyrate is indicated for multiple endpoints and may be extrapolated for the safety determination of larger ingredients that are less likely to penetrate the skin after dermal exposure). CIR is asking for the Panel’s guidance on including a further explanation of structure-activity relationship for Sucrose Acetate Isobutyrate and, if included, a rationale for the Discussion.

After reviewing the Draft Final Report, the Panel will need to verify the Discussion and Conclusion and be prepared to issue a Final Report.

[Note: In this Draft Final Report the in-text Table references are linked directly to the corresponding Table at the end of the document. In the Word version use “Ctrl + left click” on the in-text link and in the PDF version simply double (left) click on the in-text link to go directly to the Table.]

INGREDIENT/FAMILY _____Saccharide Esters______

MEETING _____Dec 2016______

Public Comment CIR Expert Panel Report Status

Priority List INGREDIENT PRIORITY LIST

SLR March 22, 2016

DRAFT REPORT June 2016 Draft Report 60 day public comment period

Table

Table IDA TR

IDA Notice IDA DRAFT TENTATIVE REPORT Draft TR

Table

Tentative Report Issue TR June 23, 2016

Draft FR DRAFT FINAL REPORT Dec 2016 60 day Public comment period

Table

Table Different Conclusion

Issue PUBLISH Final Report FR

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Report History-Saccharide Esters

March 22, 2016-The Saccharide Esters Scientific Literature Review was posted at www.cir-safety.org for public comment.

June 6-7, 2016-This is the first time the Panel saw the Draft Report of the Safety Assessment of Saccharide Esters; Sucrose Disinapate was removed from this report because it is structurally dissimilar and read-across methodology would not be applicable; The Panel issued a Tentative Report for public comment with the conclusion that the 40 saccharide esters are safe as used in cosmetics in the present practices of use and concentrations described in this assessment.

June 23, 2016-The Tentative Report was posted online for public comment.

September 26-27th, 2016-This report was not reviewed at the Sept Panel Meeting.

December 5-6th, 2016- Distributed for Comment Only -- Do Not Cite or Quote

Saccharide Esters Data Profile for December 5-6, 2016. Writer – Laura Scott Penetration ADME Acute Short- DART Carcino- Dermal Dermal Ocular Enhancement Toxicity Term Chronic genicity Irr. Sen. Irr. Toxicity Tox Genotox Cosmetics? Use Available ta Da Safety Penetration - Human In Vitro Animal Human In Vitro Animal Animal - Human Animal Animal Animal - Human Animal Animal In Vitro Vivo In Animal Animal Human Animal Human Animal

d in d in ------

Oral Other Dermal Oral Oral Oral Oral Oral Dermal Dermal Oral & IV & Oral Oral ?

Alkyl Fatty Acid Esters (single chain length) Glucose Pentaacetate N Y X Sucrose Octaacetate N N Xylityl Sesquicaprylate N N Trehalose Undecylenoate Y N Maltitol Laurate Y Y X Sucrose Laurate Y Y X X X X X X X X Sucrose Polylaurate Y N Sucrose Dilaurate Y N Sucrose Trilaurate Y N Sucrose Myristate Y Y X Raffinose Myristate N N Sucrose Palmitate Y Y X X X X X Sucrose Dipalmitate Y N Raffinose Isostearate N N Sucrose Hexapalmitate N N Sucrose Stearate Y Y X X X X X Sucrose Polystearate Y N Sucrose Oleate N Y X Sucrose Polyoleate Y N Sucrose Polylinoleate N N Trehalose Isostearate Esters Y N Raffinose Oleate N N Sucrose Distearate Y N Sucrose Tristearate Y N Sucrose Tetraisostearate Y Y X Sucrose N N Tetrahydroxystearate Sucrose Y Y X Pentahydroxystearate Sucrose Polybehenate Y Y X X Sucrose Tribehenate N N Sucrose Pentaerucate N N Sucrose Hexaerucate N N Distributed for Comment Only -- Do Not Cite or Quote

d in d in ------

Oral Other Dermal Oral Oral Oral Oral Oral Dermal Dermal Oral & IV & Oral Oral ?

Alkyl Fatty Acid Esters (mixed chain lengths) Sucrose Acetate Isobutyrate Y Y X X X X X X X X X X X X X X X X Sucrose Acetate/ Stearate Y N Sucrose Tetrastearate Triacetate Y N Sucrose Palmitate/ Stearate Y N Sucrose Palmitate-Stearate Y N Ester Sucrose Polysoyate Y Y X Sucrose Hexaoleate/ Y Y X Hexapalmitate/ Hexastearate Sucrose Cocoate Y Y X Sucrose Polycottonseedate Y Y X X Non-Alkyl Esters Sucrose Benzoate Y N

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Search Strategy for Saccharide Esters

Ingredient Cas No. Prev in NTIS FDA/ NTP TOXNET WHO ECHA HPVIS/ OECD/ EU NICNAS Web Rev Use CFR EPA SIDS Glucose Pentaacetate 3891-59-6, 604-68-2 - No X X - X - - - - X Listed, no X further info** Maltitol Laurate 75765-49-0 2008 Yes ------X

Raffinose Isostearate 1032182-34-5 - No ------X

Raffinose Myristate 91433-10-2 - No ------X - X

Raffinose Oleate 96352-58-8 - No - - - X - - - - X - X

Sucrose Acetate 126-13-6 Isobutyrate - - - Tier I - Yes X X X X X X Cosmetic, X no further info** Sucrose Acetate/ 52439-69-7 Stearate - Yes - - - X - - - - X - X

Sucrose Benzoate 12738-64-6 - Yes X X ------X Listed, no X further info** Sucrose Cocoate 91031-88-8 - Yes - X ------X Listed, no X further info** Sucrose Dilaurate 25915-57-5 - Yes - X - X - - - - X - X

Sucrose Dipalmitate* 25637-97-2 - Yes X

Sucrose Disinapate N/A - No ------X Distributed for Comment Only -- Do Not Cite or Quote

Ingredient Cas No. Prev in NTIS FDA/ NTP TOXNET WHO ECHA HPVIS/ OECD/ EU NICNAS Web Rev Use CFR EPA SIDS Sucrose Distearate 27195-16-0 - Yes - X - X - - - - X Listed, no X further info** Sucrose Hexaerucate N/A - No - X ------X

Sucrose Hexaoleate/ N/A Hexapalmitate/ - Yes - X ------X Hexastearate Sucrose 29130-29-8 Hexapalmitate - No - X - X ------X

Sucrose Laurate 25339-99-5, 37266-93-6 - Yes - X - X - - - - X Listed, no X further info** Sucrose Myristate 27216-47-3, 9042-71-1 - Yes - X - X - - - - X - X

Sucrose Octaacetate 126-14-7 - No X X - X - - - - X Listed, no X further info** Sucrose Oleate 52683-61-1 - No - X - X - - - - X - X

Sucrose Palmitate 26446-38-8, 39300-95-3 - Yes - X - X - - - - X Listed, no X further info** Sucrose Palmitate/ N/A Stearate or Sucrose - Yes - - - X ------X Stearate-Palmitate Ester* Sucrose Pentaerucate N/A - No - X ------X

Sucrose N/A Pentahydroxy- - Yes ------Stearate Sucrose Polybehenate 93571-82-5 - Yes ------X X

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Ingredient Cas No. Prev in NTIS FDA/ NTP TOXNET WHO ECHA HPVIS/ OECD/ EU NICNAS Web Rev Use CFR EPA SIDS Sucrose 93571-82-5 Polycottonseedate - Yes ------X X

Sucrose Polylaurate N/A - Yes ------X

Sucrose Polylinoleate N/A - No ------X

Sucrose Polyoleate N/A - Yes ------X - X

Sucrose Polysoyate 93571-82-5 - Yes ------X CAS# X listed; Secondary Notification Conditions do apply Sucrose Polystearate N/A - Yes ------X - X

Sucrose Stearate 25168-73-4, 37318-31-3 - Yes - X ------X Listed, no X further info** Sucrose N/A Tetrahydroxystearate - No - X ------X

Sucrose 88484-21-3 Tetraisostearate - Yes - X - X ------X

Sucrose Tetrastearate N/A Triacetate - Yes - - - X ------X

Sucrose Tribehenate 84798-44-7 - No - X ------X

Sucrose Trilaurate 94031-23-9 - Yes - X - X ------X

Sucrose Tristearate 27923-63-3 - Yes - X - X - - - - X - X Distributed for Comment Only -- Do Not Cite or Quote

Ingredient Cas No. Prev in NTIS FDA/ NTP TOXNET WHO ECHA HPVIS/ OECD/ EU NICNAS Web Rev Use CFR EPA SIDS Trehalose Isostearate 861436-89-7 Esters - Yes - - - X ------X

Trehalose N/A Undecylenoate - Yes ------X

Xylityl 181632-90-6 Sesquicaprylate - No ------X

X indicates data were available; - indicates no relevant data were available; * indicates these ingredients were not included in the original list, but appeared in the FDA’s VCRP data so have been added to the report and above; **indicates ingredients are in the Australian Inventory of Chemical Substances (AICS) and secondary notification conditions do not apply

Saccharide Esters Search Info

PubMed: 10-8-15 searched: (((((((((((((((((((((((((((((((((((sucrose AND (acetate isobutyrate OR acetate/stearate OR benzoate OR cocoate OR dilaurate OR disinapates OR distearate OR hexaerucate OR hexaolate OR hexapalmitate OR hexastearate OR laurate OR myristate OR octaacetate OR oleate OR palmitate OR palmitate/stearate OR pentahydroxy stearate OR polybehenate OR polycottonseedate OR polyaurate OR poly linoleate OR polyolate OR polysorbate OR poly stearate OR stearate OR tetrahydroxystearates OR tetraisostearate OR tetrasterate triacetate OR tribehenate OR atrial rate OR tristearate)) OR glucose pentaacetate) OR maltitol laurate) OR (raffinose AND (isostearate OR myristate OR oleate))) OR (trehalose AND (isostearate esters OR undecylenate))) OR xylitol sesquicaprylate) OR 126-13-6) OR 3891-59-6) OR 604-68-2) OR 75765-49-0) OR 1032182-34-5) OR 91433-10-2) OR 96352-58-8) OR 52439-69-7) OR 12738-64-6) OR 91031-88-8) OR 25915-57-5) OR 27195-16-0) OR 29130-29-8) OR 25339-99-5) OR 37266-93-6) OR 27216-47-3) OR 9042-71-1) OR 126-14-7) OR 52683-61-1) OR 26446-38-8) OR 39300-95-3) OR 93571-82-5) OR 25168-73-4) OR 37318-31-3) OR 88484-21-3) OR 84798-44-7) OR 94031-23-9) OR 27923-63-3) OR 861436-89-7) OR 181632-90-6. (1808 hits/27 useful); 10-20-15 searched: (sucrose) AND pentaerucate (0 hits)

Email updates are received when new articles (using similar search parameters as above) become available.

SciFinder: 10-5-15 searched: sucrose acetate isobutyrate, 126-13-6 (128 hits/13 useful); glucose pentaacetate, 3891-59-6, 604-68-2 (1299 hits/11 useful); 10-6-15 searched: maltitol laurate, 75765-49-0 (4 hits/0 useful); Raffinose Isostearate, 1032182-34-5 (0 hits); Raffinose Myristate, 91433-10-2 (11 hits/0 useful); Raffinose Oleate, 96352-58-8 (2 hits/0 useful); sucrose acetate/stearate, sucrose acetate, sucrose stearate, 52439-69- 7 (1340 hits/ 11 useful); sucrose benzoate, 12738-64-6 (32 hits/0 useful); sucrose cocoate, 91031-88-8 (11 hits/1useful); sucrose dilaurate, 25915- 57-5 (31 hits/ 0 useful); sucrose disinapate (0 hits); sucrose distearate, 27195-16-0 (60 hits/0 useful); sucrose hexaerucate (0 hits); sucrose hexaoleate, sucrose hexapalmitate, sucrose hexastearate (8 hits/0 useful); sucrose hexapalmitate, 29130-29-8 (3 hits/0 useful); 10-7-15 searched: Distributed for Comment Only -- Do Not Cite or Quote

sucrose laurate, 25339-99-5, 37266-93-6 (397 hits/10 useful); sucrose myristate, 27216-47-3, 9042-71-1 (68 hits/1 useful); sucrose octaacetate, 126-14-7 (329 hits/1 useful); sucrose oleate, 52683-61-1 (51 hits/5 useful); sucrose palmitate, 26446-38-8, 39300-95-3 (262 hits/4 useful); 10-8-15 searched: sucrose palmitate/stearate (12 hits/1 useful); sucrose pentahydroxystearate (0 hits); sucrose polybehenate, 93571-82-5 (9 hits/0 useful); sucrose polycottonseedate, 93571-82-5 (0 hits); sucrose polylaurate (138 hits/2 useful); sucrose polylinoleate (3 hits/0 useful); sucrose polyoleate (49 hits/0 useful); sucrose polysoyate, 93571-82-5 (0 hits); sucrose polystearate, sucrose stearate, 25168-73-4, 37318-31-3 (386 hits/1 useful); sucrose tetrahydroxystearate, sucrose tetraisostearate, 88484-21-3 (0 hits); sucrose tetrastearate triacetate, sucrose tribehenate, 84798-44-7 (0 hits); sucrose trilaurate, 94031-23-9 (7 hits/0 useful); sucrose tristearate, 27923-63-3 (11 hits/0 useful); trehalose isostearate esters, 861436-89-7 (0 hits); trehalose undecylenoate (0 hits); xylityl sesquicaprylate, 181632-90-6 (13 hits/ 0 useful); 10-20-15 searched: sucrose pentaerucate (0 hits)

“Keep Me Posted” (started 10-8-2015) for email updates when new articles (using similar search parameters as above) become available.

ECHA

Date accessed 2-18-2016, searched CAS# 126-13-6, listed in ECHA as “sucrose di(acetate) hexaisobutyrate” (1 hit): http://echa.europa.eu/en/registration-dossier/-/registered-dossier/5600/1

NTIS

10-20-15 searched “Glucose Pentaacetate”, “Sucrose Octaacetate” (1 hit): file:///C:/Users/lns/Downloads/PB85141117%20(1).pdf 10-20-15 searched “Sucrose Octaacetate” (1 hit): file:///C:/Users/lns/Downloads/PB97133888%20(4).pdf 10-20-15 searched “Sucrose Benzoate” (1 hit): file:///C:/Users/lns/Downloads/PB84240811%20(1).pdf

JECFA

10-28-15 searched all saccharide ester terms and CAS#s individually at www.inchem.org for JECFA-Monographs & Evaluations (0 hits)

FEMA

10-28-15 searched all saccharide ester terms and CAS #s individually at www.femaflavor.org (2 hits, same document for glucose pentaacetate and sucrose octaacetate)

Dail Med

3-29-2016 Searched for Saccharide Esters by names above at http://dailymed.nlm.nih.gov/dailymed/ ; None of the Saccharide Ester ingredients above appeared on prescription medication labels Distributed for Comment Only -- Do Not Cite or Quote

FDA

3-29-2016 Searched for Saccharide Esters by names above at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm for FDA approved drug products containing the Saccharide Ester ingredients; no hits found

3-29-2016 Searched for Saccharide Esters above at http://www.accessdata.fda.gov/scripts/cder/iig/ for inactive ingredients in FDA approved drug products; hits found: Sucrose Laurate; Sucrose Palmitate; Sucrose Stearate; Sucrose Distearate

CFR Citations

21CFR172.515 (Glucose Pentaacetate, Sucrose Octaacetate): Part 172-Food Additives Permitted For Direct Addition To Food For Human Consumption; Subpart F-Flavoring Agents and Related Substances; Section 172.515 Synthetic flavoring substances and adjuvants; Synthetic flavoring substances and adjuvants may be safely used in food in accordance with the following conditions. (a) They are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice. (b) They consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. Glucose Pentaacetate. Sucrose Octaacetate.

21CFR172.833 (Sucrose Acetate Isobutyrate): Part 172-Food Additives Permitted For Direct Addition To Food For Human Consumption; Subpart I-Multipurpose Additives; Section 172.833 Sucrose Acetate Isobutyrate. Sucrose Acetate Isobutyrate may be safely used in foods in accordance with the following prescribed conditions: (a) Sucrose Acetate Isobutyrate (CAS Reg. No. 27216-37-1)… is the chemical alpha-D- glucopyranoside, O-acetyl-tris-O-(2-methyl-1-oxopropyl)-beta-D-fructofuranosyl, acetate tris (2-methyl propanoate). (b) Sucrose Acetate Isobutyrate, a pale, straw-colored liquid, meets the following specifications:

(1) Assay: Not less than 98.8 percent and not more than 101.9 percent, based on the following formula: Assay = ((SV 0.10586)/56.1)*100, where SV=Saponification Value;

(2) Saponification value: 524-540 determined using 1 gram of sample by the “Guide to Specifications for General Notices, General Analytical Techniques, Identification Tests, Test Solutions, and Other Reference Materials,” in the “Compendium of Food Additive Specifications, Addendum 4, Food and Agriculture Organization of the United Nations (FAO), Food and Nutrition Paper 5, Revision 2” (1991), pp. 203-204…

(3) Acid value: Not to exceed 0.20 determined using 50 grams of sample by the “Guide to Specifications for General Notices, General Analytical Techniques, Identification Tests, Test Solutions, and Other Reference Materials,” in the “Compendium of Food Additives Specifications, Addendum 4, FAO Food and Nutrition Paper 5, Revision 2,” p.189 (1991)… Distributed for Comment Only -- Do Not Cite or Quote

(4) Lead: Not to exceed 1.0 milligrams/kilogram determined by the “Atomic Absorption Spectrophotometric Graphite Furnace Method, Method I,” in the “Food Chemicals Codex,” 4th ed. (1996), pp. 763-764…

(5) Triacetin: Not to exceed 0.10 percent determined by gas chromatography as described in Identification Tests, Test Solutions, and Other Reference Materials,” in the “Compendium of Food Additive Specifications, Addendum 4, FAO Food and Nutrition Paper 5, Revision 2,” (1991), pp. 13-26...

(c) The food additive is used as a stabilizer (as defined in 170.3 (o) (28) of this chapter) of emulsions of flavoring oils in nonalcoholic beverages.

(d) The total Sucrose Acetate Isobutyrate content of a beverage containing the additive does not exceed 300 milligrams/kilogram of the finished beverage.

21CFR175.105 (Sucrose Acetate Isobutyrate, Sucrose Benzoate, Sucrose Octaacetate): Part 175-Indirect Food Additives: Adhesives and Components of Coatings; Subpart B-Substances for Use Only as Components of Adhesives; Section 175.105 Adhesives. (a) Adhesives may be safely used as components of articles intended for use in packaging, transporting, or holding food in accordance with the following prescribed conditions: (1) The adhesive is prepared from one or more of the optional substances named in paragraph (c) of this section, subject to any prescribed limitations…(c) Subject to any limitations prescribed in this section and in any other regulations promulgated under section 409 of the Act which prescribes safe conditions of use for substances that may be employed as constituents of adhesives, the optional substances used in the formulation of adhesives may include the following: (1) Substances generally recognized as safe for use in food or food packaging. (2) Substances permitted for use in adhesives by prior sanction or approval….(3) Flavoring substances permitted for use in food by regulations in this part…(4) Color additives approved for use in food. (5) Substances permitted for use in adhesives by other regulations in this subchapter and substances named in this subparagraph…: Sucrose Acetate Isobutyrate, Sucrose Benzoate, Sucrose Octaacetate

21CFR172.859 (Sucrose Cocoate, Sucrose Dilaurate, Sucrose Distearate, Sucrose Laurate, Sucrose Myristate, Sucrose Oleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Tribehenate, Sucrose Trilaurate, Sucrose Tristearate): Part 172-Food Additives Permitted For Direct Addition To Food For Human Consumption; Subpart I-Multipurpose Additives; Section 172.859 Sucrose Fatty Acid Esters; Sucrose fatty acid esters identified in this section may be safely used in accordance with the following prescribed conditions:

(a) Sucrose fatty acid esters are the mono-, di-, and tri-esters of sucrose with fatty acids and are derived from sucrose and edible tallow or hydrogenated edible tallow or edible vegetable oils. The only solvents which may be used in the preparation of sucrose fatty acid esters are those generally recognized as safe in food or regulated for such use by an appropriate section in this part. Ethyl acetate or methyl ethyl ketone or dimethyl sulfoxide and isobutyl alcohol (2-methyl-1-propanol) may be used in the preparation of sucrose fatty acid esters.

(b) Sucrose fatty acid esters meet the following specifications: Distributed for Comment Only -- Do Not Cite or Quote

(1) The total content of mono-, di-, and tri-esters is not less than 80 percent as determined by a method title “Sucrose Fatty Acid Esters, Method of Assay,”….

(2) The free sucrose content is not more than 5 percent as determined by Test S.2 in the method titled “Sucrose Fatty Acid Esters, Method of Assay,”…

(3) The acid value is not more than 6.

(4) The residue on ignition (sulfated ash) is not more than 2 percent.

(5)The total ethyl acetate content is not more than 350 parts per million as determined by a method titled “Determination of Ethyl Acetate,”…

(6) Arsenic is not more than 3 parts per million.

(7) Total heavy metal content (as Pb) is not more than 50 parts per million.

(8) Lead is not more than 10 parts per million.

(9) The total content of methyl ethyl ketone or of methanol shall not be more than 10 parts per million as determined by a method titled “Methyl Ethyl Ketone Test; Methyl Alcohol Test,”…

(10) The total dimethyl sulfoxide content is not more than 2 parts per million as determined by a method entitled “Determination of Dimethyl Sulfoxide”…

(11) The total isobutyl alcohol (2-methyl-1-propanol) content is not more than 10 parts per million as determined by a method entitled “Determination of Isobutyl Alcohol”…

(c) Sucrose fatty acid esters may be used as follows when standards of identity established under section 401 of the Federal Food, Drug, and Cosmetics Act do not preclude such use:

(1) As emulsifiers as defined in 170.3 (o) (8) of this chapter, or as stabilizers as defined in 170.3 (o) (28) of this chapter…

(2) As texturizers as defined in 170.3 (o) (32) of this chapter in biscuit mixes, in chewing gum as defined in 170.3 (n) (6)… Distributed for Comment Only -- Do Not Cite or Quote

(3) As components of protective coatings applied to fresh apples, avocados, bananas, banana plantains, limes, melons (honeydew and cantaloupe), papaya, peaches, pears, pineapples, and plums to retard ripening and spoiling.

(d) Sucrose fatty acid esters are used in accordance with current good manufacturing practice and in an amount not to exceed that reasonably required to accomplish the intended effect.

21CFR172.869 (Sucrose Hexaerucate, Sucrose Hexaoleate/ Hexapalmitate/ Hexastearate, Sucrose Hexapalmitate, Sucrose Pentaerucate, Sucrose Tetrahydroxystearate, Sucrose Tetraisostearate): Part 172-Food Additives Permitted For Direct Addition To Food For Human Consumption; Subpart I- Multipurpose Additives; Section 172.869 Sucrose oligoesters. Sucrose oligoesters, as identified in this section, may be safely used in accordance with the following conditions:

(a) Sucrose oligoesters consist of mixtures of sucrose fatty acid esters with an average degree of esterification ranging from four to seven. It is produced by interesterification of sucrose with methyl esters of fatty acids derived from edible fats and oils (including hydrogenated fats and oils). The only solvents which may be used in the preparation of sucrose oligoesters are dimethyl sulfoxide, isobutyl alcohol, and those solvents generally recognized as safe in food.

(b) Sucrose oligoesters meet the specifications in the methods listed in the table…:

(1) Sucrose esters (Not less than 90%) (2) Mono-, di-, and tri-esters (Not more than 45%) (3) Tetra-, penta-, hexa-, and hepta-esters (Not less than 50%) (4) Octa-esters (Not more than 40%) (5) Free Sucrose (Not more than 0.5%) (6) Acid Value (Not more than 4.0) (7) Residue on Ignition (Not more than 0.7%) (8) Residual methanol (Not more than 10 milligrams/kilogram) (9) Residual Dimethyl Sulfoxide (Not more than 2.0 milligrams/kilogram (10) Residual Isobutyl Alcohol (Not more than 10 milligrams/kilogram) (11) Lead (Not more than 1.0 milligram/kilogram)

(c) The additive is used as an emulsifier or stabilizer in chocolate and butter-substitute spreads, at a level not to exceed 2.0 percent; except that the additive may not be used in a standardized food unless permitted by the standard of identity. Distributed for Comment Only -- Do Not Cite or Quote

21CFR172.515 (Sucrose Octaacetate): Part 172-Food Additives Permitted For Direct Addition To Food For Human Consumption; Subpart F-Flavoring Agents and Related Substances; Section 172.515 Synthetic Flavoring Substances and Adjuvants. Synthetic flavoring substances and adjuvants may be safely used in food in accordance with the following conditions. (a) They are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice. (b) They consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior- sanctioned for such use, or regulated by an appropriate section in this part. Sucrose Octaacetate.

21CFR310.536 (Sucrose Octaacetate): Part 310-New Drugs; Subpart E-Requirements for Specific New Drugs or Devices; Section 310.536 Drug products containing active ingredients offered over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent. (a) Denatoonium benzoate and Sucrose Octaacetate have been present in OTC nailbiting and thumbsucking deterrent drug products. There is a lack of adequate data to establish general recognition of the safety and effectiveness of these and any other ingredients (e.g., cayenne pepper) for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence currently available, any OTC drug product containing ingredients offered for use as a nailbiting or thumbsucking deterrent cannot be generally recognized as safe and effective.

(b) Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201 (p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any dug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs set forth in part 312 of this chapter.

(d) After March 2, 1994, any such OTC drug products initially introduced or initially delivered for introduction into interstate commerce that is not in compliance with this section is subject to regulatory action.

Although listed in PCPC Infobase for Sucrose Octaacetate the following CFR citations produced no hits when searched for on the FDA website (2/29/2016): 27CFR20.102; 27CFR20.118; 27CFR21.75; 27CFR21.131; 27CFR21.151

Distributed for Comment Only -- Do Not Cite or Quote

MINUTES FROM JUNE 2016 PANEL MEETING-SACCHARIDE ESTERS-(Day 1) DR. MARKS’ TEAM

DR. MARKS: Okay. So tomorrow I'll move

safe when formulated to be nonirritating. Let me

put that in here. Okay. Close that. And next

ingredient is the saccharide esters. This is a

first review of these 41 ingredients. It's just a

couple notes. It's a penetration enhancer. It's

a grass and food additive. And Ron, Ron, and Tom,

first, do you like the 41 ingredients -- all of

them? Should there be any ingredient which is

deleted?

DR. SHANK: I thought if we could use

read across, then all but the nonalkyl

esters -- that's the last two

(inaudible) -- I would say

(inaudible). If we can't use read

across, then I think we need the

chemists to find send [sub] groups

for us to review.

DR. HILL: Yeah. I thought they were all

fine except that the benzoate and the disenopate

[Disinapate] need to go out. They don't belong

there.

DR. MARKS: So you wouldn't even include Distributed for Comment Only -- Do Not Cite or Quote

them?

DR. HILL: No. I want them to be ditched.

DR. MARKS: That would solve your -- what you're questioning, Ron Shank.

DR. SHANK: Okay.

DR. MARKS: Tom?

DR. SLAGA: Yeah. I agree with that.

DR. MARKS: Okay. So it would be now 39 ingredients.

MS. SCOTT: Is that based on the structures?

DR. HILL: Yes.

MS. SCOTT: Okay.

DR. HILL: And the idea that --

DR. MARKS: Delete benzoate.

DR. HILL: Senopate – disenopate

[Disinapate]. Excuse me.

DR. MARKS: Disenopate [Disinapate].

Okay. And how did you like in terms of -- so you were happy with reading across, Ron Shank?

DR. SHANK: Yeah. Let's see -- for the fatty acid, ester single chain link, I used a sucrose polybehenate. For read across, I used the Distributed for Comment Only -- Do Not Cite or Quote

acetate isobutyrate and the poly cotton sedate

[polycottonseedate] for read across for the mixed chain link. And I used the grass status for the acetate isobutyrate to cover the lack of toxicity data.

DR. MARKS: And I agree. The sensitization data there --

DR. SHANK: Okay.

DR. MARKS: -- the testing we had are very high concentrations.

DR. SHANK: Right.

DR. MARKS: One hundred percent -- one hundred percent, eight-eight. The only one which was a little bit low compared to its use concentration was the sucrose acetate isobutyrate, which was tested at 20 percent. I felt with everything else that we had that the irritation sensitization would be okay.

DR. SHANK: So did I.

DR. MARKS: Tom, anything from your point do you need?

DR. SLAGA: No. I like the --

DR. MARKS: So safe for the 39 ingredients. Distributed for Comment Only -- Do Not Cite or Quote

DR. HILL: I have issues. I have two issues.

DR. MARKS: Okay.

DR. HILL: I don't think we have data sufficient to evaluate two of them.

DR. SLAGA: Out of the 39?

DR. HILL: Yes.

DR. MARKS: Did -- while you're looking at the two, Ron Hill, how did you want Laura to -- did you want in the discussion anything about the penetration enhancing with these?

That's page (inaudible).

DR. SHANK: On page 22?

DR. HILL: That definitely needs to go in. I'm not sure if it's in the right spot.

DR. MARKS: Page 47 I have it in the document.

DR. SHANK: That can be handled in the discussion. We have boilerplate for that.

DR. MARKS: Right. Okay.

DR. SHANK: It was on page 22, under dermal penetration. It starts (inaudible) and others conducted tape stripping studies on elastic vesicles. Is that relevant to cosmetics? Distributed for Comment Only -- Do Not Cite or Quote

MS. SCOTT: I don't know.

DR. SHANK: It doesn't seem like it to me, but, you know, it might be an interesting study for other purposes. But it doesn't seem to fit for evaluating cosmetic formulations.

DR. MARKS: You're talking about like nanoparticles and that sort of thing?

DR. SHANK: Well, it was --

DR. MARKS: Because I think nanotechnology is applicable to cosmetics.

DR. SHANK: It didn't say nano. It said elastic vesicles.

DR. MARKS: Elastic vesicles.

MS. SCOTT: They're 100 to 120 nanometers in size. I don't know what nano -- what you consider to be the size of the -- I mean.

DR. HILL: I didn't hone in on that all -- that issue. I just thought that the elastic vesicles are probably something that naturally forms with the substances at the right concentration. So I suspect it's -- for me -- it was entirely relevant to assessment.

DR. SHANK: Okay.

DR. HILL: But we could ask for Distributed for Comment Only -- Do Not Cite or Quote

clarification of that. It's coming from a reference though, right? So that's actually -- that's literature. I don't remember what I concluded, but I thought it was perfectly relevant.

DR. SHANK: Okay.

DR. MARKS: Okay. So any rate, we have this section on penetration enhancement and, as you said, there's a boilerplate that can go in the discussion.

MS. SCOTT: Okay.

DR. MARKS: Ron Hill, you had -- you wanted to limit it to 37 instead of 39. Where shall we -- which two was it? Which to additional did you not like and then, obviously, what's the reason why because then it would be 37 safe and two insufficient data (inaudible)?

DR. HILL: So the ones that I took issue with were the undecylenoate because we have no direct data -- including we don't have any good data to tell us whether skin hydrolysis is significant or not on any of it. So all of the add me [ADME] data was not very informative honestly for dermal applications. And all of it Distributed for Comment Only -- Do Not Cite or Quote

was on the sucrose esters only. So that didn't necessarily make me worry about most of these.

But the undecylenoate, undecylenoic acid has pharmacological activity as an antifungal and so since we have no biology data on it all and we don't know anything about its dermal penetration,

I think there's too much uncertainty to read across.

The other one that I had issues with was the xylitol ceska caprylate [Xylityl

Sesquicaprylate] because if you look at the way that that's made, there are actually a number of anhydrides in there and we don't have any information about the nature of those compounds and what's left after they form the substance. So without any direct test data, reading across was problematic for me.

DR. MARKS: So that gets back to Ron

Shank's comment if the chemists are okay with these -- all these others -- you would -- now, because of that, we already deleted two. Would you just delete these other two?

DR. HILL: I would rather -- no. I think this -- the undecylenoate needs to stay in there Distributed for Comment Only -- Do Not Cite or Quote

if there's no chemical reason to get rid of it and if it's with the class.

DR. MARKS: Yeah. Okay.

DR. HILL: Is it in use? I think it is.

I know it is. All right. So, you know --

DR. MARKS: Yes.

DR. HILL: -- I'd like to see some data for that or at least see if we can't get some data. And I think also, well, the ceska caprylate

[Sesquicaprylate] is not in use. You know, so for me I know we don't always like split conclusions, but I see why we couldn't in this particular case suggest insufficient. But what I would like to see at this point is information about method and manufacture and composite impurities and see what pops out. But since it's -- if it's not actually in use, we aren't going to get it.

DR. MARKS: Insufficient -- so this would actually be a first review. This would be an insufficient data notice at this point. We file that. And we have safe for 37 and insufficient for -- then what was it on the -- so that was the -- how do you say the first? Traylose

[Trehalose]? Distributed for Comment Only -- Do Not Cite or Quote

DR. HILL: Traylose [Trehalose], undecylenate [Undecylenoate], I believe -- undecylenoate, excuse me.

DR. SHANK: You want stability or metabolism in there?

DR. HILL: I want -- I don't know that we're going to get anything about biotransformation skin, but barring that I would like to see some safety data. What's the maximum reported use concentration again for that guy?

DR. MARKS: I didn't have it here. But that may be because there's not much in the way of use. I usually just pick the ones that have higher use or higher concentration.

DR. HILL: Yeah. I was trying to remember and I didn't make note of it where I could --

DR. MARKS: Page 47 would be the use and

(inaudible).

DR. HILL: Okay. Let me just jump there.

No, not 47. Must be 43, 44. All right. So is it going to be at the top of this use table? No.

DR. SHANK: We know five percent in leave-on. Distributed for Comment Only -- Do Not Cite or Quote

DR. HILL: Okay. I thought I remembered it being low.

DR. MARKS: Yeah. That's probably why I didn't highlight it.

DR. HILL: Yeah. That's probably why you didn't highlight it.

DR. SLAGA: More than likely, not going to be any.

DR. HILL: I tried to find it in the use table.

MS. SCOTT: It's page 45.

DR. HILL: Page 45. I just finally got there.

MS. SCOTT: Okay.

DR. SHANK: At the very bottom.

DR. HILL: At the very bottom. There we go. Up to.25 percent and rinse off. Okay. So that's not terribly disturbing then. I have to think about that, but I think I could be comfortable with that one with those concentrations.

DR. MARKS: Which one are you talking about?

DR. HILL: Undecylenoate. The other one Distributed for Comment Only -- Do Not Cite or Quote

for me is non-negotiable. We need information about that xylitol ceska caprylate [Xylityl

Sesquicaprylate] because of the way it's made.

DR. MARKS: So you want method and manufacture or what do you want?

DR. HILL: No. I want information about the composition of the final product, because it's going to be a mixture and that -- they're all mixtures. But in this particular case, this is more unusual.

DR. MARKS: Okay. So are you -- going back, do you think then the traylose undecylenate

[Trehalose Undecylenoate]--

DR. HILL: I think I can --

DR. MARKS: -- that's okay.

DR. HILL: -- yeah. I think we can go okay on that based on the concentrations of use.

DR. MARKS: Okay. So now we're --

DR. HILL: I say I think. I feel confident we can include that.

DR. MARKS: Yeah. So we're at 38 ingredients now, which would be safe and the one ingredient is insufficient. And that's the xylitol ceska caprylate [Xylityl Sesquicaprylate]. Distributed for Comment Only -- Do Not Cite or Quote

Is that correct, Ron?

DR. HILL: Ceska caprylate

[Sesquicaprylate]. We've seen lots of caprylates.

This is a ceska [sesqui].

DR. MARKS: Okay. Ron Shank? Ron -- or

Tom? So tomorrow, I presume I'll be seconding a motion. Well, I know I'll be seconding a motion.

Maybe I'll be seconding.

DR. SLAGA: Maybe you will be.

DR. MARKS: Our team feels we'll go insufficient data notice. We feel 38 of the ingredients as it stands now are safe. We weren't happy with the xylitol ceska caprylate [Xylityl

Sesquicaprylate] because of the composition. And then I'll put in here, Ron Hill, if there's questions from the other team, you can go ahead and clarify that. Does that sound good?

DR. HILL: Yes. I do want to revisit the undecylenate [Undecylenoate] for a more general issue though just to get a clarification.

So -- because I have longer note. I saw down at the bottom what I missed. What I wanted to know was when we say current manner and practice of use, do we apply that ingredient specifically? In Distributed for Comment Only -- Do Not Cite or Quote

other words, when we reviewed this and we say current use and we've got the undecylenate

[Undecylenoate] at a -- what is it.05 percent leave on,.25 percent rinse off. Will people, in formulating that particular ingredient stick within that limits, or would they likely go to the highest concentrations of the others in that group? I don't know how we interpret -- how is that interpreted in practicality? That's a Jay question, I think.

DR. SHANK: Well, it's given in the report.

DR. HILL: Yeah.

DR. SHANK: Yeah, so --

DR. HILL: Okay. So it is ingredient specific in the sense that if we're --

DR. SHANK: Yes.

DR. HILL: -- you're saying. Yeah.

That's what I thought. I just wanted to clarify.

And I also just -- this was a sort of kudo. I like the presentation in table three where we have some indication of the limits of interpretation from previous -- previous studies. I don't know if this is the only report I saw today, but I Distributed for Comment Only -- Do Not Cite or Quote

think there were several and I really like -- even though we still probably need to go back to the old report, it give us some sense of -- if we see a 25 percent there, there's a much stronger need to go back and look at details, if it says two percent and we see what that is. So I really liked -- I know it takes time and effort to put -- I wish Barb were sitting here, but -- as well. I know it takes time and effort to put those together, but for me, those are really great.

MS. SCOTT: Thanks.

DR. MARKS: Okay. Team, sound good?

DR. SLAGA: Sounds good.

MS. SCOTT: Can I just do a quick recap?

DR. MARKS: Yeah, so insufficient data notice, safe for 38 ingredients. The three that are in this report we're going to address. One is insufficient -- that's the xylitol ceska caprylate

[Xylityl Sesquicaprylate]. And we need the composition for that. And then we're deleting sucrose benzoate and sucrose disenopate

[disinapate].

MS. SCOTT: Okay. And then read across Distributed for Comment Only -- Do Not Cite or Quote

was used for sucrose poly behenate and sucrose acetate isobutyrate for the first sub group -- the alpha fatty acid esters -- the single chain length. Those two ingredients were used for read across. I'm just asking for the discussion.

DR. SHANK: I used the poly behenate for the single chain.

MS. SCOTT: Okay.

DR. SHANK: And the acetate isobutyrate for the mixed chain.

MS. SCOTT: Oh, for the mixed -- okay.

DR. HILL: Well, let me just say that the ones that say sucrose polylaurate, polystearate, polyoleate, polylunoate [polylinoleate] -- those are not mixed chains. And neither is the one at that top of the next page. So those are kind of mislocated in the table, but that doesn't really affect anything much.

MS. SCOTT: Okay.

DR. HILL: I just wanted to make aware.

And there are a number of chemistry-related things within the report --

MS. SCOTT: Okay.

DR. HILL: -- but they don't need to be Distributed for Comment Only -- Do Not Cite or Quote

discussed here.

MS. SCOTT: Oh, okay.

DR. HILL: Just for the next version, we'll get those all straightened around.

MS. SCOTT: Sounds good. And then for the mixed chain length -- the sucrose poly cotton sedate [Polycottonseedate] was used for read across I think someone said. Is that right?

DR. SHANK: I said that --

MS. SCOTT: Is that you? Okay.

DR. SHANK: -- I had both the acetate butyrate --

MS. SCOTT: Okay.

DR. SHANK: -- and poly cotton sedate

[Polycottonseedate]. But you say the poly cotton sedate is not mixed?

DR. HILL: No, that would be.

MS. SCOTT: Okay.

DR. HILL: It's the ones at the bottom of the previous page. There's the first -- so, obviously, acetate isobutyrate is mixed. But then the ones that follow, ceska caprylate

[Sesquicaprylate], polylaurate, (inaudible) at the very bottom of the previous page. Those are all Distributed for Comment Only -- Do Not Cite or Quote

single chain. I mean they're multiple substitutions unspecified, but the truth is that's true with all these ingredients. Even when it says tribehenate, we know that's going to be a mixture with some dye [di] and some tetra and so forth in there. And we don't even know if it's tri -- is the same three positions on sucrose because there are eight possibilities so. Sucrose is one example. So these are all mixtures. But the one that just says polylaurate -- they're all laurate. It's just how many of them are sent down there.

MS. SCOTT: Okay. I see what you mean.

Okay.

DR. HILL: And it's unspecified, so that's different than the ones where it says hexa.

But I think that's really a subtlety in the definition and nothing anybody needs to worry about.

MS. SCOTT: Okay.

DR. HILL: Because when it says hexa

(inaudible), for example, just above, it's not strictly -- I feel confident it's not strictly hexa. There are multiple -- multiple Distributed for Comment Only -- Do Not Cite or Quote

substitutions. Some were five. Some were

(inaudible). Those are the nature of the things that worry about reading across. But I think everybody gets to read across the -- and the only question you had like with cotton sedate.

Obivously, it's cotton sedate acid and so that's a mixture of acids. And we have information about that, so it's like we did with the vegetable oils.

DR. MARKS: Okay.

MS. SCOTT: For the wave two data, there was very little -- just summary. Is that something you want me to put into the report at all or no? It was for three ingredients, which we have no data on -- one of which has not been reported to VCRP or via counsel survey, but there is a little bit of data came in wave two on it -- sucrose pentahydroxy stearate

[Pentahydroxystearate].

DR. MARKS: Yeah. And these, as you had said in your memo, are -- these are irritation data since it's just one patch of the concentrations. And then there was the first point you make about aims [Ames]. This was reassuring, but it didn't change anything as far Distributed for Comment Only -- Do Not Cite or Quote

as I was concerned. Tom, did you have any comments to the aims [Ames] test was negative with maldital laurate [Maltitol Laurate]?

SPEAKER: There are zero details.

DR. SHANK: Really doesn't change anything, but you will add it to the report.

DR. MARKS: Yes.

MS. SCOTT: You just want me to -- you do want me to add it though?

DR. MARKS: Oh, yeah. Absolutely.

MS. SCOTT: Okay. Sounds good.

DR. MARKS: Any data we have (inaudible).

MS. FIUME: It was just that the aims

[Ames] test was negative. It didn't give any information with that.

DR. MARKS: Right. That's okay.

DR. HILL: So it gave you composition, but not the concentration tested in other details.

Is that what was -- that was what was missing, right? And that's what I -- you have the composition of the test, substance for the maldital laurate [Maltitol Laurate], but we don't know. The concentration actually tested in the way that they did the aims [Ames]. That's what Distributed for Comment Only -- Do Not Cite or Quote

we're missing.

MS. SCOTT: Right.

DR. MARKS: Any other comments?

DR. HILL: So I think it's valuable because presumably they will have followed the standard protocols.

MS. SCOTT: Okay. DR. MARKS: Okay. No more comments. We'll move onto the next ingredient, which is chamomilla recutita.

MINUTES FROM JUNE 2016 PANEL MEETING-SACCHARIDE ESTERS-(Day 1) DR. BELSITO’S TEAM

DR. BELSITO: Okay. Okay, saccharide esters, this is the first time we're looking at these 41 ingredients that are carboxylic esters or small saccharides. A lot of our data comes from the ECA [ECHA] report. And then, we got some data on wave two and again these are irritation studies not sensitization studies.

And I guess the first question always goes to Dan. Are we okay with this grouping?

DR. LIEBLER: I was okay with all of them but one. And halfway down the left-hand column of the introduction, this is pdf 19, sucrose Distributed for Comment Only -- Do Not Cite or Quote

disinapate that sinapinic acid, don't know how it snuck in here but it's definitely --

DR. BELSITO: First column?

DR. LIEBLER: First column on the left.

Sucrose disinapate.

DR. BELSITO: Disinapate, yeah, okay.

DR. LIEBLER: Yeah, that doesn't belong.

DR. BELSITO: Why?

DR. LIEBLER: It's structurally, so all of the other things are essentially common fatty acids or fatty acid mixtures that we're used to dealing with and have no problems with. Sinapinic acid is, I don't know if it's natural occurrence or not but it's structurally dissimilar. I don't know if there's a CIR safety assessment on sinapinic acid done. I'd have a different opinion. But if it's not then I would say exclude it because it has a different structure and I doubt that there's any safety data on that.

DR. BELSITO: So do we know? Did we include sinapinic acid under any of those big bodies of acids we've done?

DR. SNYDER: No, we haven't reviewed it.

DR. BELSITO: Okay. Distributed for Comment Only -- Do Not Cite or Quote

DR. LIEBLER: It's a phenol basically or a phenolic acid so it's a totally different structure than these fatty acids.

DR. BELSITO: Right. So we're recommending that sucrose disinapate be removed from this list? Okay. There are plant sources so, of course, in the discussion we'll have the botanical boilerplate. I had a question on pdf page 20 whether you all were okay with the potential residuals? So --

DR. LIEBLER: You mean, not more as?

DR. BELSITO: Yeah, I mean it just always seems that they're -- these are really mixtures of different things.

DR. LIEBLER: So this is a different way to express things than we've seen in the past, for example the mgs per kg. I mean, we could go two

[to] parts per million or something that we more commonly incorporate into our reports. And that,

I don't know if you need to introduce a new acronym here, the NMT. You know, you could perhaps say it limits are as follows.

DR. SNYDER: Does the food chemical codex refer to it at the head of 50? Distributed for Comment Only -- Do Not Cite or Quote

MS. SCOTT: Yes.

DR. LIEBLER: It does?

MS. SCOTT: Uh-huh.

DR. SNYDER: Because we had a discussion about that before. We said we were going to defer to that method of the limits in our (inaudible) counts.

DR. LIEBLER: Well, that just shows I don't spend much reading the food chemical codex.

I guess I'm now unmasked.

MS. SCOTT: Those are the units provided.

I can change them if need be.

DR. BERGFELD: Well, if we agreed to go by them we should keep --

DR. SNYDER: I think it's a good

(inaudible) point tomorrow whether we're going to adhere to those because we did that before, right, correct?

DR. BELSITO: I don't know. Have we ever referred to the chemical codex?

DR. LIEBLER: So I'm not sure why you would say like mgs per kg in a 10 gram sample. I mean, the concentration

is just two mgs per kg no matter how big Distributed for Comment Only -- Do Not Cite or Quote

the sample is so.

DR. SNYDER: It kind of seems like a lot.

DR. LIEBLER: Well, no, actually, that's a small amount. Yeah.

DR. BELSITO: Well, I mean, I guess first my question is are you comfortable with these impurities and then, I guess that was my question.

Then it raised a whole issue of whether we're going to accept limits set by the NMT. And that,

Paul, I heard you say we should discuss with the other group tomorrow but what is your feeling?

DR. SNYDER: Well, my recollection was before when we got into all those impurity issues that we talked about the limits should be based upon the way that the limits are based in other forms of limiting impurities in foods and et cetera. And so I was just saying that if this is the com -- that's why I asked if it was the way it is designated in the food codex, we should discuss whether we want to be consistent with other -- continue to be consistent with other mechanisms of reporting impurities in our documents. Or do we want to go back to the parts per million that we've done before? And just, you Distributed for Comment Only -- Do Not Cite or Quote

can convert this to parts per million obviously.

DR. BELSITO: Right.

DR. SNYDER: Yeah. I think -- I don't have a preference. I'm just saying I know we had that discussion seven years ago or how many years ago when we talked about it because what we said, well, we should limit this and we deferred to the published --

DR. BELSITO: So basically your question is units. Do we use the published units? Do we use them as published or do we convert to parts per million or parts per whatever? Is that what you're saying?

DR. SNYDER: Well, it's more to do with the acceptable limitations should be within, you know --

DR. BERGFELD: I remember that conversation where we changed.

DR. SNYDER: Yeah.

DR. BELSITO: So basically do we units as published or in a consistent fashion and if we make consistent fashion what fashion are we using?

DR. BERGFELD: What current standardization is there? Distributed for Comment Only -- Do Not Cite or Quote

DR. BELSITO: Right.

DR. SNYDER: Yeah.

DR. LIEBLER: I mean, in our reports we most commonly refer to parts per million for low-level contaminants. It's just, you know, regardless of what the food chemical codex does, that's what I've seen in our reports over the years and most commonly. I don't --

DR. BELSITO: So you would favor parts per million and just going in and making the conversions?

DR. LIEBLER: I mean, I just think that's what I'm most used to.

DR. BELSITO: Right.

DR. LIEBLER: And that's what I think --

DR. BELSITO: Most toxicologists are.

DR. BELSITO: -- our readers are most used to.

DR. BELSITO: Yeah.

DR. LIEBLER: People who read our reports are most used to. I didn't remember whether or not we had a policy on that one way or another.

DR. BERGFELD: Curt, do you remember?

DR. KLAASSEN: No, I don't remember. One Distributed for Comment Only -- Do Not Cite or Quote

way one could do this is, you know, I think most people definitely do parts per million and that's what we usually do. But since this group presents it another way maybe we could leave theirs the way it is but then, you know, give it both ways.

DR. BERGFELD: In parenthesis?

DR. KLAASSEN: Give their number as well as the parts per million in case we calculate wrong.

DR. LIEBLER: Well, mg per kg should be one ppm, right? It's one mg per gram would be one part per thousand. And then, go from gram to kilograms, another thousand. So it's -- that's your million, 10 to the sixth.

DR. KLAASSEN: It's not too difficult but --

DR. LIEBLER: I think, right, Christina?

DR.[Ms.] BURNETT: I just have to write it down.

DR. SNYDER: Well, I mean, the way the data's presented here is different because it's saying that it's -- the lead levels are acceptable up to this point. It's not telling us what the lead levels are as an impurity. That's the Distributed for Comment Only -- Do Not Cite or Quote

difference. In the other reports we have that they're at the levels of X parts per million.

Here it's --

DR. KLAASSEN: That's true.

DR. SNYDER: -- showing the data a different way. It's saying it's acceptable up to a certain level which is different than what we've done before.

DR. LIEBLER: In food?

DR. SNYDER: Correct.

DR. LIEBLER: Right. So they specify these are the acceptable levels in food. It doesn't actually tell us anything.

DR. EISENMANN: And I also think they're tying it to a method and that's why they say that in how much grams so you have -- you're supposed to measure, when you do the method, you have to take a certain amount.

DR. LIEBLER: Right.

DR. SNYDER: So we may want to just -- we need to qualify what this means then because it's different than the way we presented it previously on the impurities.

DR. KLAASSEN: Some people might think Distributed for Comment Only -- Do Not Cite or Quote

parts per million is molecules rather than grams.

DR. BELSITO: Yeah, but toxicologists who read it understand what you're talking about.

Okay. So under the impurities we favor converting things to parts per million but it's a discussion we should have with the other group whether we go with the units as recorded by the regulatory agency. In which case, that's what we have in this report or whether we use a consistent fashion and if it's a consistent fashion, what I'm hearing is people would prefer parts per million as a consistent fashion. Is that correct?

DR. SNYDER: That's fine.

DR. BELSITO: Okay. So the ingredient with the highest concentration of use, over 70 percent, is sucrose polycottonseedate and we're told that that could contain an aflatoxin. Does our standard botanical boilerplate specifically include aflatoxin or do we have to add aflatoxin to get that --

DR. SNYDER: It includes it.

DR. BELSITO: It includes it. Okay. So obviously we need the standard boilerplate. It's a penetration -- they're penetration enhancers so Distributed for Comment Only -- Do Not Cite or Quote

we need a standard boilerplate there.

The issue that I had the most concern with just to point out is nearly all of our tox data is on sucrose acetate isobutyrate, one chemical. It is the second highest in concentration, the highest being the cottonseedate as I pointed out which was 71 percent in lipstick.

We do have a sensitization assay on that concentration on lipstick.

Are you guys okay with a read-across for other toxin points using the isobutyrate? I mean,

I was but I mean, I, you know --

DR. SNYDER: Only if Dan tells us there's absorption difference -- significant absorption differences between --

DR. BELSITO: Well, that's what I was sort of asking.

DR. LIEBLER: So I think that if absorption is the gateway to toxicity, then the isobutyrate is going to be the most toxic.

DR. BELSITO: Okay.

DR. LIEBLER: All other things being equal. So it's the, yeah, I mean, I think that's -- the longer chain stuff will be absorbed Distributed for Comment Only -- Do Not Cite or Quote

more slowly and but I mean, between isobutyrate and these other fatty acids, you know, I think we're not talking about any significant toxicity anyway.

DR. BELSITO: Okay. So in the discussion that we realized most of the tox data was on the isobutyrate but this is the one that's more likely to be absorbed across the skin. On page 24 of the pdf under chronic toxicity, I know it's in the table but you don't state that the material was the isobutyrate.

So it just says reporting a one-year study in monkeys was a NOEL of but you don't state that the material was sodium acetate isobutyrate.

So in that paragraph there, you see where I am,

Laura?

MS. SCOTT: Which page are you?

DR. BELSITO: Page 24.

MS. SCOTT: Okay.

DR. BELSITO: Pdf chronic toxicity. You said summarized in table 11 and then you just say a one-year study but you don't say of what.

MS. SCOTT: Oh, okay.

DR. BELSITO: It's in the table but it Distributed for Comment Only -- Do Not Cite or Quote

should be in the print as well.

DR. BERGFELD: It does that other places, too, maybe a summary on those where you've said refer to table.

MS. SCOTT: Okay.

DR. BERGFELD: Just a short summary.

DR. BELSITO: We already clarified that the wave two were irritation studies.

DR. EISENMANN: I have a question for the panel. The car -- two-year studies should they be just described in the carcinogenicity section or should they also be described in the chronic? I tend to like -- when you split it up by duration,

I like to see them in both places.

When you did it repeat, I was okay with it being just in the cancer study but if you're going to say chronic, I want to see the chronic studies in the chronic section even if it's only a sentence that says --

DR. BELSITO: Refer to.

DR. EISENMANN: -- a two-year study --

DR. BELSITO: Right.

DR. EISENMANN: -- in rats. Though if there's no cancer, I would -- if the two-year Distributed for Comment Only -- Do Not Cite or Quote

study is negative for cancer, wouldn't you put the primary description of the study in the chronic section and then, say in the cancer section there were no tumors I the study described in the chronic section?

DR. BELSITO: I mean, you can do it either way you want.

DR. EISENMANN: But don't you --

DR. BELSITO: Yeah, I mean, I think it should be referenced in both areas.

DR. EISENMANN: Okay.

DR. SNYDER: I mean, the two-year bio assays are basically carcinogenicity studies.

That's the in -- point of interest and so sometimes you get an indication of other toxicities if there's a high mortality along the way due to some toxicity or something but in general. So that's okay. We've done that before so that's fine.

DR. KLAASSEN: Both places.

DR. BELSITO: So what is -- I'm on pdf page 50 table 8. It says the -- under procedure for sucrose cocoate, et cetera. It says, DOS,

D-O-S, was administered for nasal exposure. Distributed for Comment Only -- Do Not Cite or Quote

MS. SCOTT: Oh, dose, it's a typo, sorry.

DR. BELSITO: Oh, okay. Dose, okay. And then, the irritation -- so for the cottonseedate at 17.1 it u -- I'm on

on table 15 the irritation study. Yeah,

I mean, again, I would agree that it was probably related to the surfactants and not the cottonseedate was the irritation. And then, that brings us to table 16 under sensitization where you put non-irritating. It should be non-sensitizing, right?

MS. SCOTT: Which ingredient are we looking at?

DR. BELSITO: So table 16.

MS. SCOTT: Okay.

DR. BELSITO: Pdf 73, these are sensitization studies.

MS. SCOTT: So you're talking about sucrose polycottonseedate, the first one?

DR. BELSITO: Yeah.

MS. SCOTT: On that page?

DR. BELSITO: Well, the first, I mean, all of them but --

MS. SCOTT: All of them. Distributed for Comment Only -- Do Not Cite or Quote

DR. BELSITO: -- your conclusion ends up saying non-irritating.

DR. SNYDER: I think she could just change the title of that to sensitization and irritation studies dermal.

DR. BELSITO: Yeah.

DR. SNYDER: Because I think a lot of them have both components.

MS. SCOTT: Uh-huh, yeah.

DR. BELSITO: Right.

MS. SCOTT: Okay. So it's okay to put them in the same table?

DR. BELSITO: Yeah, I mean, they were the same studies.

MS. SCOTT: Okay. Uh-huh.

DR. BELSITO: So no sensitization and then, I guess I'm just wondering how you can say no irritation because so in the first study on that page with the sucrose polycottonseedate and

RHIPT, it says scattered positive findings from all formulations with each showing different

(inaudible) especially in sensitive

skin group, the challenge one

subject show definite (inaudible) Distributed for Comment Only -- Do Not Cite or Quote

and two subjects had doubtful

reactions. There was no

sensitization which I agree since

numbers and responses at challenge

were no higher than induction. But

that suggests to me that there was

irritation but as per the prior

comment, I think it was from other

components of the mixture and not

from the cottonseedate.

And then, it's the same thing again down below. That's the same study, two facial cleansing cloths, where the authors concluded that it was likely that the irritation was from other components. So I just -- simply saying non-irritating almost invalidates if you read what happened the results of the study. So I think you need to say that, you know, I'm sure that it's non-irritating because as with that prior study on page 71 pdf, that the conclusion was that the irritation was due to constituents in the formulation and non-sucrose polycottonseedate.

MS. SCOTT: Okay.

DR. BELSITO: So I mean, I think you Distributed for Comment Only -- Do Not Cite or Quote

simply can't say not irritating because that's not what the data you showed would tell me if I was just looking at that specific table and not thinking of what the formulation that was tested because otherwise we would have to go with a conclusion safe when formulated to be non-irritating and I don't think we need to make that conclusion for these ingredients.

MS. SCOTT: Okay.

DR. BELSITO: Okay, so if I can recap, we're going to go with the safe as used. We're going to drop the sinapinic acid derivative.

We're going to use the boiler botanical plate and a respiratory botanical plate? Respiratory --

DR. LIEBLER: Botanical plate?

DR. BELSITO: Yeah. Respiratory boilerplate, these are in aerosolized, right, potentially? Penetration enhancement.

DR. SNYDER: Botanic --

DR. BELSITO: Well, that's the botanical boilerplate right? So botanical, penetration, respiratory boilerplates, a discussion, in the discussion, why we're using the isobutyrate as the read-across for all of our tox end points Distributed for Comment Only -- Do Not Cite or Quote

essentially. And just in the interest of disclosure for isobutyrate, we have a 20 percent maximum that was tested for sensitization and it's used up to 31 percent in eye product and 27 percent in a lip product. I didn't think we needed to say that we wanted those.

I mean, I -- these really aren't sensitizers but just make you aware of it. Are you comfortable with that?

DR. LIEBLER: I agree with you.

MS. SCOTT: Can you repeat that? Sorry.

The last part?

DR. BELSITO: Well, the maximum use concentration for sodium acetate isobutyrate is 31 percent for an eye product and 27 percent for a lip product. And the maximum that we have tested for sensitization irritation is 20 percent. And so I didn't think we needed data at 31 percent to justify going with that but I just am pointing that out that, and I don't even know if it's that important to put in the discussion.

DR. SNYDER: I don't think so.

DR. BELSITO: Yeah. I just wanted to --

MS. SCOTT: Oh, okay. Distributed for Comment Only -- Do Not Cite or Quote

DR. SNYDER: At that level.

DR. BELSITO: You just make everyone aware of it in case some did have issues and the

Marks team may well have issues. And then, you can say that I did my job and looked at all of them. Okay. Anything else? Okay.

MINUTES FROM JUNE 2016 PANEL MEETING-SACCHARIDE ESTERS-DAY 2

DR. BERGFELD: -- to invite a speaker.

Any other additions, comments? Okay, then we -- time to move on? All right then. Dr.

Belsito, the saccharides.

DR. BELSITO: Yes, so this is our first go around for this group of 41 ingredients that are carboxylic esters of small saccharides. We received quite a bit of data including some additional data in wave II, a negative AIMs

[Ames], and two irritation studies. And based upon this, we thought that we could go safe as used, possibly using the caveat of formulated to be nonirritating because of some questionable results in cotton seed. But overall, I'm not sure that we need that nonirritating in the conclusion, we could just discuss those studies. They were Distributed for Comment Only -- Do Not Cite or Quote

largely with facial wipes that would contain detergents and other reasons. One was with a sunscreen. But the conclusion of those studies was that they were nonirritating, which suggested to me they thought it was from other ingredients.

So definitely safe as used. And the question is whether to include when formulated to be nonirritating. What? Oh, yeah, I'm sorry. And one that the sinapinic acid derivative, Dan thought was structurally dissimilar and should be removed from this report.

DR. BERGFELD: Dr. Marks?

DR. MARKS: Our team to a large extend

[extent] felt the same, Don, as your team.

However, we had a little different conclusion. We thought an insufficient data notice would be indicated, safe for 38 ingredients. The one, which, Ron Hill, you can clarify, the xylitol sesquicaprylate [Xylityl Sesquicaprylate] needed composition of that. He wanted to see the composition before he felt that could be safe.

And then we deleted, actually, different -- two different ingredients than the one you mentioned.

We deleted the non-alkyl esters. The sucrose Distributed for Comment Only -- Do Not Cite or Quote

benzoate and the sucrose disinapate.

DR. BELSITO: Well the disinapate is one we deleted, but it's the only one, so I'll move your deletions over to Dan and my colleagues for comments.

DR. LIEBLER: So benzoic acid, I think we've got a review history on, right?

SPEAKER: I think so.

DR. LIEBLER: Hasn't that been reviewed and safe?

DR. BELSITO: Yes.

DR. HILL: It was my logic that we don't have information when this is given dermally, that in fact hydrolysis occurs in the skin for any of these. We just -- what we have for (inaudible) relates to oral, and that's different. And even that data is sketchy, to use a sort of non-technical term, because of the ways that they were done.

DR. LIEBLER: Yeah, so I guess I didn't share that concern. I'm not sure where that point leads, Ron.

DR. HILL: I wanted to see that one and the sinapate split out in to a separate report. Distributed for Comment Only -- Do Not Cite or Quote

That's really what I prefer to see, but that --

DR. LIEBLER: Yeah, the sinapinic acid is a phenolic acid. It's really dissimilar. And I asked, yesterday, if there was any review history on it. Apparently not. So that was enough for me to disqualify that one, whereas with the benzoid,

I didn't really have any concern.

DR.[Ms.] SCOTT: It has been reviewed -- benzoic acid. Safe as used --

DR. LIEBLER: Right.

DR.[Ms.] SCOTT: -- In 2011.

DR. LIEBLER: Okay. So anyway, I would split the difference there. The sinapinic acid, it's used as a matrix for multi mass spectrometry.

That's the only time I've ever heard of it anyway.

But it's, you know, not only is it structurally dissimilar, I mean really structurally dissimilar with this group, that I don't -- I couldn't vouch for the safety of its chemistry.

DR. HILL: Sinapinic acid has a pharmacology associated with it. There's a natural products chemist at our institutions whose been doing work on that. So that the other thing that I noted. Distributed for Comment Only -- Do Not Cite or Quote

I am not concerned about benzoic acid.

I'm concerned about the fact that we have no data that tells us that that in fact would be hydrolyzed, especially, administered dermally. So we don't have any direct safety data. And given that, and I think the second point is that it's structurally dissimilar to the others in terms of the alkyl groups. And so, read across for me becomes impossible.

DR. LIEBLER: But are you concerned that it would be hydrolyzed or that it would not be?

DR. HILL: That it would not be. If it is hydrolyzed, no problem. But if it -- because

(inaudible) sucrose and benzoic acid. But if it's not hydrolyzed, there could be a whole biology for that that we've not captured in any level or any form as best I can see.

DR. HILL: Yeah that's -- I didn't share that concern. I just wanted to make sure where I understood your point. I don't share the concern.

I mean I just don't think there's anything beyond speculative about hazard with respect to a molecule like that.

DR. LIEBLER: I consider it my personal Distributed for Comment Only -- Do Not Cite or Quote

responsibility to speculate when there is enough cause for speculation. In my humble opinion, there is cause in this case. Enough said.

DR. BELSITO: Okay. So they also then wanted to eliminate xylitol sesquicaprylate

[Xylityl Sesquicaprylate].

DR. HILL: No eliminate. I wanted composition information about the final product because if you look at the method of manufacturer compared to others, it starts with xylitol mixed anhydrides and, excuse me, and hydrides in some case. So we don't know what the final conversion products for that is. And, again, we have no direct data. So I would -- I just wanted to see some information. And I believe they should have it about what the composition of that final product is after you do that method of manufacturer because I'm not clear that it gives us something very comparable to all these other ones that I'm trying to read across from.

DR. BELSITO: Dan, comment?

DR. LIEBLER: If they're in hydrides used in the synthesis, I would think that they would be consumed by reactions with product solvents that Distributed for Comment Only -- Do Not Cite or Quote

are used to solubilize the reactants. So I really don't fear any concern about that.

DR. BERGFELD: Jim, you want to --

DR. MARKS: (inaudible) with that -- those comments, I think Ron, Tom, we could second the motion you've made. And then we'll just delete only the sucrose disinapate.

DR. BELSITO: And go safe as used with the rest.

DR. MARKS: Yep.

DR. BERGFELD: Okay.

DR.[Ms.] SCOTT: Can I just ask one question?

DR. BERGFELD: Certainly, go ahead.

DR. SCOTT: Are you the subgroups okay -- the way that they're organized?

DR. BELSITO: Mm-hmm.

DR.[Ms.] SCOTT: Okay.

DR. HILL: Now, I'm telling you, you need to move the ones that say single chain, that are, if in fact, single chain -- those four to the single-chain group. Other than that, no problem.

DR.[Ms.] SCOTT: No. Okay.

DR. HILL: That's the last three on that Distributed for Comment Only -- Do Not Cite or Quote

first page and the first one on the second page.

But that doesn't affect anything. It doesn't affect our read across or any other thing, just an organization thing.

DR.[Ms.] SCOTT: Okay.

DR. BERGFELD: Don, can you repeat -- oh,

I'm sorry, go ahead.

DR. HELDRETH: I was just going to ask -- is that the panel consensus, however?

DR. HILL: Why would it not be? If you say polylaurate, that's a single chain.

DR. HELDRETH: I just wanted to make sure for Laura's sake that somebody else didn't have a different opinion on this.

DR. BERGFELD: Dan?

DR. LIEBLER: Could you briefly explain what you're referring to?

DR. HILL: Just trying to find the best spot to do it. Okay, so, Table 1 is the easiest place to see this. And she's got it organized in columns. So alkyl fatty acid ester single chain length, and then there's one alkyl fatty acid esters mixed chain length. So in fact, the -- there -- let me see, actually, there are Distributed for Comment Only -- Do Not Cite or Quote

six of them. Xylitol sesquicaprylate [Xylityl

Sesquicaprylate], that's all caprylate. Sucrose polylaurate, that's all polylaurate -- that's all laurate. Sucrose polystearate, that's all stearate. Sucrose polyoleate, that's all oleate.

You get the picture.

DR. LIEBLER: Sure, I understand.

DR. HILL: Down to tetraisostearate, which is all isostearate. So that's only one chain length, and it's just a matter of how many of them are on the sugar moiety.

DR. LIEBLER: Correct. And, no, I agree,

Ron's got a good point. Yeah, that's easy to fix.

DR. HILL: But it doesn't affect my interpretation of the data in any (inaudible) --

DR. LIEBLER: That's right. It's just if you make a heading that defines them as a single chain length or mixed chain length. They need to be either single or mixed in the right columns, and a couple of them aren't in the right columns.

DR. HILL: And the point I made yesterday was if you take, for example, something like sucrose trilaurate, that doesn't mean that every single one of those has only three lauric acids on Distributed for Comment Only -- Do Not Cite or Quote

it, trilauric will actually be a mixture. It will have some dye [di], some tetra, maybe some penta.

And we don't know which positions they're actually substituted on from the information we have, and I don't think they necessarily know that. And ACL groups tend to jump around on sugars even if you start with a single compound depending on the conditions.

DR. LIEBLER: So see, Laura, this is what you get for trying to organize by chain length.

DR. HILL: No, I appreciate your organization by chain length very much.

DR. BERGFELD: Don, do you want to rescind your motion?

DR. BELSITO: Yes, so the motion was safe as used for all of them except for sucrose disinapate, which we're taking out of this report.

And in the discussion, we need to bring in the botanical boilerplate, the respiratory boilerplate, and that's it.

DR. BERGFELD: Did you want to mention anything about penetration enhancer?

DR. BELSITO: Yeah, penetration enhancement. Sorry, you're right. Thank you. Distributed for Comment Only -- Do Not Cite or Quote

Yeah, that was number one on my list actually.

DR. BERGFELD: Okay. Any additions to that, Jim?

DR. MARKS: No, just what's already in there. There are GRAS and food additives too.

DR. BERGFELD: Okay. We'll call the question. All those in favor of safe, please

(inaudible) by raising your hand? Against? Okay.

I want to get this --

DR. HILL: Two ingredients.

DR. BERGFELD: Okay. That's all right.

All right, Dr. Marks, you're up next, again.

Silanes -- alkoxyl silanes.

Distributed for Comment Only -- Do Not Cite or Quote

Safety Assessment of Saccharide Esters as Used in Cosmetics

Status: Draft Final Report for Panel Review Release Date: November 11, 2016 Panel Meeting Date: December 5-6, 2016

Distributed for Comment Only -- Do Not Cite or Quote

ABSTRACT

This is a safety assessment of 40 saccharide ester ingredients as used in cosmetics. The saccharide esters function in cosmetics as, emollients, skin conditioning-agents, fragrance ingredients, and emulsion stabilizers. The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the relevant data for these ingredients. The Panel concluded that the saccharide esters are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

INTRODUCTION

This safety assessment includes the 40 saccharide esters listed below. Maltitol Laurate has been reviewed previously by the Panel; in 2008, the Panel concluded that this ingredient is safe as used in cosmetics.1 Although no safety test data were available for Maltitol Laurate, nor was it used in cosmetics at the time it was previously reviewed, available Maltitol and Lauric Acid safety test data were used by the Panel to infer safety for Maltitol Laurate. The saccharide esters below are listed in alphabetical order; they are also shown in Table 1, ordered by sub-groups according to chain length. Glucose Pentaacetate Sucrose Palmitate/ Stearate or Sucrose Stearate-Palmitate Ester Maltitol Laurate Sucrose Pentaerucate Raffinose Isostearate Sucrose Pentahydroxystearate Raffinose Myristate Sucrose Polybehenate Raffinose Oleate Sucrose Polycottonseedate Sucrose Acetate Isobutyrate Sucrose Polylaurate Sucrose Acetate/Stearate Sucrose Polylinoleate Sucrose Benzoate Sucrose Polyoleate Sucrose Cocoate Sucrose Polysoyate Sucrose Dilaurate Sucrose Polystearate Sucrose Dipalmitate Sucrose Stearate Sucrose Distearate Sucrose Tetrahydroxystearate Sucrose Hexaerucate Sucrose Tetraisostearate Sucrose Hexaoleate/Hexapalmitate/Hexastearate Sucrose Tetrastearate Triacetate Sucrose Hexapalmitate Sucrose Tribehenate Sucrose Laurate Sucrose Trilaurate Sucrose Myristate Sucrose Tristearate Sucrose Octaacetate Trehalose Isostearate Esters Sucrose Oleate Trehalose Undecylenoate Sucrose Palmitate Xylityl Sesquicaprylate

Sucrose Palmitate/Stearate, Sucrose Dipalmitate, and Sucrose Stearate-Palmitate Ester are not found in the International Cosmetic Ingredient Dictionary and Handbook (Dictionary),2 but they are included in the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP) as ingredients used in cosmetic products.3 Thus, they are included in this safety assessment. The VCRP provides data on Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate Ester as individual ingredients, however structurally they are considered to have the same definition; thus, they are presented in the Definitions and Functions table (Table 2) as one entry under both names. The saccharide esters have various reported functions in cosmetics, including use as emollients, skin conditioning agents, fragrance ingredients, emulsion stabilizers, and plasticizers.2 Xylityl Sesquicaprylate is used as an antimicrobial agent, humectant, skin conditioning agent, and surfactant. Trehalose Undecylenoate is used as a hair conditioning agent and surfactant. Functions reported for each ingredient are listed in Table 2. The saccharide ester ingredients in this report are structurally-related carboxylic acid esters of simple saccharides. Most of these carboxylic acids are fatty acids or mixtures of fatty acids from plant sources. All of the saccharide moieties of these ingredients, except Raffinose and Xylitol, have been evaluated by the Panel (2014) and found to be safe as used in cosmetics; the conclusions for these saccharide moieties are presented in Table 3.1,4-15 A safety assessment of Decyl Glucoside and other alkyl glucosides (differing from the glucose ester ingredients of this report only in the number of glucose equivalents) was completed (2013) with the conclusion of safe as used in cosmetics when formulated to be non-irritating.16 Several of the constituent acids that are used to synthesize some of the saccharide esters in this report have been reviewed previously by the Panel and found to be safe as used in cosmetics; summaries of those safety conclusions are also presented in Table 3.1,4-15

Distributed for Comment Only -- Do Not Cite or Quote

Sucrose Acetate Isobutyrate is generally recognized as safe (GRAS) for use as a direct food additive in the United States.17 Given its GRAS status, the focus of this assessment for Sucrose Acetate Isobutyrate will be on assessing the potential for topical effects, primarily dermal irritation and sensitization. Study reports and unpublished data included in this safety assessment were found on the European Chemicals Agency (ECHA) website,18 on the Australian Government Department of Health’s National Industrial Chemicals Notification and Assessment Scheme (NICNAS) website,19,20 and in a report published by the World Health Organization (WHO).21 The ECHA and NICNAS websites provide data summaries from industry. The WHO report is cited when industry data submitted to the WHO are included in this safety assessment.

CHEMISTRY

Definition and Structure The ingredients in this report are all carboxylic esters of small saccharides. These synthetic ingredients are the end products of the esterification of simple saccharides with a carboxylic acid, such as acetic acid or a fatty acid. The sugar entity that comprises the saccharide esters is glucose (monosaccharide), sucrose (disaccharide composed of glucose and fructose), the sugar alcohol maltitol derived from maltose (a disaccharide composed of two glucose molecules, α-1,4 bond), trehalose (disaccharide composed of two glucose molecules, α-1,1 bond), raffinose (trisaccharide composed of galactose, glucose, and fructose), or xylityl derived from the sugar alcohol xylitol, which is derived from xylose (monosaccharide). While the names and definitions of some of these ingredients imply single, discrete chemical entities, it is more likely that all are mixtures of saccharide esters varying in chain-length, degree of esterification, and/or regiospecificity of subsititution. For example, Maltitol Laurate contains a monoester of maltitiol and lauric acid but, without further specification, it is unknown whether it also contains 1) other chain-length fatty acid residues (e.g., myristate), 2) di-, tri-, or tetra-esters, or 3) esterification at a different active site (free hydroxyl group). (Figure 1)

Figure 1. Maltitol Laurate, a saccharide ester The wide variation in hydrophilic-lipophilic balance (HLB), which is characteristic of small-saccharide (sugar) esters, allows these chemicals to function as oil-in-water (high HLB values) and water-in-oil emulsifiers (low HLB values).22 The less-highly substituted esters (e.g. mono-, di-, and tri-) are used for water-in-oil or oil-in-water emulsions, depending on the degree of esterification. More highly substituted sucrose esters have lower HLB values (increased lipophilicity); less highly substituted esters have higher HLB values (increased hydrophilicity). Secondary to the extent of substitution is the influence of the fatty acid chain length; the shorter the chain, the higher the HLB value. The ingredients included in this safety assessment are defined (in order by sub-groups according to chain-length) in Table 2, and structures and functions in cosmetics, as presented in the Dictionary, are also provided. Chemical and Physical Properties Sucrose fatty acid esters (e.g., Sucrose Laurate) may be stiff gels, soft solids, or white/slightly gray powders (Table 4).23 Generally, they are sparingly soluble in water, depending on the percentage of mono esters, and soluble in ethanol. For instance, Sucrose Trilaurate has an estimated water solubility of 1.35 x 10-12 mg/l, while Sucrose Laurate (i.e., two fewer ester groups) has an estimated water solubility of 42.37 mg/l.24 Method of Manufacture Sucrose fatty acid esters (e.g., Sucrose Laurate) that are used in food may be prepared from sucrose, transesterifying with the methyl or ethyl esters of edible fatty acids, or with edible, naturally-occurring vegetable oils (fatty esters of glycerol), using food-grade solvents such as ethyl acetate, methyl ethyl ketone, dimethyl sulfoxide, or isobutanol.23 Impurities Lead impurities are acceptable at not more than (NMT) 1 mg/kg (1 ppm) in Sucrose Acetate Isobutyrate used in food (based on atomic absorption spectrophotometric method), with a Sucrose Acetate Isobutyrate purity of not less than (NLT) 98.8% and NMT 101.9%, according to the Food Chemicals Codex.23 The saponification value of Sucrose Acetate Isobutyrate used in food is acceptable at NLT 524 and NMT 540 (acid value acceptable at NMT 0.2). The following acceptance criteria apply to sucrose fatty acid esters (purity

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NLT 80.0% of combined mono-, di-, and triesters of sucrose) in food: NMT 2 mg/kg (2 ppm) lead (based on atomic absorption spectrophotometric method); NMT 2 mg/kg (2 ppm) dimethyl sulfoxide (based on gas chromatography/flame photmetric detection method; NMT 350 mg/kg (350 ppm) ethyl acetate, NMT 10 mg/kg (10 ppm) isobutanol, NMT 10 mg/kg (10 ppm) methanol, and NMT 10 mg/kg (10 ppm) methyl ethyl ketone (based on gas chromatography/flame ionization method); NMT 6 acid value; NMT 5.0% free sucrose (based on high-performance liquid chromatography/refractive index method); NMT 2.0% sulfated ash residue on ignition. Sucrose Polycottonseedate Sucrose Polycottonseedate contains mixtures of cottonseed acid esters.2 Cottonseed Acid is derived from Cottonseed Oil; impurities that may be found in cottonseed oils, and are known to be toxic, include gossypol, aflatoxin, cyclopropenoid fatty acids, heavy metals, polychlorinated biphenyls, and pesticide residues.25 In a CIR safety assessment published in 2001,25 the Panel concluded that Hydrogenated Cottonseed Oil, Cottonseed (Gossypium) Oil, Cottonseed Acid, Cottonseed Glyceride, and Hydrogenated Cottonseed Glyceride are safe as used in cosmetic products, with the stipulation that established limits on gossypol (< 450 ppm), heavy metals (lead ≤ 0.1 mg/kg; arsenic ≤ 3 ppm; mercury ≤1 ppm), and pesticide concentrations (NMT 3 ppm with NMT 1 ppm for any specific residue) are not exceeded.

USE

Cosmetic The Panel evaluates the safety of the cosmetic ingredients included in this assessment based on the expected use of and potential exposure to the ingredients in cosmetics. The data received from the FDA are collected from manufacturers through the FDA’s VCRP, and include the use of individual ingredients in cosmetics by cosmetic product category. The data received from the cosmetic industry are collected by the Personal Care Products Council (Council) in response to a survey of the maximum reported use concentrations by product category. VCRP data obtained from the FDA in 20163 indicate that saccharide esters in this safety assessment are currently reported to be used in a total of 970 cosmetic formulations. Among the ingredients most frequently used are Sucrose Acetate Isobutyrate (274 reported uses), Sucrose Cocoate (139 reported uses), and Sucrose Stearate (156 reported uses) (Table 5). All the other in-use saccharide esters are reported to have less than 75 uses, individually. The 2015-2016 concentration of use survey data 26 indicate the highest maximum reported concentrations of use are as follows: 31% Sucrose Acetate Isobutyrate (up to 31% in eye shadow and foundation; up to 27% in lipstick); 14.3% Sucrose Benzoate (up to 14.3% in nail polish and enamel); 20.6 % Sucrose Cocoate (up to 20.6% in shaving soap); 87.7% Sucrose Polycottonseedate (up to 87.7% in lipstick); 15% Sucrose Tetrastearate Triacetate (up to 10% in lipstick and up to 15% in mascara). The frequency and concentration of use data are summarized, alphabetically by ingredient, in Table 5. Following the Council’s industry survey there were no concentrations of use reported for Sucrose Dipalmitate and Sucrose Palmitate/Stearate or Sucrose Stearate-Palmitate Ester. Although listed together in Table 1 and Table 2, Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate Ester are listed separately in Table 5 because the data for each are reported separately by the VCRP.3 Only one ingredient (Maltitol Laurate) has been reviewed previously by the Panel, but there were no frequency or concentration of use data for this ingredient presented in the 2008 report.1 According to 2016 VCRP data, there is one reported use of this ingredient in shampoos non-coloring.3 The 14 saccharide esters that are included in this safety assessment, but are not currently in use according to the VCRP and Council industry survey, are presented in Table 6. In some cases, reported uses of saccharide esters were available in the VCRP data, but concentration of use data were not provided. For example, Maltitol Laurate is reported to be used in 1 cosmetic formulation, but no use concentration data were reported.3 Conversely, there were instances in which no reported uses were indicated in the VCRP data, but a use concentration was provided for the ingredient in the industry survey. For example, Trehalose Undecylenoate was not reported in the VCRP data, but the industry survey indicated that it is used in leave-on formulations at up to 0.05% (in tonics, dressings, and other hair grooming aids) and in rinse-off formulations at up to 0.25%.26 It should be presumed in these cases that there is at least one use in every category for which a concentration of use is reported. Saccharide esters were reported to be used in perfumes, hair sprays, and deodorant sprays, and therefore, could possibly be inhaled. As examples, Sucrose Laurate was reportedly used in pump hair sprays at concentrations up to 1.2%; Sucrose Stearate was reportedly used in aerosol deodorant sprays at concentrations up to 0.23%.26 In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm, with propellant sprays yielding a greater fraction of droplets/particles below 10 µm compared with pump sprays.27,28,29,30 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.27,28 There is some evidence indicating that deodorant spray products can release substantially larger fractions of particulates having aerodynamic equivalent diameters in the range considered to be respirable.28 However, the information is not sufficient to determine whether significantly greater lung exposures result from the use of deodorant sprays, compared to other cosmetic sprays. Sucrose Tristearate was reported to be used in face powders at concentrations up to 2%26 and could possibly be inhaled. Conservative estimates of inhalation exposures to respirable particles during the use of loose powder

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cosmetic products are 400-fold to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace.31-33 Saccharide esters were reported to be used in cosmetic formulations indicative of potential eye exposure (Sucrose Acetate Isobutyrate up to 31% in eye shadow), possible mucous membrane exposure (Sucrose Polycottonseedate up to 87.7% in lipstick), and possible ingestion (Sucrose Polycottonseedate up to 87.7% in lipstick).3,26 These ingredients are also incorporated into various baby products (e.g. Sucrose Stearate is reported to be used in 4 baby products, but no concentration of use was reported).3 None of the saccharide esters named in this report are restricted from use in any way under the rules governing cosmetic products in the European Union.34 Non-Cosmetic The non-cosmetic uses of the saccharide esters (Table 7) consist largely of either direct or indirect food additives, as specified in the Code of Federal Regulations Title 21. Sucrose fatty acid esters are listed as direct food additives (21CFR172.859). Sucrose Acetate Isobutyrate is GRAS for use as a direct food additive in the United States.17 Sucrose Octaacetate has been present in over the counter (OTC) drugs as nail-biting and thumb-sucking deterrents. However, the FDA has stated that Sucrose Octaacetate cannot be generally recognized as safe and effective in this application because the available safety data are not adequate to assess the safety of the use of Sucrose Octaacetate for this purpose (21CFR310.536): “Any OTC drug product that is labeled, represented, and promoted as a nailbiting or thumbsucking deterrent is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an approved application or abbreviated application…is required for marketing. In the absence of an approved new drug application or abbreviated new drug application, such product is also misbranded under section 502 of the act. Clinical investigations designed to obtain evidence that any drug product labeled, represented, or promoted for OTC use as a nailbiting or thumbsucking deterrent is safe and effective for the purpose intended must comply with the requirements and procedures governing the use of investigational new drugs…” (21CFR310.536). The following saccharide esters are listed as inactive ingredients in FDA approved drug products: Sucrose Laurate at 30 mg in a gelatin-coated capsule for oral administration; Sucrose Palmitate at 10 mg in a powder for suspension intended for oral administration; Sucrose Stearate/ Sucrose Distearate at 5% (w/w) in a topical emulsion cream; Sucrose Stearate at up to 44.5% in a sustained-action capsule or an extended-release tablet for oral administration.35

TOXICOKINETIC STUDIES

Dermal Penetration Human Sucrose Laurate Honeywell-Nguyen et al. conducted tape-stripping studies on the transport of elastic vesicles into human skin to understand the effects of occlusion and the duration and volume of application.36 Vesicles have been used to increase the transport rate of drugs through the skin, although in tests reported here drugs were not used in the vesicle formulations. Elastic liquid-state vesicles (100-120 nm and composed of molar ratio 50:50:5; Sucrose Laurate: micelle-forming surfactant PEG-8-L: stabilizer sulfosuccinate) containing Sucrose Laurate (30% mono-, 40% di-, and 30% triesters) were evaluated in human subjects (n ≥ 3). In all of the tests a 0.05 M citrate buffer solution (pH 5.0) was used as a control applied to the skin; no vesicles without Sucrose Laurate were used as a control. Electron micrographs corresponding to tape strip 1 (skin surface) and either 9 or 15 (deeper layers of stratum corneum) were reported for all the test conditions. In the duration test, the vesicles were applied non-occlusively (20-µL to a 1-cm2 skin surface area), and tape-stripping was performed 1 and 4 hours after the solution had dried (evaporation of vesicle solutions was necessary to establish an osmotic gradient thought to facilitate transport into the skin). After the 1 and 4-hour treatments, vesicles were observed up to the 9th and 15th strips, respectively, with extensive vesicle fusion (multiple vesicles forming conglomerates at the skin surface and in stratum corneum) in the 4-hour treatment. In the volume test, 20-µL and 100-µL of vesicle formulation were applied non-occlusively, and tape-stripping was performed 1 hour after the solution had dried. The skin surface showed no difference, based on comparison of skin structure as seen in electron micrographs, between the 20-µL and 100-µL volumes; however, in the stratum corneum the 100-µL volume, as compared to 20-µL, increased the amount of intact vesicles (maintaining individual vesicle formation as depicted in electron micrographs) and fused vesicle material in the 9th strip. The presence of intact and fused vesicles was also noted in the electron micrographs of the first tape strips with the 20-µL and 100-µL treatments; little vesicle material was observed in the 15th tape strips at either volume tested. The effect of occlusion was evaluated in a test performed by applying 100-µL of vesicle formulation, both occlusively and for comparison, non-occlusively, for 1 hour, after which the skin surface was wiped off and tape-stripping performed. Results from the occlusion test were: the skin surface contained vesicles (intact and fused, similar to controls) for occluded and non-occluded samples and lipid plaques (the authors postulated that lipid plaques were the dispersal of vesicle fragments or components into the stratum corneum) in the occluded samples; unlike in non-occluded samples, the occluded samples showed that the stratum corneum had few intact vesicles in the 9th strip and lipid plaques were found in the 9th and 15th strips; lipid plaques may have enhanced skin permeability by disrupting intercellular skin structure organization; very few intact vesicles were present in the

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deeper layers of the stratum corneum during occlusion. Fast penetration of vesicles into the stratum corneum for non-occlusive treatment was noted. The researchers indicated that non-occlusive conditions facilitated the elastic vesicle incorporation into the skin by establishing a transepidermal osmotic gradient. Penetration Enhancement A synopsis of penetration enhancement experiments is provided below; details are provided in Table 8. In Vitro Penetration enhancement tests in vitro showed Sucrose Laurate (1.5%) evaluated in the pH range of 6 to 8 in mouse skin to be a potent percutaneous absorption enhancer for the drug lidocaine,37 and in rat skin Sucrose Laurate (30% aqueous solution) was found to be a penetration enhancer for the drug cyclosporine.38 Experiments in micropig skin, evaluating polyphenols in oil-in-water microemulsions (25:19:5:60, Sucrose Laurate:ethanol:isopropyl myristate:water), showed rapid distribution from the microemulsion vehicle to the epidermis, but slower dispersion from epidermis to dermis; hydrophilic polyphenols were distributed slightly more to the epidermis and hydrophobic (small molecular weight) polyphenols distributed mainly to the dermis.39 Sucrose Laurate and Sucrose Myristate (variable between 0.1-3 mg/mL) showed a concentration-dependent enhancement of paracellular permeability of a fluorescein isothiocyanate labelled dextran marker in human nasal epithelial cells.40 In a nanoemulsion, Sucrose Stearate (1%) was a permeation enhancer for progesterone in an in vitro porcine skin test.41 Animal Animal tests revealed that Sucrose Laurate (5% in a hydrogel) increased skin hydration and penetration of the drug ibuprofen in a mouse tape-stripping experiment;42 in rabbits, Sucrose Laurate (5% and 15% in a hydrophilic gel) increased epidermal skin-fold thickness and was a percutaneous absorption enhancer of the drug estradiol.43 In an experiment in which rats were exposed to the drug sumatriptan succinate and 0.5% Sucrose Laurate by intranasal administration, results showed that Sucrose Laurate enhanced the effect of intranasal absorption of sumatriptan succinate.44 Sucrose Cocoate (0.5%), when exposed via nasal administration using a pipette or by ocular installation, was found to increase the absorption of drugs (insulin and calcitonin) nine-fold (nasal) and four-fold (ocular) in rats.45 Human Sucrose Palmitate (2%) and Sucrose Stearate (0.5%) in a tape-stripping (12x) experiment in human subjects increased skin absorption of the drug aceclofenac, which was then detected at all depths of the stratum corneum.46 Sucrose Oleate and Sucrose Laurate, both tested at 2% and 10% in human subjects, increased skin penetration of the drug 4-hydroxy-benzonitrile.47 Absorption, Distribution, Metabolism, Excretion (ADME) A brief summary of absorption, distribution, metabolism, and excretion studies is provided below; details are provided in Table 9. In Vitro Experiments showed that a mixture of 1 µmol/ml Sucrose Palmitate and Sucrose Stearate (14C-labels on either the sucrose or ester portion) was not transported from mucosal to serosal solution in everted intestinal sacs of rats; hydrolysis by mucosal homogenates from the rats was 10% to 30%, compared with little hydrolysis in whole blood.48 Results from another rat test indicated that up to 250 µg/ml 14C-Sucrose Acetate Isobutyrate (label on sucrose) was 75% hydrolyzed by intestinal homogenates in 6 hours; less hydrolysis occurred in the stomach and liver.49 A study, in which human fecal homogenates were incubated with 1 mg/ml and 0.1 mg/ml 14C- Sucrose Acetate Isobutyrate (label on sucrose), resulted in 40% and 60% hydrolysis, respectively, in 16 hours.49 Animal In oral studies in rats, Glucose Pentaacetate (20% aqueous solution, no radioactive label used) was rapidly absorbed (> 90% in 4 hours),50 and excretion occurred mostly in the feces after administration of a 14C-radiolabeled Sucrose Palmitate and Sucrose Stearate mixture (details on radiolabeling are specified in Table 9);48 a mixture of sucrose esters (250 mg/kg, radiolabels on either sucrose or ester portion, see Table 9 for details), including Sucrose Hexastearate, were hydrolyzed prior to intestinal absorption (less esterified compounds were better absorbed) and largely excreted in feces (> 96% to 99% of radioactivity) at 120 hours post-dosing;51 200 mg/kg of Sucrose Octaisobutyrate (a component of Sucrose Acetate Isobutyrate, 14C label on sucrose) was excreted in feces (78% to 93% of dosed radioactivity), excreted as a volatile product (3% to 15% of dosed radioactivity), and eliminated in urine (1% to 2% of dosed radioactivity).52 In dogs and monkeys orally administered 200 mg/kg of Sucrose Octaisobutyrate (14C label on sucrose) no dosed radioactivity was detected in whole blood or plasma and excretion in feces was 77% to 94% of dosed radioactivity and 62% to 85% of dosed radioactivity, respectively.52 In dogs, Sucrose Octaisobutyrate was slowly absorbed with less extensive hydrolysis in the gut, compared to rats; in monkeys it was not absorbed or hydrolyzed in the gut.52 Human In single-dose (0.1 g or 1.0 g Sucrose Acetate Isobutyrate) and multi-dose (1 g/day Sucrose Acetate Isobutyrate for 7 days) oral exposure studies, results indicated that < 0.4% were excreted in urine as the parent compound or metabolite with a disaccharide moiety.49 In a fecal excretion study, 0.1 g/day Sucrose Acetate Isobutyrate was administered to 1 subject for 7 days and no unchanged Sucrose Acetate Isobutyrate or metabolites were detected in fecal samples. The absorption of partially esterified sucrose molecules

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from the intestinal tract was insignificant. In a different test, human subjects were administered a single, oral dosage of 1.0 to 1.2 mg/kg Sucrose Acetate Isobutyrate (radiolabel on sucrose) and exhaled 41% to 66% of dosed radioactivity in the breath within 30 days post-administration; 15% to 21% of dosed radioactivity was eliminated in urine and 10% of dosed radioactivity was excreted in feces.53

TOXICOLOGICAL STUDIES

Acute Toxicity Studies Provided below is a synopsis of the acute (single-exposure) toxicity studies that are presented in detail in Table 10.

The LD50 was reported to be > 20 g/kg in a study in which a single dosage of Sucrose Acetate Isobutyrate was dermally applied to 18 rats. For rats and monkeys orally administered single dosages of Sucrose Acetate Isobutyrate, the LD50 was reported to be > 5 g/kg and > 20 g/kg, respectively.18 In dogs orally administered a single dosage of 2 g/kg Sucrose Acetate Isobutyrate, an increase in plasma bromosulfophthalein (BSP) levels was reported.21 Constituent esters of Sucrose Acetate Isobutyrate, namely Sucrose Hexaacetate Diisobutyrate and Sucrose Octaisobutyrate, were both shown to increase BSP levels in dogs when single dosages up to 1 g/kg were orally administered; however body weight and gross clinical observations were unaffected by the treatment. Overall, single, high dosages of Sucrose Acetate Isobutyrate, administered through dermal and oral exposure, were well-tolerated in animals. Short-Term Toxicity Studies Below is a synopsis of the short-term toxicity studies that are presented in detail in Table 11. Animal Sucrose Acetate Isobutyrate was well-tolerated in orally exposed animals. In rats, a no-observed-adverse-effect-concentration (NOAEC) was reported for doses up to 10% daily in the diet for 6 weeks (decrease in mean heart weight for treated males was noted);54 monkeys dosed up to 10 g/kg/day in the diet (for 15 days) showed no change in body weight, food consumption, or clinical parameters;21 mice dosed up to 5 g/kg/day in the diet (for 4 weeks) were unaffected by the treatment;55 in a 2-week study in dogs dosed up to 0.5% daily in the diet, BSP retention was reported at 0.3% and 0.5%.21 Sucrose Polysoyate was orally administered to rats and dogs. In rats dosed for 28 days, a NOEC of 15% was reported; softer feces, lower growth rates (dose-related), and a dose- dependent heart weight decrease were observed.19,20 Two studies in dogs reported a NOAEC and no-observed-effect-concentration (NOEC) of 15% daily in the diet for 28 days; results showed a higher food consumption in treated animals compared to controls, yet hematology, urine, and organs were unaffected by treatment.19,20 Human There were 3 different studies conducted in human subjects orally administered up to 0.02 g/kg/day Sucrose Acetate Isobutyrate for 14 days; results showed no blood chemistry or hematological abnormalities.21 Subchronic Toxicity Studies Below is a synopsis of the subchronic toxicity studies that are presented in detail in Table 11. A NOAEL of 10% daily in the diet was reported in a 12-week study in rats orally administered Sucrose Acetate Isobutyrate; a decrease in mean heart weights in all treated males was observed.54 In 13-week studies in rats dosed with up to 9% Sucrose Acetate Isobutyrate daily in the diet, slight diarrhea was reported, but no toxic effects were observed.18,21 Dogs orally administered up to 5% Sucrose Acetate Isobutyrate daily in the diet for 91 days showed a moderate elevation in serum alkaline phosphatase (SAP) liver enzyme, heavier liver weights compared to controls, and a functional effect on the liver (reversible when Sucrose Acetate Isobutyrate was removed from the diet).18 In rats orally administered Sucrose Polysoyate for approximately 90 days a NOEC of 15% daily in the diet was reported; softer feces and lower growth rates were noted, an increase in food consumption was seen with increasing doses, however no toxicity was observed.19,20 Chronic Toxicity Provided below is a summary of the chronic toxicity studies that are presented in detail in Table 11. Sucrose Acetate Isobutyrate was evaluated in monkeys in a 1-year study in which a NOAEL of 2.4 g/kg/day (the highest dosage rate tested) was reported.56 Although statistically significant changes in hematological parameters were reported at the higher dosage rates (1.45 to 2.4 g/kg/day), overall the treatment was well-tolerated. Reported from a 1-year rat study testing Sucrose Acetate Isobutyrate was a NOAEL of 2 g/kg/day (highest dosage rate tested).55 Body weight gain decreases were observed in males and females (2 g/kg/day); 1 female death (0.5 g/kg/day) was noted, 1 female was killed in a moribund condition (2 g/kg/day), and 1 control and 2 treated rats died during blood collection. Small, but statistically significant hematology differences between control and treated groups occurred at varying dosage rates and timepoints in the study; however all resolved by 54 weeks. The same researchers conducted 2-year toxicity studies (including evaluations for carcinogenicity; see Carcinogenicity section in-text) in rats and mice. Survival rates for rats were 46% to 78% and for mice were 66% to 80%. The NOAELs reported for rats and mice were 2 g/kg bw/day (highest dosage rate tested) and 2.5 g/kg/day, respectively. In mice, the NOAEL did not include the highest dosage rate tested (5 g/kg/day) because at that dosage rate there was a treatment-related decrease in mean absolute and relative kidney weights observed at

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necropsy in males, compared to controls. Another 2-year toxicity study (carcinogenicity evaluations were performed; see Carcinogenicity section in-text) was conducted in rats (concentration up to 9.38% in diet).21 A dose-related increase in absolute and relative kidney weights was noted; however the organ weight findings were deemed inconclusive because of discrepancies in male body weights, as compared to controls, and low survival numbers. Within 10 weeks of the study, 4 males dosed with 9.38% died (massive hemorrhages in multiple organs were reported), but the deaths were not attributed to treatment (no further details specified).

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES

Provided below is a summary of the DART studies that are presented in detail in Table 12. Four oral-exposure DART studies were conducted for Sucrose Acetate Isobutyrate in rats and rabbits. In a 3-generation dietary study in which male rats were dosed daily for 10 weeks and female rats for 2 weeks prior to mating, teratogenic and developmental toxic effects were not observed and a NOAEL of 2 g/kg/day, the highest dosage rate tested, was reported.57 In another dietary study, rats fed 9.38% in the diet for 5 weeks (rats bred 3x during weeks 9-36) showed fewer pregnancies and fewer pup births with survival to weaning. However, this was attributed to the potentially reduced nutritive value of the diet.21 In a study in which rabbits were dosed on days 7-19 of gestation by gavage, a NOAEL of 1.2 g/kg/day was reported; 2 of 16 rabbits dosed at this level died on day 17 of gestation, but teratogenic or developmental toxic effects were not observed.42

GENOTOXICITY STUDIES

Below is a synopsis of the genotoxicity studies that are presented in detail in Table 13. In Vitro Maltitol Laurate and Sucrose Acetate Isobutyrate were evaluated in vitro. Maltitol Laurate (40%) was negative in an Ames test performed using Salmonella typhimurium.58 An Ames test conducted in S. typhimurium cells showed that Sucrose Acetate Isobutyrate was negative for genotoxicity as a mutagen, clastogen, and DNA-damaging agent at concentrations up to 10,000 µg/plate (non-toxic; no increase in number of revertants).59 A mutation assay in Chinese Hamster Ovarian/Hypoxanthine-Guanine Phosphoribosyl Transferase (CHO/HGPRT) cells showed no increase in mutation frequency up to 1000 µg/ml Sucrose Acetate Isobutyrate. A chromosomal aberration assay in CHO cells showed no increase in aberrations up to 2000 µg/ml Sucrose Acetate Isobutyrate. An unscheduled DNA synthesis assay in rat hepatocytes was non-toxic for test substance Sucrose Acetate Isobutyrate at concentrations up to 10,000 µg/ml. In Vivo A study in which male rats were administered a single dosage (2000 mg/kg) of Sucrose Acetate Isobutyrate by gavage and subsequently mated with untreated females several times during the 7 weeks post-dosing yielded negative results for dominant lethal mutations.18

CARCINOGENICITY STUDIES

Animal Sucrose Acetate Isobutyrate In a 2-year chronic study (Table 11) that also evaluated carcinogenicity, F344 rats (n=50/sex/dosage rate) were fed a diet containing Sucrose Acetate Isobutyrate.55 The nominal dosage rates were 0 (control group 1), 0 (control group 2), 0.5, 1.0, and 2.0 g/kg/day. The highest tested concentration of Sucrose Acetate Isobutyrate in the diet (less than 5%) was not expected to cause nutritional deficiencies in this long-term study. Sucrose Acetate Isobutyrate was not carcinogenic; no treatment-related tumors were found, only tumors typical of those that occur spontaneously in the F344 rat were noted. 55 A 2-year chronic dietary study (Table 11), also evaluating carcinogenicity was conducted in B6C3F1 mice (n=50/sex/dosage rate). A 4-week range finding study (Table 11) was conducted at 0, 0.625, 1.25, 2.5, and 5.0 g/kg/day Sucrose Acetate Isobutyrate (n=10/sex/dosage rate). Results indicated that Sucrose Acetate Isobutyrate was well-tolerated. Dosage rates selected for the 2-year carcinogenicity study were 0, 0, 1.25, 2.5, and 5.0 g/kg/day Sucrose Acetate Isobutyrate (highest dietary concentration of Sucrose Acetate Isobutyrate at 4.4%). Sucrose Acetate Isobutyrate was not carcinogenic; tumors found were typical of those that occur spontaneously in the B6C3F1 mouse and were not treatment-related. Carcinogenicity in Sprague-Dawley rats was evaluated (n=10/sex/dose level) at 0%, 0.38%, and 9.38% Sucrose Acetate Isobutyrate in the diet for 2 years in a chronic study (Table 11).21 No Sucrose Acetate Isobutyrate treatment-related lesions were found upon histological examination, therefore the study results were negative for carcinogenicity.

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OTHER RELEVANT STUDIES

Cytotoxicity Studies Provided below is a synopsis of cytotoxicity studies presented in detail in Table 14. In Vitro Tests on various cell cultures were conducted to evaluate the cytotoxicity of Sucrose Laurate and/or Sucrose Myristate. Human nasal epithelial cell death in the lactate dehydrogenase assay of Sucrose Laurate was <25% at 0.1 mg/ml and of Sucrose Myristate was 50%- 75% at 0.1-0.3 mg/ml; the 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay test indicated that cell viability was 100% with 0.1 mg/ml Sucrose Laurate and 100% with 0.03 mg/ml Sucrose Myristate.40

DERMAL IRRITATION AND SENSITIZATION STUDIES

Irritation Details of dermal irritation and sensitization studies found in Table 15 and Table 16 are summarized below. Animal Skin irritation testing of Sucrose Laurate in animals resulted in the following: a hydrogel formulation (concentration of Sucrose Laurate unknown) containing 5% ibuprofen was non-irritating to mouse skin;42 5% and 15% hydrophilic gel formulations (also containing drug estradiol) yielded increased epidermal thickness and some irritation potential when tested in rabbits;43 a 2% solution was non-irritating when tested in guinea pigs.38 Sucrose Acetate Isobutyrate (0.5 ml applied directly to shaved skin with an occlusive covering for 24 hours) was non-irritating to guinea pig skin.18 The saccharide esters evaluated were generally non-irritating, with sporadic occurrences of slight irritation. Human Sucrose Stearate and Sucrose Palmitate (up to 2% in a nanoemulsion containing the drug aceclofenac), evaluated for irritation potential in a 24-hour occlusive patch test in human subjects, produced a decrease in stratum corneum hydration. However, no adverse skin reactions were visible and the treatment was tolerable to the skin.46 Human patch tests evaluating Sucrose Pentahydroxystearate (100%) and Sucrose Tetraisostearate (100%) for irritation were negative (0% after 24 hours, no further details specified).58 Sucrose Polycottonseedate (up to 1% in formulation) was slightly irritating in a 21-day occlusive patch test in human subjects.20 Sucrose Polycottonseedate (up to 13% solution) and Sucrose Polybehenate (up to 3% solution) were non-irritating in a 5- day occlusive patch test in human subjects.19,20 Moderate skin irritation observed in 4 of 30 humans subjects dermally exposed to cleansing cloths containing Sucrose Polycottonseedate (up to 17.19%) was thought to be caused by constituents in the formulation other than the saccharide ester.20 Overall, the saccharide esters were characterized as non-irritating to human skin in the studies summarized in this safety assessment; for the intermittent irritation noted in a few of the tests (see Table 15 and Table 16), it was reported to be slight to mild in a relatively small percentage of the total population of subjects evaluated. Sensitization Animal Slight, transient irritation was noted in a study testing Sucrose Acetate Isobutyrate (20% solution in 9:1, acetone: corn oil) for 24 hours on hairless guinea pig skin.60 A delayed sensitization experiment was also conducted in guinea pigs (induction and challenge phase concentrations were not specified) and no sensitization was reported. In a Guinea Pig Maximization Test evaluating Sucrose Acetate Isobutyrate (1% solution at induction; 10% solution at challenge), no sensitization was observed.18 Sucrose Acetate Isobutyrate was non-sensitizing in animals. Human Sucrose Acetate Isobutyrate (20% solution) in a human repeat insult patch test (HRIPT) was non-irritating and non-sensitizing.18 In a HRIPT, Sucrose Polybehenate (~3%) and Sucrose Polycottonseedate (~13%) were non-irritating and non-sensitizing19,20 Sucrose Polycottonseedate (~16-17% in facial cleansing cloths) was non-irritating and non-sensitizing in a HRIPT.20 Sucrose Polycottonseedate (88% in a lipstick topcoat matrix) was non-sensitizing in human subjects and the only reaction reported was skin staining in 1 subject.61 The saccharide esters evaluated were non-sensitizing in human subjects.

OCULAR IRRITATION

Animal Sucrose Laurate A study in Japanese white female rabbits was conducted to evaluate the effects of Sucrose Laurate on rabbit eyes.62 A Maximum Draize Rabbit Eye Score (MDES) test was performed by instilling 0.1 ml of 10% Sucrose Laurate solution, prepared from a 38% Sucrose Laurate solution, into the conjunctival sac of the left eye (right eye served as untreated control) of each of three rabbits. There

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was no eye washing post-application. Observations were made at 1, 3, 6, 24, 48, 72, and 96 hours post-treatment. The observed MDES score reported for Sucrose Laurate was 21 (no further irritation results provided). The threshold score of around 20 was considered by the authors to be the value below which corneal damage was not observed. Sucrose Acetate Isobutyrate A study evaluating the irritation of Sucrose Acetate Isobutyrate in New Zealand White rabbit eyes was conducted.18 The guidelines followed in this study were similar to OECD 405 (Acute Eye Irritation/Corrosion), using good laboratory practice (GLP). To all of the eyes of three rabbits 0.1 ml of a 50% Sucrose Acetate Isobutyrate dilution in corn oil was instilled into the conjunctival sac (3 washed and 3 unwashed eyes, following application). To another unwashed eye, 0.1 ml of corn oil was instilled into the conjunctival sac for use as a control. Observations were noted for 72 hours post-application. The control performed as expected. Moderate erythema of conjunctivae and nictitating membranes were noted in all unwashed eyes 1 hour post-application; slight erythema of conjunctivae and nictitating membranes observed in 2 of 3 unwashed eyes 24 hours post-application. At 48 hours post-application 2 of 3 unwashed eyes were normal and at 72 hours post-application all 3 unwashed eyes were normal. There was slight (in 2 of 3 eyes) to moderate (in 1 of 3 eyes) erythema of conjunctivae and nictitating membranes in washed eyes 1 hour post-application. All washed eyes were normal at 24 hours post-application (no corneal or adnexal staining seen when eyes were examined with fluorescein dye). Sucrose Acetate Isobutyrate was slightly irritating to rabbit eyes.

SUMMARY

The 40 saccharide esters included in this safety assessment have a variety of reported functions in cosmetics, i.e. surfactants, humectants, emulsion stabilizers, emollients, and skin conditioning agents. VCRP data obtained from the FDA in 2016 indicate that saccharide esters named in this safety assessment are used in a total of 970 cosmetic formulations. Sucrose Acetate Isobutyrate has the highest reported number of uses (274) with the next highest reported for Sucrose Stearate (156) and Sucrose Cocoate (139). Concentration of use industry survey data obtained by the Council in 2015-2016 indicate that the highest maximum reported concentrations of use are for Sucrose Polycottonseedate (87.7% in lipstick), Sucrose Acetate Isobutyrate (31% in eye shadow and foundation; 27% in lipstick), Sucrose Cocoate (20.6% in shaving soap), Sucrose Benzoate (14.3% in nail polish and enamel), and Sucrose Tetrastearate Triacetate (15% in mascara and 10% in lipstick). There were no concentrations of use reported in a Council industry survey for Sucrose Dipalmitate and Sucrose Palmitate/Stearate or Sucrose Stearate-Palmitate Ester. Saccharide esters are used as penetration enhancers in pharmaceutical applications. They are also incorporated into foods as direct and indirect food additives (i.e. flavoring substances and emulsion stabilizers). Sucrose Acetate Isobutyrate is a GRAS direct food additive. Sucrose Laurate, Sucrose Palmitate, Sucrose Stearate, and Sucrose Distearate are listed as inactive ingredients in FDA approved drug products. Human dermal penetration studies showed at 1- hour post dermal (non-occlusive) application of elastic vesicles (containing a molar ratio of 50:50:5; Sucrose Laurate: micelle-forming surfactant PEG-8-L: stabilizer sulfosuccinate) that Sucrose Laurate was observed up to the 9th tape strip and after 4 hours up to the 15th strip, suggesting that Sucrose Laurate permeated the stratum corneum. The in vitro penetration enhancement studies demonstrated that Sucrose Laurate was a percutaneous absorption enhancer for the drug lidocaine at pH 6, in mice. Micropig experiments (in vitro) showed that Sucrose Laurate enhanced skin incorporation of polyphenols with accumulation of hydrophilic polyphenols occurring more in the epidermis and accumulation of lower molecular weight hydrophobic polyphenols more in the dermis. Sucrose Laurate, in in vitro rat skin tests, exhibited effective skin penetration-enhancing properties for dermal hydrophilic drug (cyclosporine A) delivery. Sucrose Laurate and Sucrose Myristate (variable between 0.1-3 mg/mL) showed a concentration-dependent enhancement of paracellular permeability of a fluorescein isothiocyanate labelled dextran marker in human nasal epithelial cells. Sucrose Stearate was shown to be an emulsifier and dermal drug (e.g., fluconazole) penetration enhancer in pig skin (in vitro). Penetration enhancement studies (in vivo) testing Sucrose Laurate in mice showed increased skin hydration and penetration of ibuprofen and facilitated the absorption of lipophilic hydrocarbon components of the hydrogel (vehicle containing Sucrose Laurate) in the stratum corneum. Sucrose Laurate was a good intranasal absorption enhancer for the drug sumatriptan in rats. Experiments conducted in rabbits in vivo showed that Sucrose Laurate increased dermally administered drug (estradiol) bioavailability by 15%; Sucrose Laurate was a percutaneous absorption enhancer in single dose drug (estradiol) applications, but less effective after multiple applications. Skin biopsies from the application sites of rabbits treated with 5% and 15% Sucrose Laurate exhibited substantially greater thickness. Sucrose Cocoate, when exposed via nasal administration using a pipette or by ocular installation, was found to increase the absorption of drugs (insulin and calcitonin) nine-fold (nasal) and four-fold (ocular) in rats. In human subjects, Sucrose Palmitate (2%) and Sucrose Stearate (0.5%) were found to be absorption enhancers of the dermally applied drug aceclofenac, which was subsequently detected at all depths of the stratum corneum. Toxicokinetic studies in vitro showed that a mixture of Sucrose Palmitate and Sucrose Stearate (1 µmol/ml, 14C-labels on either sucrose or ester portion) was not transported from mucosal to serosal solution in everted intestinal sacs of rats; hydrolysis by mucosal homogenates from the rats was 10% to 30%, compared with little hydrolysis in whole blood. Results from another rat test indicated

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that up to 250 µg/ml 14C-Sucrose Acetate Isobutyrate (label on sucrose) was 75% hydrolyzed by intestinal mucosa in 6 hours; less hydrolysis occurred in the stomach and liver. A study in which human fecal homogenates were incubated with 1 mg/ml or 0.1 mg/ml 14C-Sucrose Acetate Isobutyrate (label on sucrose) resulted in 40% and 60% hydrolysis, respectively, in 16 hours. Toxicokinetic tests conducted in rats (oral exposure) revealed the following: Glucose Pentaacetate (20% aqueous solution, no radioactive label used) was rapidly absorbed (> 90%) in 4 hours; a mixture of Sucrose Palmitate and Sucrose Stearate (up to 250 mg/kg) was excreted in feces (30% to 67% of dosed radioactivity), exhaled (11% to 49% of dosed radioactivity), and not detected in urine or blood at 120 hours post-dosing; a mixture of sucrose esters (250 mg/kg), including Sucrose Hexastearate, were hydrolyzed prior to intestinal absorption (less esterified compounds were better absorbed) and largely excreted in feces (> 95% of dosed radioactivity) at 120 hours post-dosing; 200 mg/kg of Sucrose Octaisobutyrate (a component of Sucrose Acetate Isobutyrate) was excreted in feces (78% to 93% of the dose of radioactivity), excreted as a volatile product (3% to 15% of the dose of radioactivity), and eliminated in urine (1% to 2% of the dose of radioactivity). In dogs and monkeys orally administered 200 mg/kg of Sucrose Octaisobutyrate no radioactivity was detected in whole blood or plasma and excretion in feces was 77% to 94% of dose of radioactivity and 62% to 85% of the dose of radioactivity, respectively. In dogs, Sucrose Octaisobutyrate was slowly absorbed with less extensive hydrolysis in the gut, compared to rats; in monkeys it was not absorbed or hydrolyzed in the gut. In single-dose (0.1 g or 1.0 g Sucrose Acetate Isobutyrate) and multi-dose (1 g/day Sucrose Acetate Isobutyrate for 7 days) oral- exposure toxicokinetic studies in human subjects, results indicated that < 0.4% were excreted in urine as the parent compound or metabolite with a disaccharide moiety. In a fecal excretion study, 0.1 g/day Sucrose Acetate Isobutyrate was administered to 1 subject for 7 days and no unchanged Sucrose Acetate Isobutyrate or metabolites were detected in fecal samples. The absorption of partially esterified sucrose molecules from the intestinal tract was insignificant. In a different study in human subjects who were administered a single, oral dosage of 1.0 to 1.2 mg/kg Sucrose Acetate Isobutyrate exhaled 41% to 66% of the oral dose of radioactivity in the breath within 30 days post-administration; 15% to 21% of the dose of radioactivity was eliminated in urine and 10% of was excreted in feces.

The acute toxicity studies in rats evaluated dermal and oral exposure to Sucrose Acetate Isobutyrate for which LD50 > 20 g/kg and LD50 > 5 g/kg were reported, respectively. In one study, rats and mice were orally dosed with 25.6 g/kg of Sucrose Acetate Isobutyrate. No mortality was observed for the mice and 1 of the 7 rats died. Sucrose Acetate Isobutyrate (5 g/kg) and Sucrose Octaisobutyrate (5 g/kg) were orally administered to monkeys in a study which found that liver metabolism parameters were unaffected by the treatment. However, in dogs that were orally administered 2 g/kg Sucrose Acetate Isobutyrate, measured plasma concentrations of BSP were found to be elevated. In another test in monkeys the LD50 was reported to be > 20 g/kg for oral administration of Sucrose Acetate Isobutyrate. In short-term studies, Sucrose Acetate Isobutyrate was well-tolerated in orally exposed animals. In rats, a NOAEC was reported for doses up to 10% daily in the diet for 6 weeks; monkeys dosed up to 10 g/kg/day in the diet (15 days) showed no change in body weight, food consumption, or clinical parameters; mice dosed up to 5 g/kg/day in the diet (4 weeks) were unaffected by the treatment; in a 2-week study in dogs dosed up to 0.5% daily in the diet, BSP retention was reported at 0.3% and 0.5%. In rats dosed with Sucrose Polysoyate in the diet for 28 days, a NOEC of 15% was reported; softer feces, lower growth rates (dose-related), and a dose- dependent heart weight decrease were observed. Two studies in dogs reported a NOAEC and a NOEC of 15% daily in the diet for 28 days for Sucrose Polysoyate; results showed a higher food consumption in treated animals compared to controls, yet hematology, urine, and organs were unaffected by treatment. In a 12-week subchronic study in rats orally administered Sucrose Acetate Isobutyrate a NOAEC of 10% daily in the diet was reported; a decrease in mean heart weights in all treated males was observed. In 13-week studies in rats dosed with up to 9% Sucrose Acetate Isobutyrate daily in the diet, slight diarrhea was reported, but no toxic effects were observed. Dogs orally administered up to 5% of Sucrose Acetate Isobutyrate daily in the diet for 91 days, showed a moderate elevation in serum alkaline phosphatase (SAP) liver enzyme, heavier liver weights compared to controls, and a functional effect on the liver (reversible when Sucrose Acetate Isobutyrate was removed from the diet). In rats orally administered Sucrose Polysoyate for approximately 90 days a NOEC of 15% daily in the diet was reported; softer feces and lower growth rates were noted, an increase in food consumption was seen with increasing doses, however no toxicity was observed. Chronic toxicity studies testing Sucrose Acetate Isobutyrate orally administered to animals reported a NOAEL of 2 g/kg/day for 1year in rats and a NOAEL of 2.4 g/kg/day for 1 year in monkeys. In the rat study, body weight gain decreases were observed in males and females (2 g/kg/day); 1 female death (0.5 g/kg/day) was noted, 1 female was killed in a moribund condition (2 g/kg/day), and 1 control and 2 treated rats died during blood collection. In 2-year studies conducted in animals the NOAELs reported for rats and mice were 2 g/kg/day (highest dosage rate tested) and 2.5 g/kg/day, respectively. In mice, the NOAEL did not include the highest dosage rate tested (5 g/kg/day) because at that dosage rate a treatment-related decrease in mean absolute and relative kidney weights was observed at necropsy in males compared to controls. Another 2-year study conducted in rats (dosing up to 9.38% in diet) showed a dose-related increase in absolute and relative kidney weights, however the organ weight findings were deemed inconclusive because of discrepancies in male body weights compared to controls and low survival numbers. Within 10 weeks of the study, 4 males dosed with 9.38% died (massive hemorrhages in multiple organs were reported), but the deaths were not attributed to treatment (no further details specified).

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Developmental and reproductive toxicity studies reported a NOAEL of 2 g/kg/day Sucrose Acetate Isobutyrate in rats (dosed daily in the diet for 10 weeks, males, and for 2 weeks, females, prior to mating) and a NOAEL of 1.2 g/kg/day Sucrose Acetate Isobutyrate in rabbits (dosed on days 7-19 of gestation by gavage). Sucrose Acetate Isobutyrate was not found to impair reproduction or produce toxic teratogenic/developmental effects in rats and rabbits. Rats fed 9.38% Sucrose Acetate Isobutyrate for 5 weeks (rats bred 3x in weeks 9-36) resulted in decreased pregnancies and decreased number of pups surviving to weaning, but this may have been attributed to compromised nutritional value of the diet at high Sucrose Acetate Isobutyrate concentrations. Maltitol Laurate (40%) was negative in an Ames test performed using S. typhimurium. An Ames test conducted in S. typhimurium cells showed that Sucrose Acetate Isobutyrate was negative for genotoxicity as a mutagen, clastogen, and DNA-damaging agent at concentrations up to 10,000 µg/plate (non-toxic; no increase in number of revertants). A mutation assay in CHO/HGPRT cells showed no increase in mutation frequency up to 1000 µg/ml Sucrose Acetate Isobutyrate. A chromosomal aberration assay in CHO cells showed no increase in aberrations up to 2000 µg/ml Sucrose Acetate Isobutyrate. An unscheduled DNA synthesis assay in rat hepatocytes was non-toxic for test substance Sucrose Acetate Isobutyrate at concentrations up to 10,000 µg/ml. An in vivo animal study in rats tested for dominant lethal mutations showed negative results up to 2000 mg/kg Sucrose Acetate Isobutyrate (male rats were dosed once by gavage 2 hours prior to mating with untreated females; males were mated several times with untreated females during the 7 weeks post-dosing). Carcinogenicity bioassays, of 2-year duration, were conducted in rats (up to 2 g/kg/day Sucrose Acetate Isobutyrate) and mice (up to 5 g/kg/day Sucrose Acetate Isobutyrate); study results were negative for carcinogenicity. Another test in rats dosed up to 9.38% Sucrose Acetate Isobutyrate in the diet for 2 years indicated no treatment-related lesions. Cytotoxicity tests evaluating Sucrose Laurate and Sucrose Myristate on human nasal epithelial cells showed cell death in a lactate dehydrogenase assay was < 25% for Sucrose Laurate (0.1 mg/ml) and was 50%-75% for Sucrose Myristate (0.1-0.3 mg/ml); the 3- (4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay test indicated that cell viability was 100% for Sucrose Laurate (0.1 mg/ml) and 100% for Sucrose Myristate (0.03 mg/ml). Dermal exposure studies in test animals indicated that Sucrose Laurate (unknown concentration) in a hydrogel was non-irritating, and 5% to 15% had some irritation potential, but was well-tolerated. A 20% Sucrose Acetate Isobutyrate solution caused slight, transient irritation. In humans, Sucrose Palmitate and Sucrose Stearate (up to 2% in oil/water nanoemulsions) substantially decreased hydration in the stratum corneum during an occlusive irritation profile test, however no adverse skin reactions were visually observed and the treatment was tolerable to the skin. In human patch tests evaluating irritation, Sucrose Pentahydroxystearate (100%) and Sucrose Tetraisosterate (100%) were negative (0% after 24 hours, no further details); Sucrose Polycottonseedate at 0.5-1% was slightly irritating. Moderate skin irritation observed in 4 of 30 humans subjects dermally exposed to cleansing cloths containing Sucrose Polycottonseedate (up to ~17%) was thought to be caused by constituents in the formulation and not the saccharide ester. A 1% solution (at induction) of Sucrose Acetate Isobutyrate was non-sensitizing in a Guinea Pig Maximization Test. In humans, Sucrose Acetate Isobutyrate (20% in a HRIPT) was found to be non-irritating and non-sensitizing; in a HRIPT Sucrose Polybehenate (~3%) and Sucrose Polycottonseedate (~13%) were non-irritating and non-sensitizing; a HRIPT evaluating Sucrose Polycottonseedate (up to ~17%) was deemed to be non-irritating and non-sensitizing; Sucrose Polycottonseedate (88% in a lipstick topcoat matrix) in a HRIPT was found to be non-sensitizing and the only reaction reported was skin staining in 1 subject. A 10% Sucrose Laurate solution and a 50% Sucrose Acetate Isobutyrate solution were slightly irritating to rabbit eyes.

DISCUSSION

The Panel considered relevant systemic toxicity, reproductive and developmental toxicity, genotoxicity, carcinogenicity, and irritation and sensitization data to assess the safety of the saccharide esters. They noted an absence of systemic toxicity at high dosages of Sucrose Acetate Isobutyrate in acute dermal (LD50 > 20 g/kg) and oral (LD50 > 5 g/kg) exposure studies in rats, in a two-week oral study in humans (0.02 g/kg/day Sucrose Acetate Isobutyrate), and in chronic, oral administration animal studies (2-year duration, NOAELs of 2 to 2.5 g/kg/day). Sucrose Acetate Isobutyrate was non-toxic in developmental and reproductive tests, showed an absence of genotoxic potential in an Ames test and genetic mutation experiments, and was non-carcinogenic in chronic studies. Sucrose Laurate (10%) and Sucrose Acetate Isobutyrate (50%) were slightly irritating to rabbit eyes; however the doses applied were considerably higher than the concentrations at which those ingredients are reported to be used in cosmetics. The saccharide esters are metabolized to products that are common, physiologic intermediates and nutrients, thus supporting a safe toxicity profile. The data presented in this safety assessment affirm the lack of toxicity of saccharide esters for use in cosmetics. The Expert Panel noted gaps in the data available to address some endpoints for some of the saccharide esters in this safety assessment. However, structure-activity relationships and similarities in reported functions and concentrations of use in cosmetics of the ingredients group enable the extrapolation (read-across) of the data available for some of the ingredients to the ingredients with data gaps to support the safety of the entire group. For instance, read-across was applied to the single-chain length subgroup of these ingredients to assess the potential for dermal irritation and sensitization of these ingredients based on the data available for Sucrose Polybehenate to address these endpoints. For the mixed-chain length subgroup, read-across was applied using multiple-endpoint safety data for Sucrose Acetate Isobutyrate and dermal irritation and sensitization safety data for Sucrose Polycottonseedate.

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As part of the safety determination, the Panel recalled the GRAS status of Sucrose Acetate Isobuyrate, for use as a direct food additive, and the use of several saccharide esters as direct and indirect food additives. In animal and human studies evaluating several saccharide esters, dermal irritation was reported to be none, in most cases, and slight to mild in sporadic occurrences. In one animal study, up to 15% Sucrose Laurate yielded some evidence of irritation potential, but was noted to be generally well-tolerated. In humans, Sucrose Polycottonseedate was slightly irritating (up to 1%) in one study, but in 2 other studies (~13% and ~16-17%) it was not irritating; tested at 88% (lipstick topcoat, n=108 subjects) in a HRIPT, Sucrose Polycottonseedate was non-sensitizing, and the only reaction reported was one instance of skin staining during induction. Moderate irritation responses were reported in one human study (up to 17% Sucrose Polycottonseedate). However, the researchers conducting the study suspected the irritation was related to constituent ingredients in the formulation and not to Sucrose Polycottonseedate. Therefore, the Panel considered the potential for saccharide esters to cause dermal irritation to be low and not of concern. The sensitization data reported in this safety assessment indicated that saccharide esters are non-sensitizing. The Panel recognized that saccharide esters can enhance the penetration of other ingredients through the skin. The Panel cautioned that care should be taken when formulating cosmetic products that may contain these ingredients in combination with any ingredients for which safety was based on data supporting a lack of dermal absorption, or for which dermal absorption was a concern. The Panel expressed concern about pesticide residues and heavy metals that may be present in botanical ingredients. They emphasized that the cosmetics industry should continue to use current good manufacturing practices (cGMPs) to limit impurities. Aflatoxins have been detected in Cottonseed Oil. The Panel believes that aflatoxins will not be present at levels of toxicological concern in Cottonseed Oil or Cottonseed Oil derivatives (e.g., Cottonseed Acid), used in the esterification reaction with sucrose to produce Sucrose Polycottonseedate. The Panel recognized the USDA designation of ≤ 15 ppb as corresponding to “negative” aflatoxin content. The Panel discussed the issue of incidental inhalation exposure from perfumes, hair sprays, deodorant sprays, and face powders. There were no inhalation toxicity data available. Sucrose Laurate is reportedly used at concentrations up to 1.2% in cosmetic products that may be aerosolized and Sucrose Tristearate is used up to 2% in face powder that may become airborne. The Panel noted that droplets/particles produced in cosmetic aerosols and loose-powder cosmetic products would not be respirable to any appreciable amount. In principle, inhaled droplets/particles deposited in the nasopharyngeal and thoracic regions of the respiratory tract may cause toxic effects depending on their chemical and other properties. However, coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. A detailed discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.

CONCLUSION

The CIR Expert Panel concluded that the following 40 ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment: Glucose Pentaacetate* Sucrose Pentaerucate* Maltitol Laurate Sucrose Pentahydroxystearate* Raffinose Isostearate* Sucrose Polybehenate Raffinose Myristate* Sucrose Polycottonseedate Raffinose Oleate* Sucrose Polylaurate Sucrose Acetate Isobutyrate Sucrose Polylinoleate* Sucrose Acetate/Stearate Sucrose Polyoleate Sucrose Benzoate Sucrose Polysoyate Sucrose Cocoate Sucrose Polystearate Sucrose Dilaurate Sucrose Stearate Sucrose Dipalmitate Sucrose Tetrahydroxystearate* Sucrose Distearate Sucrose Tetraisostearate Sucrose Hexaerucate* Sucrose Tetrastearate Triacetate Sucrose Hexaoleate/Hexapalmitate/Hexastearate Sucrose Tribehenate* Sucrose Hexapalmitate* Sucrose Trilaurate Sucrose Laurate Sucrose Tristearate Sucrose Myristate Trehalose Isostearate Esters Sucrose Octaacetate* Trehalose Undecylenoate Sucrose Oleate* Xylityl Sesquicaprylate* Sucrose Palmitate Sucrose Palmitate/Stearate or Sucrose Stearate-Palmitate Ester

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*Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group.

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TABLES

Table 1. Saccharide Esters-subgroups ordered by chain length. Alkyl Fatty Acid Esters-single chain length* Alkyl Fatty Acid Esters-mixed chain length* Non-Alkyl Esters Glucose Pentaacetate (C2) Sucrose Acetate Isobutyrate (C2, C4 branched) Sucrose Benzoate Sucrose Octaacetate (C2) Sucrose Acetate/Stearate (C2, C18) Xylityl Sesquicaprylate (C8) Sucrose Tetrastearate Triacetate (C18, C2) Trehalose Undecylenoate (C11:1) Sucrose Palmitate/ Stearate or Sucrose Palmitate-Stearate Ester** Maltitol Laurate (C12) (C16, C18) Sucrose Laurate (C12) Sucrose Polysoyate (Soybean Oil fatty acid distribution: Oleic Acid, Sucrose Polylaurate (C12) C18:1, 11.5-60.0%; Linoleic Acid, C18:3, 2.9- Sucrose Dilaurate 2(C12) 12.1%)14 Sucrose Trilaurate 3(C12) Sucrose Hexaoleate/ Hexapalmitate/ Hexastearate (C16, C18, C18:1) Sucrose Myristate (C14) Sucrose Cocoate (Coconut Oil fatty acid distribution: Caproic Acid, Raffinose Myristate (C14) C6, 0-1%; Caprylic Acid, C8, 5-9%; Capric Acid, Sucrose Palmitate (C16) C10, 6-10%; Lauric Acid, C12, 44-52%; Myristic Sucrose Dipalmitate (C16) Acid, C14, 13-19%; Palmitic Acid, C16, 8-11%; Raffinose Isostearate (C16 branched) Palmitoleic Acid, C16:1, 0-1%; Stearic Acid, C18, 1 Sucrose Hexapalmitate 6(C16) -3%; Oleic Acid, C18:1, 5-8%; Linoleic Acid, Sucrose Stearate (C18) C18:2, trace-2.5%)14 Sucrose Polystearate (C18) Sucrose Polycottonseedate (Cottonseed Oil fatty acid distribution: Sucrose Oleate (C18:1) Myristic Acid, C14, 2%; Palmitic Acid, Sucrose Polyoleate (C18:1) C16, 21%; Oleic Acid, C18:1, 30%; Sucrose Polylinoleate (C18:2) Linoleic Acid, C18:2, 45%; Stearic Acid, Trehalose Isostearate Esters (C18 branched) C18, trace; Arachidic Acid, C20, trace)14 Raffinose Oleate (C18) Sucrose Distearate 2(C18) Sucrose Tristearate 3(C18) Sucrose Tetraisostearate (C18 branched) Sucrose Tetrahydroxystearate 4(C18:OH) Sucrose Pentahydroxystearate 5(C18:OH) Sucrose Polybehenate (C22) Sucrose Tribehenate 3(C22) Sucrose Pentaerucate 5(C22:1) Sucrose Hexaerucate 6(C22:1) *Carbon chain length is indicated in parentheses; the number of double bonds or the double bonded hydroxyl group (in structures where these exist) within the chain is preceded by a colon **In the FDA VCRP data, both names are listed, but they refer to the same ingredient.

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Alkyl Fatty Acid Esters (single chain length)

Glucose Pentaacetate Glucose Pentaacetate is the pentaester of glucose and acetic acid. Emulsion Stabilizers; Fragrance Ingredients 3891-59-6

604-68-2

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Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Octaacetate Sucrose Octaacetate is an acetylation product of sucrose. It conforms to Denaturants; Fragrance the formula: Ingredients 126-14-7

Xylityl Sesquicaprylate Xylityl Sesquicaprylate is a mixture of mono- and diesters of caprylic Antimicrobial Agents; Skin- acid and the hexitol anhydrides derived from xylitol. Conditioning Agents-Humectant; 181632-90-6 Surfactants-Emulsifying Agents

[wherein R is hydrogen or the residue of caprylic acid (C8), where one or two R groups are caprylic acid residues]

Trehalose Undecylenoate Trehalose Undecylenoate is the ester formed by the reaction of trehalose Emulsion Stabilizers; Skin- with undecylenic acid. Conditioning Agents

[wherein R is hydrogen or the residue of undecylenic acid (C11:1), where one R group is an undecylenic acid residue]

Maltitol Laurate Maltitol Laurate is the ester of maltitol and lauric acid that conforms to Skin-Conditioning Agents- the formula: Emollient; Slip Modifiers 75765-49-0

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Laurate Sucrose Laurate is a mixture of sucrose esters of lauric acid consisting Skin-Conditioning Agents- primarily of the monoester. Emollient; Surfactants- 25339-99-5 Emulsifying Agents

37266-93-6

[wherein R is hydrogen or the residue of lauric acid (C12), where one R group is a lauric acid residue]

Sucrose Polylaurate Sucrose Polylaurate is a mixture of esters of lauric acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- Emulsifying Agents

[wherein R is hydrogen or the residue of lauric acid (C12)]

Sucrose Dilaurate Sucrose Dilaurate is the diester of lauric acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 25915-57-5 Emulsifying Agents

[wherein R is hydrogen or the residue of lauric acid (C12), where two R groups are lauric acid residues]

Sucrose Trilaurate Sucrose Trilaurate is the triester of lauric acid and sucrose. Surfactants-Emulsifying Agents; Surfactants-Solubilizing Agents 94031-23-9

[wherein R is hydrogen or the residue of Lauric Acid (C12), where three R groups are lauric acid residues]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Myristate Sucrose Myristate is the monoester of myristic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 27216-47-3 Emulsifying Agents

9042-71-1

[wherein R is hydrogen or the residue of myrisitic acid (C14), where one R group is a myristic acid residue]

Raffinose Myristate Raffinose Myristate is the ester of raffinose and myristic acid. Skin-Conditioning Agents; Emollient; Surfactants- 91433-10-2 Emulsifying Agents

[wherein R is hydrogen or the residue of myristic acid (C14), where at least one R is the residue of myristic acid]

Sucrose Palmitate Sucrose Palmitate is the monoester of palmitic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 26446-38-8 Emulsifying Agents

39300-95-3

[wherein R is hydrogen or the residue of palmitic acid (C16), where one R group is a palmitic acid residue]

[Sucrose Dipalmitate] [Sucrose Dipalmitate is the diester of palmitic acid and sucrose. N/A

***Reported to the FDA’s VCRP, but not recited in the INCI Dictionary

25637-97-2

wherein R is hydrogen or the residue of palmitic (C16) acid, where two R groups are palmitic acid residues]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Raffinose Isostearate Raffinose Isostearate is the ester of raffinose and isostearic acid. Skin-Conditioning Agents- Emollient; Slip Modifiers 1032182-34-5

Sucrose Hexapalmitate Sucrose Hexapalmitate is the hexaester of sucrose and palmitic acid. Surfactants-Dispersing Agents; Surfactants-Emulsifying Agents 29130-29-8

[wherein R is hydrogen or palmitoyl, in which 6 instances of R are palmitoyl]

Sucrose Stearate Sucrose Stearate is the monoester of stearic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 25168-73-4 Emulsifying Agents

37318-31-3

[wherein R is hydrogen or the residue of stearic acid (C18), where one R group is a stearic acid residue]

Sucrose Polystearate Sucrose Polystearate is a mixture of esters of stearic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- Emulsifying Agents

[wherein R is hydrogen or the residue of stearic acid (C18)]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Oleate Sucrose Oleate is the monoester of oleic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 52683-61-1 Emulsifying Agents

[wherein R is hydrogen or the residue of oleic acid (C18:1), where one R group is a oleic acid residue]

Sucrose Polyoleate Sucrose Polyoleate is a mixture of esters of oleic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- Emulsifying Agents

[wherein R is hydrogen or the residue of oleic acid (C18:1)]

Sucrose Polylinoleate Sucrose Polylinoleate is a mixture of esters of linoleic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- Emulsifying Agents

[wherein R is hydrogen or the residue of linoleic acid (C18:2)]

Trehalose Isostearate Esters Trehalose Isostearate Esters is the product obtained by the esterification Skin-Conditioning Agents- of isostearic acid and trehalose. Emollient 861436-89-7 (generic)

[wherein R is hydrogen or the residue of isostearic acid (C18:branched)]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Raffinose Oleate Raffinose Oleate is the ester of raffinose and oleic acid. Skin-Conditioning Agents- Emollient; Surfactants- 96352-58-8 Emulsifying Agents

[wherein R is oleate in one instance, and hydrogen in all other instances]

Sucrose Distearate Sucrose Distearate is a mixture of sucrose esters of stearic acid Skin-Conditioning Agents- consisting primarily of the diester. Emollient; Surfactants- 27195-16-0 Emulsifying Agents

[wherein R is hydrogen or the residue of stearic acid, where two R groups are stearic acid residues]

Sucrose Tristearate Sucrose Tristearate is the triester of stearic acid and sucrose. Skin-Conditioning Agents- Emollient 27923-63-3

[wherein R is hydrogen or the residue of stearic acid (C18), where three R groups are stearic acid residues]

Sucrose Tetraisostearate Sucrose Tetraisostearate is a mixture of esters of isostearic acid and Skin-Conditioning Agents- sucrose, consisting primarily of the tetraester. Emollient; Surfactants- 88484-21-3 Emulsifying Agents

[wherein R is hydrogen or the residue of isostearic acid (C18:branched), where four R groups are isostearic acid residues]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Tetrahydroxystearate Sucrose Tetrahydroxystearate is the tetraester of sucrose and Skin-Conditioning Agents- hydroxystearic acid. Emollient

[wherein R is hydrogen or the residue of hydroxystearic acid (C18:OH), where four R groups are hydroxystearic acid residues]

Sucrose Pentahydroxystearate Sucrose Pentahydroxystearate is the pentaester of sucrose and Skin-Conditioning Agents- hydroxystearic acid. Humectant

[wherein R is hydrogen or the residue of hydroxystearic acid (C18:OH), where five R groups are hydroxystearic acid residues]

Sucrose Polybehenate Sucrose Polybehenate is a mixture of esters of behenic acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 93571-82-5 Emulsifying Agents

[wherein R is hydrogen or the residue of behenic acid (C22)]

Sucrose Tribehenate Sucrose Tribehenate is the triester of behenic acid and sucrose. Skin-Conditioning Agents- Emollient 84798-44-7

[wherein R is hydrogen or the residue of behenic acid (C22), where three R groups are behenic acid residues]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Pentaerucate Sucrose Pentaerucate is the pentaester of sucrose and erucic acid. Skin-Conditioning Agents- Emollient; Surfactants

[wherein R is hydrogen or the residue of erucic acid (C22:1), where five R groups are erucic acid residues]

Sucrose Hexaerucate Sucrose Hexaerucate is the hexaester of sucrose and erucic acid. Skin-Conditioning Agents- Emollient; Surfactants- Emulsifying Agents

[wherein R is hydrogen or the residue of erucic acid (C22:1), where six R groups are erucic acid residues]

Alkyl Fatty Acid Esters (mixed chain lengths)

Sucrose Acetate Isobutyrate Sucrose Acetate Isobutyrate is the mixed ester of sucrose and acetic and Plasticizers isobutyric acids. 126-13-6

[substitution pattern as described in the CAS file]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Acetate/Stearate Sucrose Acetate/Stearate is the mixed ester of sucrose with acetic and Skin-Conditioning Agents- stearic acids. Emollient 52439-69-7

[**one example of a mixed ester]

Sucrose Tetrastearate Triacetate Sucrose Tetrastearate Triacetate is a mixture of esters of stearic acid, Skin-Conditioning Agents- acetic acid and sucrose. Emollient

[wherein R is hydrogen or the residue of stearic (C18) or acetic (C2) acid, where four R groups are stearic acid residues and three R groups are acetic acid residues]

[Sucrose Palmitate/Stearate or [Sucrose Palmitate/Stearate is the monoester of sucrose and palmitic N/A Sucrose Palmitate-Stearate Ester] acid or stearic acid.

***Both of the above names are reported to the FDA VCRP, but are not recited in the INCI Dictionary; the 2 names refer to the same ingredient

wherein R is hydrogen or the residue of palmitic (C16) or stearic (C18) acid, where one R group is an acid residue]

Sucrose Polysoyate Sucrose Polysoyate is a mixture of esters of soy acid and sucrose. Skin-Conditioning Agents- Emollient; Surfactants- 93571-82-5 Emulsifying Agents

[wherein R is hydrogen or the residue of a fatty acid derived from soy]

Distributed for Comment Only -- Do Not Cite or Quote

Table 2. Definitions, structures, and functions of the ingredients in this safety assessment.2;CIR Staff Name & CAS No. Definition & Structure Function(s)

Sucrose Hexaoleate/ Sucrose Hexaoleate/Hexapalmitate/Hexastearate is the hexaester of Surfactants-Dispersing Agents; Hexapalmitate/Hexastearate sucrose and oleic, palmitic, and stearic acids. Surfactants-Emulsifying Agents

[wherein R is residue of oleic (C18:1), palmitic (C16), or stearic (C18) acid]

Sucrose Cocoate Sucrose Cocoate is a mixture of sucrose esters of coconut acid, Skin-Conditioning Agents- consisting primarily of the monoesters. Emollient; Surfactants- 91031-88-8 Emulsifying Agents

[wherein R is hydrogen or the residue of a fatty acid derived from coconut acid, where at least one, and in most instances only one, R is a fatty acid residue]

Sucrose Polycottonseedate Sucrose Polycottonseedate is a mixture of esters of cottonseed acid and Skin-Conditioning Agents- sucrose. Emollient; Surfactants- 93571-82-5 Emulsifying Agents

[wherein R is hydrogen or the residue of a fatty acid derived from cotton seed]

Non-Alkyl Esters

Sucrose Benzoate Sucrose Benzoate is the disaccharide ester [of benzoic acid and sucrose] Plasticizers that conforms generally to the formula: 12738-64-6

[one example substitution pattern]

Distributed for Comment Only -- Do Not Cite or Quote

Table 3. Constituent sugars, alcohols, and acids with CIR conclusions Constituents Conclusion (year issued; maximum use concentration reported) Reference SUGAR or SUGAR ALCOHOL Glucose Safe as used (2014; 91% in leave-ons; 97.8% in rinse-offs) 15 Maltitol (sugar alcohol derived from the sugar Maltitol: Safe as used (2008; 8% in leave-ons; 15% in rinse-offs) 1,15 Maltose) Maltose: Safe as used (2014; 0.5% in leave-ons; 0.5% in rinse-offs) Sucrose Safe as used (2014; 58% in leave-ons; 65% in rinse-offs) 15 Trehalose Safe as used (2014; 2% in leave-ons; 1% in rinse-offs) 15 Xylose (Xylityl* is derived from the sugar alcohol Safe as used (2014; 0.11% in leave-ons; 1% in rinse-offs) 15 xylitol*, which is derived from the sugar Xylose) ACID Acetic Acid Safe as used (2012; 0.0004% in leave-ons; 0.3% in rinse-offs) 13 Benzoic Acid Safe as used (2011; 5% in leave-ons; 5% in rinse-offs) 11,12 Coconut Acid Safe as used (2011; not reported in leave-ons; 14% in rinse-offs) 10,14,63 Cottonseed Acid Safe as used (2011; no reported use) 14,25 Hydroxystearic Acid Safe as used (1999; 10% in leave-ons; not reported in rinse-offs) 9 Isostearic Acid Safe as used (1983; 10% leave-ons; 5% rinse-offs); Reaffirmed in 2005 7,8 Lauric Acid Safe as used (1987; 1% in leave-ons; 25% in rinse-offs); Reaffirmed 2006 5,6 Myristic Acid Safe as used (2010; 10% in leave-ons; 19% in rinse-offs) 4-6 Oleic Acid Safe as used (1987; 25% in leave-ons; 50% in rinse-offs); Reaffirmed in 2006 5,6 Palmitic Acid Safe as used (1987; 25% in leave-ons; 25% in rinse-offs); Reaffirmed in 2006 5,6 Soy Acid Safe as used (2011; no reported use) 14 Stearic Acid Safe as used (1987; 50% in leave-ons; 50% in rinse-offs); Reaffirmed in 2006 5,6 *Not previously reviewed by the Panel

Table 4. Chemical and Physical Properties Property Value Reference Glucose Pentaacetate Molecular Weight (g/mol) 390.33 64 Density (g/ml) 1.30 ± 0.1a 65 Melting Point (°C) 130-131.5b 66 Water Solubility at pH 7, 25 °C Slightly soluble 65 Log P 0.634 ± 0.488a 65

Maltitol Laurate Molecular Weight (g/mol) 527a 67

Raffinose Isostearate Molecular Weight (g/mol) 3435a 67

Raffinose Myristate Molecular Weight (g/mol) 687a 67

Raffinose Oleate Molecular Weight (g/mol) 785.89 64

Sucrose Acetate Isobutyrate Physical Form Clear, pale yellow, viscous liquid 23 Molecular Weight (g/mol) 846.91 64 Density (g/ml) 1.22 ± 0.1a 65 Water Solubility Slightly soluble 23 Other Solubility Very soluble in essential oils (orange); soluble in ethanol, ethyl acetate 23 Log P 6.619 ± 0.825a 65

Sucrose Acetate/ Stearate Molecular Weight (g/mol) 651a 67

Distributed for Comment Only -- Do Not Cite or Quote

Table 4. Chemical and Physical Properties Property Value Reference

Sucrose Benzoate Molecular Weight (g/mol) 446a 67 Melting Point (°C) 98 (from patent) 68

Sucrose Dilaurate Molecular Weight (g/mol) 706.90 64

Sucrose Dipalmitate Molecular Weight (g/mol) 819a 67

Sucrose Distearate Molecular Weight (g/mol) 875.22 64 Melting Point (°C) 76-78b 69

Sucrose Hexaerucate Molecular Weight (g/mol) 2265a 67

Sucrose Hexapalmitate Molecular Weight (g/mol) 1772.75 64

Sucrose Laurate Molecular Weight (g/mol) 524.60 64 Water Solubility (mg/l) 42.37a 24

Sucrose Myristate Molecular Weight (g/mol) 569.66 64 Melting Point (°C) 180-186b 70

Sucrose Octaacetate Molecular Weight (g/mol) 678.59 64 Density (g/ml) 1.37 ± 0.1a 65 Melting Point (°C) 89-93b 71 Water Solubility (g/L) 0.909 (hygroscopic) 72 Other Solubility Very soluble in methanol, chloroform; soluble in ether 72 Log P 1.440 ± 0.812a 65

Sucrose Oleate Molecular Weight (g/mol) 607a 67 Melting Point (°C) 54-56b 69

Sucrose Palmitate Molecular Weight (g/mol) 552a 67

Sucrose Pentaerucate Molecular Weight (g/mol) 1945a 67

Sucrose Pentahydroxystearate Molecular Weight (g/mol) 2039a 67

Sucrose Polybehenate Physical Form at 20°C, 760 mmHg White waxy solid 19 Density (g/ml) at 72 °C 900-950 19 Melting Point (°C) 72 19 Water Solubility at 24 °C (g/L) ≤ 4.26 x 10-5 19 Log Pow (n-octanol/water) at 20 °C 3.55 ± 0.16 19

Sucrose Polycottonseedate Physical Form Amber, viscous liquid 20 Density at 71 °C (g/L) 900-950 20 Water Solubility at 24 °C (g/L) 4.96 x 10-6 to 4.26 x 10-5 20 Log Pow (n-octanol/water) at 20 °C 3.55 ± 0.16 20

Sucrose Stearate Molecular Weight (g/mol) 608.76 64 Melting Point (°C) 67-71b 73

Distributed for Comment Only -- Do Not Cite or Quote

Table 4. Chemical and Physical Properties Property Value Reference Sucrose Tetrahydroxystearate Molecular Weight (g/mol) 1472a 67

Sucrose Tetraisostearate Molecular Weight (g/mol) 1408a 67

Sucrose Tetrastearate Triacetate Molecular Weight (g/mol) 1534a 67

Sucrose Tribehenate Molecular Weight (g/mol) 1310a 67

Sucrose Trilaurate Molecular Weight (g/mol) 889.20 64 Water Solubility (mg/l) 1.35 x 10-12 a 24

Sucrose Tristearate Molecular Weight (g/mol) 1141.68 64

Trehalose Undecylenoate Molecular Weight (g/mol) 509a 67

Xylityl Sesquicaprylate Molecular Weight (g/mol) 278.34c 65 Density (g/ml) 1.17 ± 0.06c 65 Water Solubility at pH 7, 25 °C Slightly solublec 65 Log P 1.387 ± 0.735c 65 acomputational bmeasured ccomputational, calculated from a mono-caprylate-substituted Xylityl moiety

Distributed for Comment Only -- Do Not Cite or Quote

Table 5. Current frequency and concentration of use of saccharide esters according to duration and exposure3,26 # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) Maltitol Laurate Sucrose Acetate Isobutyrate Sucrose Acetate Stearate Totals* 1 NR 274 0.0084-31 2 0.3 Duration of Use Leave-On NR NR 273 0.0084-31 2 0.3 Rinse-Off 1 NR 1 0.1 NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 22 0.5-31 2 NR Incidental Ingestion NR NR 18 0.41-27 NR NR Incidental Inhalation-Spray NR NR spray: 2 NR NR NR possible: 1b Incidental Inhalation-Powder NR NR powder: 1 NR NR possible: 0.3c possible: 1b Dermal Contact NR NR 41 0.5-31 2 0.3 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR 210 0.0084-9 NR NR Mucous Membrane NR NR 18 0.41-27 NR NR Baby Products NR NR NR NR NR NR Sucrose Benzoate Sucrose Cocoate Sucrose Dilaurate Totals* 48 0.21-14.3 139 0.0001-20.6 13 0.00000004-0.45 Duration of Use Leave-On 48 1.4-14.3 91 0.0001-4 10 0.00000004-0.45 Rinse-Off NR 0.21 48 0.05-20.6 3 0.18 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 8 NR 2 0.00000004 Incidental Ingestion NR NR 14 0.0001-0.98 NR 0.013 Incidental Inhalation-Spray NR NR possible: 30a; 12b possible: 0.12a possible: 6b NR Incidental Inhalation-Powder NR NR powder: 1 possible: 0.05-4c possible: 6b possible: 0.17-0.45c possible: 12b Dermal Contact NR 0.21 121 0.05-20.6 13 0.00000004-0.45 Deodorant (underarm) NR NR 11a not spray: 0.49 NR NR Hair - Non-Coloring NR NR 4 0.05-0.12 NR NR Hair-Coloring NR NR NR NR NR NR Nail 48 1.4-14.3 NR NR NR NR Mucous Membrane NR NR 29 0.0001-1.3 NR 0.013 Baby Products NR NR 1 NR NR NR Sucrose Dipalmitate Sucrose Distearate Sucrose Hexaoleate/ Hexapalmitate/ Hexastearate Totals* 1 NR 67 0.0003-5.5 NR 5 Duration of Use Leave-On NR NR 63 0.0003-5.5 NR 5 Rinse-Off 1 NR 4 1.1 NR NR Diluted for (Bath) Use NR NR NR 0.011 NR NR Exposure Type Eye Area NR NR 20 1-5.5 NR NR Incidental Ingestion NR NR 1 0.57-1.8 NR NR Incidental Inhalation-Spray NR NR possible: 11a; 25b possible: 1.2a NR NR Incidental Inhalation-Powder NR NR possible: 25b powder: 0.015 NR NR possible: 0.5-2c Dermal Contact 1 NR 51 0.0003-2 NR 5 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR 1 1.2 NR NR Hair-Coloring NR NR NR 1.1 NR NR Nail NR NR 2 NR NR NR Mucous Membrane NR NR 2 0.011-1.8 NR NR Baby Products NR NR NR NR NR NR

Distributed for Comment Only -- Do Not Cite or Quote

Table 5. Current frequency and concentration of use of saccharide esters according to duration and exposure3,26 # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) Sucrose Laurate Sucrose Myristate Sucrose Palmitate Totals* 42 0.0003-3 3 0.1-6 74 0.000012-3 Duration of Use Leave-On 28 0.0003-3 NR 6 60 0.000012-3 Rinse-Off 12 0.05-3 3 0.1-0.3 14 0.00004-3 Diluted for (Bath) Use 2 NR NR NR NR 0.008 Exposure Type Eye Area 4 0.0003-3 1 NR 7 0.000012-3 Incidental Ingestion 1 0.05-0.1 NR 0.1 NR 0.02 Incidental Inhalation-Spray spray: 1; spray: 0.6-1.2 NR possible: 0.1a spray: 1; possible: 0.0004a possible: 3a; 12b possible: 0.05a possible: 11a; 32b Incidental Inhalation-Powder powder: 1; possible: 0.05-3c NR NR powder: 1 powder: 0.008 possible: 12b possible: 32b possible: 0.0008- 1.5c Dermal Contact 40 0.0003-3 3 6 70 0.000012-3 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 0.05-1.5 NR 0.3 4 0.00004-0.05 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR 0.00002 Mucous Membrane 6 0.05-1 NR 0.1 NR 0.008-0.02 Baby Products 3 NR NR NR 3 NR Sucrose Palmitate/Stearate** Sucrose Polybehenate Sucrose Polycottonseedate Totals* 1 NR 2 1-6 23 0.5-87.7 Duration of Use Leave-On 1 NR 2 1-6 22 0.5-87.7 Rinse-Off NR NR NR NR 1 2.8 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 1 4 3 1-1.5 Incidental Ingestion NR NR NR 6 4 87.7 Incidental Inhalation-Spray possible: 1b NR NR spray: 1 possible: 8a; 6b NR Incidental Inhalation-Powder possible: 1b NR NR NR possible: 6b possible: 1c Dermal Contact 1 NR 1 1 19 0.5-2.8 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR 6 4 87.7 Baby Products NR NR NR NR NR NR Sucrose Polylaurate Sucrose Polyoleate Sucrose Polysoyate Totals* 1 0.01-0.039 1 NR 19 0.51-4.9 Duration of Use Leave-On 1 0.01-0.039 NR NR 19 0.51-4.9 Rinse-Off NR NR 1 NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR 4.9 Incidental Inhalation-Spray possible: 1a NR NR NR 17a; 2b NR Incidental Inhalation-Powder NR possible: 0.01- NR NR 2b NR 0.039c Dermal Contact 1 0.01-0.039 NR NR 19 0.51-1 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR 1 NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR 4.9 Baby Products NR NR NR NR NR NR

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Table 5. Current frequency and concentration of use of saccharide esters according to duration and exposure3,26 # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) # of Uses Max Conc Use (%) Sucrose Polystearate Sucrose Stearate Sucrose Stearate-Palmitate Ester** Totals* 16 0.7-6 156 0.0001-6 2 NR Duration of Use Leave-On 16 1-6 126 0.0001-6 2 NR Rinse-Off NR 0.7 30 0.04-3 NR NR Diluted for (Bath) Use NR NR NR 0.069 NR NR Exposure Type Eye Area 1 1-6 32 0.0003-6 NR NR Incidental Ingestion 3 1-2.5 1 0.079-0.2 NR NR Incidental Inhalation-Spray possible: 3a; 1b NR spray: 1 possible: 0.2-2.2a NR NR possible: 29a; 49b Incidental Inhalation-Powder powder: 3 possible: 1.7c powder: 1 possible: 0.013- powder: 2 NR possible: 1b possible: 49b 3.9c

Dermal Contact 12 1-1.7 137 0.0003-6 2 NR Deodorant (underarm) NR NR NR spray: 0.23 NR NR not spray: 0.45 Hair - Non-Coloring NR NR 3 0.3-2.2 NR NR Hair-Coloring NR 0.7 NR NR NR NR Nail NR NR 3 0.0001 NR NR Mucous Membrane 3 1-2.5 3 0.069-0.2 NR NR Baby Products NR NR 4 NR 2 NR Sucrose Tetraisostearate Sucrose Tetrastearate Triacetate Sucrose Trilaurate Totals* 3 0.01-5 61 0.0086-15 2 0.004 Duration of Use Leave-On 3 0.01-5 61 0.0086-15 2 0.004 Rinse-Off NR NR NR 10 NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 3 0.01-5 38 0.55-15 2 NR Incidental Ingestion NR 1 7 0.0086-10 NR 0.004 Incidental Inhalation-Spray NR NR possible: 2a NR NR NR Incidental Inhalation-Powder NR NR NR possible: 1-2c NR NR Dermal Contact NR 0.01-5 49 0.5-10 2 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR 1 7 0.0086-10 NR 0.004 Baby Products NR NR NR NR NR NR Sucrose Tristearate Trehalose Isostearate Esters Trehalose Undecylenoate Totals* 19 0.38-2 NR 0.5 NR 0.0005-0.25 Duration of Use Leave-On 17 0.38-2 NR 0.5 NR 0.05 Rinse-Off 2 NR NR NR NR 0.0005-0.25 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion 1 0.38-0.75 NR NR NR NR Incidental Inhalation-Spray possible: 9a; 6b NR NR NR NR possible: 0.05a Incidental Inhalation-Powder possible: 6b powder: 2 NR NR NR NR possible: 2c Dermal Contact 18 0.5-2 NR 0.5 NR 0.0005 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR 0.05-0.25 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 1 0.38-0.75 NR NR NR 0.0005 Baby Products NR NR NR NR NR NR *Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses **Although structurally Sucrose Stearate-Palmitate Ester and Sucrose Palmitate/Stearate have the same definition they are listed separately here because VCRP data for each is individually recited a Includes products that can be sprays, but it is not known whether the reported uses are sprays b Not specified whether this product is a spray or a powder or neither, but it is possible it may be a spray or a powder, so this information is captured for both categories of incidental inhalation c Includes products that can be powders, but it is not known whether the reported uses are powders NR – no reported use

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Table 6. Ingredients not currently reported to be in use3 Glucose Pentaacetate Sucrose Hexapalmitate Sucrose Polylinoleate Raffinose Isostearate Sucrose Octaacetate Sucrose Tetrahydroxystearate Raffinose Myristate Sucrose Oleate Sucrose Tribehenate Raffinose Oleate Sucrose Pentaerucate Xylityl Sesquicaprylate Sucrose Hexaerucate Sucrose Pentahydroxystearate

Table 7. Non-Cosmetic Uses Ingredient Non-Cosmetic Use References Glucose Pentaacetate Direct food additive, synthetic flavoring substance 21CFR172.515; 74 Sucrose Acetate Isobutyrate Direct food additive, stabilizer of flavoring oil emulsions used in 21CFR172.833; nonalcoholic beverages, Sucrose Acetate Isobutyrate content in beverage ≤ 21CFR175.105; 17; 75; 76 300 mg/kg of finished beverage; indirect food additive-component of adhesives; GRAS-as a stabilizer of flavoring oil emulsions used in alcoholic beverages; FDA established ADI (acceptable daily intake) up to 20 mg/kg/day; WHO established ADI up to 20 mg/kg/day Sucrose Benzoate Indirect food additive-component of adhesives; FDA reported cumulative 21CFR175.105; 77 estimated daily intake 0.00035 mg/kg/day Sucrose Cocoate, Sucrose Dilaurate, Direct food additive-multipurpose additives, sucrose fatty acid esters 21CFR172.859 Sucrose Distearate Sucrose Hexaerucate, Sucrose Direct food additive-multipurpose additives, Sucrose Oligoesters 21CFR172.869 Hexaoleate/Hexapalmitate/Hexastearate, Sucrose Hexapalmitate Sucrose Laurate, Sucrose Myristate Direct food additive-multipurpose additives, sucrose fatty acid esters 21CFR172.859 Sucrose Octaacetate Direct food additive; synthetic flavoring substance; indirect food additive- 74; 21CFR172.515; component of adhesives; drug product containing active ingredients 21CFR175.105; offered OTC as nail-biting/thumb-sucking deterrent, however, due to the 21CFR310.536 lack of safety data in this application Sucrose Octaacetate is not GRAS in OTC drug products used as nail-biting/thumb-sucking deterrents Sucrose Oleate, Sucrose Palmitate Direct food additive-multipurpose additives, sucrose fatty acid esters 21CFR172.859 Sucrose Pentaerucate Direct food additive-multipurpose additives, Sucrose Oligoesters 21CFR172.869 Sucrose Stearate Direct food additive-multipurpose additives, sucrose fatty acid esters 21CFR172.859 Sucrose Tetrahydroxystearate, Sucrose Direct food additive-multipurpose additives, Sucrose Oligoesters 21CFR172.869 Tetraisostearate Sucrose Tribehenate, Sucrose Trilaurate, Direct food additive-multipurpose additives, sucrose fatty acid esters 21CFR172.859 Sucrose Tristearate

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Table 8. Penetration Enhancement Studies Test Substance(s) Species/ Sample Concentration/ Exposure Procedure Results Reference Strain Type/Test Dosage (Vehicle) Route Population-Sex IN VITRO Sucrose Laurate Mouse Full-thickness Aqueous, 1.5% Stratum At time zero 0.5 ml of lidocaine solution For lidocaine with 1.5% Sucrose Laurate, 37 (mono- 81%; di-, tri-, dorsal skin excised Sucrose Laurate at corneum (1 (varying pH’s) containing either 0 or 1.5% permeability coefficient increased up to pH poly- 19%) from female mice pH 6, 7, 8, 10 cm2) mounted Sucrose Laurate was applied to skin, 8; permeability coefficients at pH 6 and 7 on flow- receptor fluid collected hourly for 6 h, with Sucrose Laurate were larger than through teflon negative controls used controls; at low lidocaine concentrations, diffusion cell Sucrose Laurate increased permeation rate at pH 6; for saturated lidocaine solutions at low pH, Sucrose Laurate was a potent percutaneous absorption enhancer but, at high pH Sucrose Laurate had almost no effect on permeation; permeation rate at pH 8 or 10 decreased due to interaction of unionized lidocaine with Sucrose Laurate micelles not participating in permeation Sucrose Laurate Yucatan Skin oil-in-water Skin (0.83 cm2 Skin was exposed to microemulsion Sucrose Laurate (surfactant component in 39 Micropig microemulsion diffusion area) containing polyphenols (chlorogenic the microemulsion) enhanced skin containing Sucrose mounted in acid/resveratrol), buffered for 6, 20, and 40 incorporation of polyphenols at 6, 20, 40 h Laurate used for drug Franz-type h then assayed; for comparison a in epidermis and at 20 and 40 h in dermis; delivery; diffusion (37°C microemulsion containing polyoxyethylene hydrophilic polyphenol distributed slightly composition ratio water jacket), 2- sorbitan monooleate (Tween 80) as the more in epidermis, and hydrophobic (small 25:19:5:60, Sucrose h pretreatment surfactant and no Sucrose Laurate was also molecular weight) polyphenol distributed Laurate:ethanol:iso- with 150 mM evaluated mainly in dermis; rapid distribution from propyl NaCl microemulsion to epidermis, but slower myristate:water distribution from epidermis to dermis

Sucrose Laurate Rat (ICO: Hairless female 5 g cyclosporin A Skin samples 100-µL receptor-fluid samples taken at 4, 8, Skin penetration rate of cyclosporine A was 38 OFA) rats, abdominal was dissolved in 100 (2.54 cm2 24, 28, 32 and 48 h and replaced by 0.153 µg/ml·h in Sucrose Laurate solution; and dorsal skin (4 ml of 30% Sucrose diffusion area) equivalent saline/methanol solution; at 48 h Sucrose Laurate exhibited intermediate skin samples; 35-mm Laurate (aqueous) mounted in skin removed from cell and stratum penetration enhancing properties; efficacy diameter; Franz-type corneum tape-stripped 15x; remaining skin experiment performed with cyclosporine A subcutaneous fat diffusion cell was homogenized and assayed; negative dissolved in Sucrose Laurate formulations removed); dermis (32°C water controls were used (i.e., 2% Sucrose Laurate in micellar and epidermis skin jacket) solution or 2% Sucrose Laurate in hydrogel) thickness 0.30- demonstrated that Sucrose Laurate is an 0.35 mm effective dermal penetration enhancer for hydrophilic substances

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Table 8. Penetration Enhancement Studies Test Substance(s) Species/ Sample Concentration/ Exposure Procedure Results Reference Strain Type/Test Dosage (Vehicle) Route Population-Sex Sucrose Laurate and Human RPMI 2650 Variable between Cells cultured Cells treated and transepithelial electrical Sucrose Laurate and Sucrose Myristate 40 Sucrose Myristate human nasal 0.01 and 3 mg/ml in Transwell resistance measured; paracellular showed a substantial transepithelial epithelial cells filter inserts permeability experiments performed using electrical resistance (characterizing the (cells used to fluorescein isothiocyanate labelled dextran permeability of tight junctions for sodium model as a marker across epithelial cells; positive ions in cell cultures) decrease at 0.1 mg/ml absorption from and negative controls were used and irreversible drop at 0.3 mg/ml; the respiratory substantial enhancement of paracellular zone of human permeability of nasal epithelial cell layers, nasal effects were dose-dependent epithelium, limitations include no cilia and no air- liquid interface) Sucrose Stearate Pig Skin Nanoemulsions (used Hair-free Receptor chamber filled with phosphate Sucrose Stearate was shown to be an 78 for dermal drug porcine skin buffer; diffusion cells at 32°C for 24 h then emulsifier with physical and chemical delivery); 2.5% w/w (area 1.13 cm2) 0.6 g of nanoemulsion (mixture of aqueous stability; pH decreased with increasing Sucrose Stearate in treated with and oil phase described) placed on skin in Sucrose Stearate concentrations due to aqueous phase dermatome (1.2 donor chamber; 200 µL samples removed residual, non-esterified fatty acids (up to w/hydrophilic drugs mm), frozen, from the receptor chamber at intervals for 10%, based on manufacturer supplied info); (fluconazole and thawed; skin analysis (of drug content) and replaced by drug permeation enhancement comparable minoxidil); lecithin patches fresh receptor medium; lecithin emulsions to that of lecithin-based emulsions in oil-phase clamped were used as a comparison to Sucrose w/lipophilic drugs between donor Stearate emulsions; controls without drugs (fludrocortisone and receptor were used, but no controls without Sucrose acetate and chambers of Stearate were used flufenamic acid) Franz-type diffusion cells Sucrose Stearate Pig Abdominal skin Nanoemulsions (used Hair-free Receptor chamber filled with propylene Sucrose Stearate was a skin permeation 41 for dermal drug porcine skin glycol/ water; diffusion cells at 32°C for 48 enhancer for progesterone and helped to delivery); 1% w,w (area 1.13 cm2) h then 0.6 g of nanoemulsion (mixture of stabilize the nanoemulsion Sucrose Stearate in treated with aqueous and oil phase described) placed on aqueous phase with dermatome (1.2 skin in donor chamber; 200 µL samples cyclodextrin; mm), frozen, removed from the receptor chamber at tocopherol, thawed; skin intervals for analysis (of drug content) and phytosphingosine, patches replaced by fresh receptor medium; and progesterone in clamped negative controls used oil phase between donor and receptor chambers of Franz-type diffusion cells ANIMAL

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Table 8. Penetration Enhancement Studies Test Substance(s) Species/ Sample Concentration/ Exposure Procedure Results Reference Strain Type/Test Dosage (Vehicle) Route Population-Sex Sucrose Laurate Mouse 15-wk old male Sucrose Laurate Dermal Tape-stripping (up to 18x) used to collect Minimal changes in lipid and protein 42 (SKH-1 mice (unknown corneocytes from uppermost layer of dorsal structure of stratum corneum observed; hairless concentration) in skin 30 min post treatment; negative stratum corneum took up lipophilic mice) hydrogel containing controls used hydrocarbon components of the gel; 5% ibuprofen biopsies from skin treated with 5% and 15% showed increased eosinophils, lymphocytes and polymorphonuclear cells compared to untreated skin; Sucrose Laurate gel increased skin hydration and penetration of ibuprofen Sucrose Laurate Rabbit Male rabbits, n=9 5% and 15%, w/w Dermal Rabbits fasted 24 h pre-treatment and Bioavailability parameters were 43 (White Sucrose Laurate in during treatment; 100 mg gels were applied substantially higher after single application New hydrophilic gels (also on days 1 and 7 to hairless (shaved) 3x3 cm of oestradiol with 15% compared to Zealand) containing 60 µg skin area; days 2-6 placebos applied; blood oestradiol with 5%; epidermal skin-fold oestradiol and a samples taken from marginal ear vein 0.5 thickness and infiltration was observed with preservative), pH 6 thru 12 h post administration; skin biopsies 5% and 15%; elevated levels of eosinophils, (taken from application site and untreated lymphocytes and polymorphonuclear cells skin) evaluated for epidermal thickness; were observed in biopsy samples of skin negative controls used exposed to 5% and 15% compared to controls; multiple applications with 5% and 15% showed decreased penetration- enhancing effect compared to single application; results indicate that Sucrose Laurate is a percutaneous absorption enhancer Sucrose Laurate Rat Male rats, n=25 0.5% Sucrose Nasal in situ nasal perfusion technique performed: Intranasal absorption-enhancing effect 44 (Sprague – (in vivo study) Laurate (solution trachea of anesthetized rats cannulated, tube (increasing with time and concentration); Dawley) contained varying inserted through esophagus into posterior of absolute drug bioavailability of 30% (in amounts of drug nasal cavity, drug solution containing vivo rat experiment) sumatriptan Sucrose Laurate circulated, aliquots succinate) removed up to 2 h; positive and negative controls were used in vivo studies performed by microsyringe administration into nasal cavity and IV administration (drug only) via tail vein, blood samples collected 2 h post-dosing; negative controls used

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Table 8. Penetration Enhancement Studies Test Substance(s) Species/ Sample Concentration/ Exposure Procedure Results Reference Strain Type/Test Dosage (Vehicle) Route Population-Sex Sucrose Cocoate, Rat Male, For nasal Nasal, Ocular Dose was administered for nasal exposure sucrose monodecanoate was found to be the 45 sucrose (Sprague- formulations 0.125%, via a pipetter; IV (drug only) through right predominant sucrose ester in Sucrose n=3-6/experiment monodecanoate, Dawley) 0.25%, or 0.5% femoral vein of anesthetized rats; through Cocoate; plasma concentrations of insulin sucrose Sucrose Cocoate ocular exposure via pipetter in left eye of after nasal exposure to Sucrose Cocoate monododecanoate, containing either anesthetized rat; negative controls used concentrations of 0.125% to 0.5% increased sucrose insulin or calcitonin; (not linearly, i.e. physiological response to monotridecanoate, ocular formulation Following administration of Sucrose insulin has an effect maximum) compared sucrose 0.5% Sucrose Cocoate solution blood glucose and insulin to controls; Sucrose Cocoate increased monotetradecanoate Cocoate w/insulin or levels were monitored absorption of insulin through the ocular calcitonin; vehicle route from 5µU/ml to 59 µU/ml (0.5% (aqueous ethanol Sucrose Cocoate); nasal absorption of solution) insulin with Sucrose Cocoate caused larger increase in plasma insulin levels (9x) than ocular delivery of the same insulin concentration (4x); similar effect observed for calcitonin nasal vs. ocular absorption; sucrose esters with acyl chains of C12-C14 were most effective nasal peptide- absorption enhancers HUMAN Sucrose Palmitate Human Healthy, female Nanoemulsions:oil Dermal Tape-Stripping Study: Nanoemulsions (25 2% Sucrose Palmitate (hydrophilic), 0.5% 46 (80% mono-, 17% subjects, n=4 phase- (drug µL/cm2) applied to 4 cm2 forearm surface Sucrose Stearate (intermediate di-, 3% tri-), Sucrose (tape-stripping aceclofenac), 1-2% area for 2 h, after which residual test lipophilicity), and 1.5% egg lecithin were Stearate (48% mono- study) (w/w) egg lecithin, substance removed, tape-stripping superior in in vivo tape-stripping for , 34% di-, 14% tri-) 10% medium chain performed at least 12x; negative controls increasing skin absorption of aceclofenac; triglycerides, 10% used aceclofenac detected at all depths into Castor oil, 0.05% stratum corneum compared to controls (this butylhydroxy- attributed to small droplet size/ large toluene; surface area for close and prolonged skin aqueous phase- contact; lipid bilayer perturbation observed 0-2% (w/w) Sucrose in stratum corneum from phospholipids and Palmitate; 0-2% sucrose esters) (w/w) Sucrose Stearate Sucrose Oleate, Human Healthy, female 2% or 10% Sucrose Dermal Test formulation (1.5 ml) applied via filter Sucrose Oleate and Sucrose Laurate 47 Sucrose Laurate subjects, n=6 Oleate, 2% or 10% paper (11.5 x 4.5 cm), affixed to skin with increased 4-hydroxy-benzonitrile Sucrose Laurate in occlusive film for 1 h, then filter paper penetration vs. control (2% Sucrose Laurate Transcutol; 4- removed and skin cleaned; Transepidermal with Transcutol synergistically increased hydroxy-benzonitrile water loss measured up to 4 h post admin; penetration the most); C-H asymmetric and (drug evaluated) Penetration of 4-hydroxy-benzonitrile symmetric stretching bands of lipid evaluated by tape-stripping tests in a similar methylene groups showed decreases in experiment as above (including absorption and frequency shifts to higher pretreatment of skin with Sucrose Oleate wave numbers, temporarily altering stratum and Sucrose Laurate for 1 h); negative corneum barrier properties to increase controls used penetration; no sustained increase in water loss from test formulation

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species/ Sample Concentration/ Dosage Procedure Results Reference Strain Type/Test (Vehicle) Population-Sex IN VITRO Sucrose Palmitate Rat (Wistar) Male rats, three Intestinal Absorption Studies: Intestinal absorption studies- bicarbonate buffer 1 h after incubation 14C-sucrose esters 48 (mono-) and 10-cm segments 1 µmol/ml 14C-sucrose esters solutions were incubated for 1 h; serosal fluid, concentrations decreased and sucrose, Sucrose Stearate of rat small mucosal fluid and tissue were assayed for stearic acid, and palmitic acid Pancreatic Fluid Hydrolysis: (mono-, di-); intestine used to radioactivity; no controls used concentrations increased showing that 2mM 14C-sucrose esters >95% purity prepare everted substantial hydrolysis occurred; Artificial Pancreatic Fluid Hydrolysis-artificial 14 sacs; also used in Liver and Mucosa Hydrolysis: substantial amount of C-sucrose esters pancreatic fluid aliquots were removed at 0, 0.5, 1, 2, this study were 20 mM 14C-sucrose esters were absorbed into intestinal tissues; and 4 h and assayed; no controls used 14 rat liver there was no notable transport of C- Whole Blood Hydrolysis: 5 homogenates, Hydrolysis by Liver Homogenates and Intestinal labeled sucrose esters from mucosal to mM 14C-sucrose esters intestinal mucosa Mucosa- incubation for up to 4 h for liver serosal solution via intestinal tissues; homogenates, (in the above experiments a homogenates and 1 h for mucosal homogenates; no enzymes in intestinal mucosal more artificial mixture of 14C-sucrose esters controls used important in hydrolysis of sucrose esters pancreatic fluids, was used, radiolabels were on than enzymes in digestive fluid Hydrolysis by Whole Blood-performed by adding 1 and whole blood sucrose or on the ester portion of 14 ml of 5 mM C-sucrose esters to buffered solution of Rate of hydrolysis by mucosal the molecule) blood and incubated up to 1 h and assayed; no homogenates was faster than by artificial controls used pancreatic juice; in 10 min hydrolysis of 10% administered radioactivity of Sucrose Mono-Stearate (radiolabel on sucrose) and 30% administered radioactivity of Sucrose Mono-Palmitate (radiolabel on ester); in 30 min hydrolysis of 9% administered radioactivity of Sucrose Mono-Stearate (radiolabel on ester) and 15% of Sucrose Mono-Palmitate (radiolabel on ester) In 1 h liver homogenates hydrolyzed 20% of Sucrose Mono-Stearate or Sucrose Mono-Palmitate (location of radiolabel not specified) In 1 h hydrolysis of 14C-sucrose esters in whole blood showed 10% of Sucrose Mono-Palmitate and 2.4% of Sucrose Mono-Stearate (location of radiolabel not specified) Sucrose Acetate Rat (Wistar) Both sexes; 10 mg/ml 14C-Sucrose Acetate Rat homogenates of the gut contents, liver, and 14C-Sucrose Acetate Isobutyrate was 49 Isobutyrate homogenates of Isobutyrate (gut content intestinal mucosa were prepared and assayed; hydrolyzed (under anaerobic conditions) gut contents, homogenates); 25 or 250 negative controls used by intestinal homogenates (75% of liver, and µg/ml 14C-Sucrose Acetate administered radioactivity in 6 h); intestinal mucosa Isobutyrate (liver/ intestinal intestinal mucosa hydrolyzed (under mucosa homogenates) aerobic conditions) 14C-Sucrose Acetate Isobutyrate greater than liver (Radiolabel on the sucrose) homogenates, presence of low molecular weight esters increased as hydrolysis progressed; little hydrolysis in stomach

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species/ Sample Concentration/ Dosage Procedure Results Reference Strain Type/Test (Vehicle) Population-Sex Sucrose Acetate Human fecal homogenate 0.1 or 1 mg/ml 14C-Sucrose Human fecal homogenates were prepared and 40% administered radioactivity (1 mg/ml) 49 Isobutyrate Acetate Isobutyrate (fecal assayed; human feces bacteria cultured, hydrolysis was hydrolyzed by fecal homogenates in homogenates); 100 µg/ml 14C- was measured; negative controls used 16 h (< 2% administered radioactivity was Sucrose Acetate Isobutyrate hydrolyzed completely to sucrose); 60% (bacteria isolated from human administered radioactivity (0.1 mg/ml) feces) was hydrolyzed by fecal homogentates (5% completely de-esterified) in 16 h; 2 (Radiolabel on the sucrose) strains each of E. coli, Streptococcus and Bacteroides and 1 strain of bifidobacteria resulted in > 15% hydrolysis of 14C- Sucrose Acetate Isobutyrate in 20 h (many E. coli and Lactobacillus strains yielded < 5% hydrolysis) ANIMAL Oral Glucose Rat (Wistar) Male rats, Aqueous non-radioactive 20% Intestinal Absorption Study-rats were dosed (2-ml, Gastrointestinal tract absorption is rapid (> 50 Pentaacetate fasted prior to Glucose Pentaacetate (intestinal single) and at time intervals of ½, 1, 2, and 4 h were 90% in 4 h when measured by glucose and dosing; n=37 absorption study); 10% killed and gastrointestinal tract analyzed by just under 90% in 4 h when measured by total for all radioactive Glucose Pentaacetate saponification to determine residual Glucose acetate); 2% of radioactivity recovered studies (repeated-dose study, label on Pentaacetate amounts; negative controls used from feces at 48 h; radioactive equilibrium glucose); 10% radioactive by 7days; rats exposed to 10% Glucose Repeated Dose Retention Study-rats were dosed (1- Glucose Pentaacetate Pentaacetate for 2 yr excreted 76% of dose ml) daily for 2, 7, or 14 days then were killed and (metabolism study, label on (glucose labeled) as radiolabeled CO carcass assayed for radioactivity; no controls used 2 glucose in dosages administered compared to rats not previously exposed to some animals and label on Metabolism Study-rats were dosed (2-ml, single) and to Glucose Pentaacetate (excreted 65% of acetate for dosing in others) placed in a metabolic chamber where a continuous dose, glucose labeled, as radiolabeled radioactive gas analyzer recorded specific activity and CO2); Glucose Pentaacetate is hydrolyzed 14 integrated total CO2 for 48 h post-dosing; urine and to lesser acetylated metabolites which are feces collect during this 48 h period; no controls used detected in urine

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14 48 Sucrose Palmitate Rat (Wistar) Male rats fasted Excretion Study: 100 or 250 Excretion Study: single dosage, CO2, urine, feces Within 120 h post-dosing 30% (Sucrose (mono-) and prior to dosing mg/kg 14C-sucrose esters (water were analyzed for radioactivity; negative controls Mono-Stearate with label on sucrose) to Sucrose Stearate vehicle) with the radiolabel on used 67% (Sucrose Di-Stearate with label on (mono-, di-); >95% sucrose or on either the di-stearate) 14C-sucrose esters were Absorption Via Mesenteric Lymphatic System: purity palmitate or stearate; in some excreted in feces and 11% (Sucrose Di- performed by cannulating thoracic ducts of animals only radiolabeled Stearate with label on di-stearate) to 49% anaesthetized rats, fasting then dosing (single) rats, sucrose, radiolabeled stearic acid (Sucrose Mono-Stearate with label on lymph collected at 2, 4, 6, 10, 24 h; negative controls or radiolabeled palmitic acid sucrose) of dosed radioactivity exhaled; used were administered urinary excretion of radioactivity was 14 Absorption Via Portal System: single dosage, blood 0.7% (Sucrose Di-Stearate with label on Lymph Study: 250 mg/kg C- samples from portal and femoral veins taken at 1, 2, di-stearate) to 4.9% (Sucrose Mono- sucrose esters (water vehicle) and 4 h then assayed for radioactivity; no controls Stearate with label on sucrose) of the with the radiolabel on sucrose in used dosage; no intact sucrose ester was found Sucrose Mono-Stearate, on in the urine mono-stearate in Sucrose Mono- Stearate, on di-stearate in Little intact Sucrose Stearate was Sucrose Di-Stearate, on mono- transported from the intestinal tract to palmitate in Sucrose Mono- lymph (1.8% recovery of Sucrose Mono- Palmitate; in some animals only Stearate with label on sucrose, compared radiolabeled sucrose (140 to 20% recovery of Sucrose Mono- mg/kg, water vehicle) or Stearate with label on mono-stearate); radiolabeled stearic acid (117 sucrose esters were hydrolyzed to yield mg/kg, coza oil vehicle) were sucrose and fatty acids that were administered transferred from the intestine to lymph Portal System Study: 250 No intact sucrose esters were detected in mg/kg 14C-sucrose esters with blood the radiolabel on sucrose in

Sucrose Mono-Stearate, radiolabel on the mono-stearate in Sucrose Mono-Stearate, or radiolabel on mono-palmitate in Sucrose Mono-Palmitate Sucrose Rat (Fischer Male rats, n=3 200 mg/kg 14C-Sucrose Animals fasted prior to dosing; single dosage (by 3%-15% of radioactivity was excreted as 52 Octaisobutyrate-(a 344) (metabolism Octaisobutyrate (label on gavage); rats placed in metabolism cages for 5 days volatile products, 1%-2% of radioactivity component of studies) and sucrose) post-dosing; food available ad lib.; collections from was excreted in urine, 78%-93% of Sucrose Acetate n=3 (blood expired air traps to measure CO2 were made at 2, 4, 6, radioactivity was excreted in feces; peak Isobutyrate) study) 8, 10, 12, and 24 h and at successive 12 h intervals for excretion (in 14CO2, urine, and feces) of 5 days post-dosing; urine and feces were collected at radioactivity was 24-36 h post-dosing 4, 8, 12, 24 h intervals for 5 days post-dosing; bile suggested delayed absorption, < 0.2% collected (through catheter) 2-6 h intervals for 48 h excreted in bile, evidence of extensive gut post-dosing, and blood analysis (collected from hydrolysis; no radioactivity found in abdominal aorta) was performed 2, 4, 8, 12, and 24 h whole blood or plasma post-dosing post-dosing; no controls used

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14 14 52 Sucrose Dog (Beagle) male dogs, n=3 200 mg/kg C-Sucrose Animals fasted prior to dosing; single dosage (by ≤1% radioactivity in CO2, < 2% in urine, Octaisobutyrate-(a Octaisobutyrate (label on gavage); dogs placed in metabolism cages for 5 days 77%-94% in feces, 2%-10% in bile; no component of sucrose) post-dosing and fed 2x/day; collections from expired radioactivity recovered as volatile Sucrose Acetate air traps to measure CO2 were made at 2, 4, 6, 8, 10, products within 24 h of treatment Isobutyrate) 12, and 24 h and at successive 12 h intervals for 5 indicating a slow absorption rate, less days post-dosing; urine and feces were collected at 4, extensive hydrolysis in gut; no 8, 12, 24 h intervals for 5 days post-dosing; bile radioactivity found in whole blood or collected (through catheter) 2-6 h intervals for 48 h plasma post-dosing post-dosing, and blood analysis (collected from a saphenous vein) was performed 2, 4, 8, 12 h and longer intervals post-dosing; no controls used Sucrose Monkey male monkeys, 200 mg/kg 14C-Sucrose Animals fasted prior to dosing; single dosage (by 62%-85% radioactivity excreted in feces, 52 14 Octaisobutyrate-(a (Cynomolgus) n=3 Octaisobutyrate (label on gavage); monkeys placed in metabolism cages for 5 < 2% radioactivity eliminated in CO2, ≤ component of sucrose) days post-dosing and fed 2x/day; collections from 1% radioactivity recovered in urine, not Sucrose Acetate expired air traps to measure CO2 were made at 2, 4, 6, hydrolyzed in gut or absorbed, 0.1%-0.2% Isobutyrate) 8, 10, 12, and 24 h and at successive 12 h intervals for radioactivity excreted in bile, little 5 days post-dosing; urine and feces were collected at intestinal metabolism occurred; no 4, 8, 12, 24 h intervals for 5 days post-dosing; bile radioactivity found in whole blood or collected (through catheter) 2-6 hr intervals for 48 h plasma post-dosing post-dosing, and blood analysis (collected from a saphenous or radial vein) was performed 4, 8, 12, 24, 36, and 48 h post-dosing; no controls used Sucrose Acetate Rat (Wistar) Both sexes 50 mg/kg 14C-Sucrose Acetate Metabolism studies were conducted in female rats > 90% radioactivity remained in intestinal 49 Isobutyrate Isobutyrate (female rats); 20 dosed by oral intubation; rats housed in metabolism tract 6 h post-dosing (60% in small mg/kg 14C-Sucrose (one female cages with free access to food and water; rats killed at intestine); hydrolysis occurred with <30% rat); 20 mg/kg 14C-Sucrose 6 or 24 h post-dosing and total radioactivity radioactivity recovered from small Acetate Isobutyrate ( male rats); measured; no controls used intestine and caecum; urinary excretion of 14 14 0.4 mg C-Sucrose Acetate 14 radioactivity 4.9% of dose; expired CO2 14 A single female rat dosed by oral intubation ( C- Isobutyrate or 0.15 mg C- showed complete hydrolysis to glucose Sucrose 20 mg/kg) and urine collected over 24 h; this Sucrose / 5-cm length of small and fructose at 2.4% of dose; 90% was a negative control intestines radioactivity excreted by 24 h (< 8% in 14 Dosages administered directly into caecum (to gastro-intestinal tract); 50% excreted (label on sucrose in C-Sucrose 14 14 evaluate absorption and hydrolysis of C-Sucrose from CO2; fecal excretion was 33% of Acetate Isobutyrate label) Acetate Isobutyrate) of anaesthetized male rats; rats dose; 87% of dose in small intestine placed in metabolism cage and killed at 3 or 6 h post- remained after 1 h whereas control (14C- dosing; negative controls used sucrose) < 30% after 30 min; 14C-Sucrose Acetate Isobutyrate hydrolyzed in Intestinal absorption studies were conducted in gastrointestinal tract prior to absorption; anaesthetized male rats by administering dosage hydrolysis decreases from duodenum to through 3 separate 5-cm sections of small intestine caecum (less hydrolysis in caecum with loops (absorptive durations post-dosing were up to 1 direct administration vs. small intestine h); after dosing loops were excised, washed with after oral dosing); end result of orally saline and wall homogenates and washings were administered 14C-Sucrose Acetate assayed for radioactivity; negative controls used Isobutyrate similar to that of 14C-Sucrose

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14 53 Sucrose Acetate Rat For Sucrose-U- 26, 28, 89, 98 mg/kg Sucrose-U- Metabolic parameters (CO2, urine, feces) were For 5.8 and 11.2 mg/kg Sucrose-U- C Isobutyrate 14C Acetate 14C Acetate Isobutyrate in corn evaluated after a single dosage; post-dosing the rats Acetate Isobutyrate 59% and 52% of Isobutyrate oil; 5.8 and 11.2 mg/kg Sucrose- were placed in metabolic cages for 3 days (rats fed an radioactivity was detected in breath, 11% treatments n=6 U-14C Acetate Isobutyrate in aqueous emulsion of Sucrose-U-14C Acetate radioactivity and 13% radioactivity were aqueous emulsion; 400 mg/kg Isobutyrate) or 4 days (rats fed Sucrose-U-14C Acetate detected in urine, 23% and 27% Sucrose-14C and 112 mg Isobutyrate in corn oil); for rats housed 3 days radioactivity were detected in feces within Sucrose/4 ml by stomach tube samples to measure metabolic parameters were 3 days post-dosing; 6.0% and 6.6% in collected every 24 h; for rats housed 4 days samples carcass after 3 days post-dosing; Sucrose- to measure metabolic parameters were collected every 14C rapidly absorbed and metabolized 14 1.5 h for the first 15 h and then successively at 8-16 h to CO2 intervals; negative controls used

53 Sucrose Acetate Dog n=2 4.8 and 3.0 mg/kg Sucrose-U- Metabolic parameters (CO2, urine, feces) were 28% and 27% radioactivity was detected Isobutyrate 14C Acetate Isobutyrate in evaluated after a single dosage; post-dosing the dogs in breath, 7% and 5% radioactivity aqueous emulsion were placed in metabolic cages; samples to measure detected in urine, 53% and 46% metabolic parameters were collected every 1.5 h for radioactivity detected in feces within 7 the first 15 h and then successively at 8-16 h days post-dosing intervals; negative controls used Sucrose Acetate Rat n=3 Oral dosages: 19.8 (rat 1), 41.5 Non-Good Laboratory Practice (GLP) study; Single Material passed slowly through 18 Isobutyrate (rat 2), or 50.6 (rat 3) mg/kg oral dosage; rat bile ducts cannulated and bile gastrointestinal tract (no feces) for rat 1 Sucrose-14C(U) Acetate collected (after intragastric intubation) continuously (78% radioactivity in intestines 3 days Isobutyrate; no dosage specified for 65 h (rat 1) and 2-3 days (rats 2 and 3); no post-dosing); rapid peak in bile for intragastric intubation controls used elimination 1-2 h post-dosing, falling off 3-4 h post-dosing for rats 2 and 3; 12.4% and 35.1% of radioactivity detected in feces at 96 h and 72 h with 19.4% and 5.0% in intestines at death for rats 2 and 3; low levels of radioactivity detected in blood of all 3 rats Sucrose Acetate Rat, Dog Rats n=3; Dog , 4.0 mg/kg Sucrose-14C(U) Non-GLP study; test animals were fed unlabeled Dog: 67-75% of radioactivity was 18 nd Isobutyrate (Beagle) male n=1 Acetate Isobutyrate Sucrose Acetate Isobutyrate for 7 days (2 trial) and eliminated in feces within 7.5-9 h; 2%-6% 4 days (3rd trial) before dosing with Sucrose-14C(U) radioactivity excreted in bile after 11-16 h; Acetate Isobutyrate emulsion; 15 g unlabeled Sucrose results from rat tests not provided Acetate Isobutyrate in corn oil administered to dog

just prior to 3rd trial; bile ducts of rats and dog cannulated and bile collected 11-16 h following single oral dosage; feces analyzed; no details of 1st trial provided; no controls used

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species/ Sample Concentration/ Dosage Procedure Results Reference Strain Type/Test (Vehicle) Population-Sex Sucrose Acetate Rat Rat-male, corn Unlabeled Sucrose Acetate Non-GLP study; unlabeled Sucrose Acetate Rats fed unlabeled Sucrose Acetate 18 Isobutyrate (Holtzman) oil Isobutyrate 2.5, 5 g/kg (prelim Isobutyrate administered in preliminary study; single Isobutyrate eliminated ethanol-extractable administration study); 14C-Sucrose Acetate dosages administered; post-dosing (corn oil) acetate and isobutyrate 16%-60% of n=2/dosage; Isobutyrate (label on sucrose) in metabolism parameters monitored for 4 days; post- administered dose within 6 days, at 2.5 aqueous corn oil 26,28,89,98 mg/kg; 14C- dosing (aqueous emulsion) parameters monitored for mg/kg increased urinary excretion of emulsion n=2 Sucrose Acetate Isobutyrate 3 days; no controls used combined acetic acid equivalent to 36%- for 14C-Sucrose (label on sucrose) in aqueous 46% of administered dose Acetate emulsion 5.8,11.2 mg/kg; 371, Isobutyrate; 405 mg/kg 14C-Sucrose Corn oil dosed rats showed 45%-50% n=2 for 14C- (aqueous) radioactivity was absorbed at higher Sucrose dosages, 74%-82% radioactivity was absorbed from intestinal tract at lower dosages; Sucrose Acetate Isobutyrate rapidly eliminated (all dosages), 90%-93% radioactivity was eliminated within 4 days with 97% of the total radiolabeled elimination occurring within 2 days; 55- 14 67% of dosage metabolized to CO2 in 4 days; 23-28% eliminated in urine in 4 days; unabsorbed material in feces was Sucrose Acetate Isobutyrate or highly acylated sucrose; Sucrose Acetate Isobutyrate metabolized to sucrose and partially acylated sucrose in gut and was absorbed; higher dosages were not as well absorbed as lower dosages

Aqueous emulsion dosage of Sucrose Acetate Isobutyrate largely absorbed from gut; unabsorbed material in feces was highly acylated sucrose; > 73% radioactivity was excreted as CO2 in exhaled air in 3 days; 14%-18% radioactivity was eliminated in urine; no fat incorporation of Sucrose Acetate Isobutyrate detected

Rats dosed with 14C-Sucrose exhaled 77%- 14 83% of dosage as CO2 in 3 days (elimination of radioactivity in urine and feces was very small); 10%-13% dosed radioactivity detected in carcass

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14 21 Sucrose Acetate Rat Male, n=? 27 or 100 mg/kg C-Sucrose Single dosage administered and CO2 in exhaled air, Gastrointestinal tract absorption of Isobutyrate (Holtzman) Acetate Isobutyrate (label on urine, feces, blood, liver, and kidney evaluated; use of administered radioactivity was 74%-82% Sucrose) (vehicle=corn oil) controls not specified (27 mg/kg) and 45%-50% (100 mg/kg); eliminated 88%-90% radioactivity by 48 h; 100 mg/kg radioactivity eliminated 54%-56% as CO2 and 26%-28% radioactivity in urine; 27 mg/kg radioactivity eliminated 63%-67% as CO2 and 23%-25% radioactivity in urine; <1% radioactivity remaining in gastrointestinal tract, blood, liver, kidney at 4 days post- admin; 24 h feces samples had Sucrose Acetate Isobutyrate + metabolites; most of radioactivity in urine was identified as sucrose with other unidentified compounds present Sucrose Acetate Rat Male, n=? 100 mg/kg 14C-Sucrose Acetate Single dosage administered and metabolic parameters 3-3.5 h post administration: 78%-84% 21 Isobutyrate (Holtzman) Isobutyrate (label on Sucrose) monitored; use of controls not specified radioactivity was recovered from gastrointestinal tract; 7%-9% radioactivity from stomach, intestinal, caecal tissues; < 4% radioactivity was excreted in breath, urine, feces; gastrointestinal tract + organ extracts contained sucrose, partially- acylated sucrose esters, and unchanged Sucrose Acetate Isobutyrate Sucrose Acetate Rat Not specified 14C-Sucrose Acetate Isobutyrate, Single dosage administered; use of controls not Eliminated 7%-10% radioactivity in urine 21 Isobutyrate no further details provided specified within 30-46 h post-dosing; 14C molecules larger than sucrose not detected in urine (sucrose, glucose, and fructose absent) Sucrose Acetate Dog Not specified 14C-Sucrose Acetate Isobutyrate, Single dosage administered; use of controls not Eliminated 2.8%-5.2% of radioactivity in 21 Isobutyrate no further details provided specified urine within 29-30 h post-dosing; 14C molecules larger than sucrose not detected in urine (sucrose, glucose, and fructose absent)

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14 51 sucrose Rat (Wistar) Male rats, n=3 250 mg/kg C-sucrose esters 24 h fast, rats dosed (single); expired CO2, urine, At 120 h post-dosing for radioactivity tetrastearate, per formulation (sucrose tetrastearate, Sucrose feces collected 120 h post-dosing; blood, tissue, and labeled on ester portion ≥ 99% was found Sucrose Hexastearate, sucrose lymph analyzed; use of controls not specified in feces, ≤ 1.6% in expired CO2, and ≤ Hexastearate, octastearate; 14C radiolabels 0.3% in urine; lesser esterification sucrose octastearate were on either the sucrose or the compounds were better absorbed; for ester portion of the molecule) dosed radioactivity labeled on sucrose portion ≥ 96% was found in feces, ≤ 1.5% in expired CO2, and ≤ 1.0% in urine; sucrose esters were hydrolyzed before absorbed in the intestines; by 120 h post- dosing 14C sucrose esters (label on ester) were found in fat, lymph node, liver, other organs and tissues, and blood samples; by 1 to 8 h post-dosing small levels of 14C sucrose esters (label on sucrose) were detected in blood, tissues, and organs; in lymph samples analyzed 120 h post- dosing (label on ester) ≤ 7.6% radioactivity detected and by 96 h post- dosing (label on sucrose) < 0.3% of radioactivity was detected HUMAN Oral Sucrose Acetate Human Males n=2 (single All Sucrose Acetate Isobutyrate For 5 days 24 h urine samples were collected in the 0.1 g or 1 g showed < 0.4% was excreted 49 Isobutyrate dose); Males n=2 dissolved in butter: single dose single dose study, urine was assayed for sucrose, free in urine as parent compound or (multi-dose); n=1 of 0.1 or 1.0 g ; 1g/day x7 days and esterified; For 7 days 24 h urine sample collected metabolites with disaccharide moiety; (fecal excretion (multi-dose study); 0.1g/day x7 (in the multi-dose study urine was assayed for total with 1 g/day x 7 days, similar result as study); n=2 (sucrose days (fecal excretion study sucrose); For 3 days feces collected post-dosing and above; with 0.1 g/day x 7 days in 1 clearance study) used); each subject administered assayed for glucose; Urine collected at 3, 12, and 24 h subject, no unchanged Sucrose Acetate 100, 250, and 500 mg sucrose iv and assayed for glucose after acid hydrolysis (sucrose Isobutyrate or metabolite detected in fecal as 10% (w/v) on different days clearance study); negative controls were used samples; absorption of partially esterified sucrose molecules from intestinal tract is insignificant; urinary excretion following iv dosing showed 50% sucrose recovered in urine after 3 h at all three dose levels

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species/ Sample Concentration/ Dosage Procedure Results Reference Strain Type/Test (Vehicle) Population-Sex Sucrose Acetate Human n=7 subjects total 1.0-1.2 mg/kg Sucrose-U-14C Human subjects were administered a single dosage; Subjects eliminated in breath 41-66% 53 Isobutyrate Acetate Isobutyrate (n=6) and breath samples were collected at 1-1.5 h intervals radioactivity, urine 15-21% of 0.2 mg/kg (n=1) in non- from 0.5 to 16 h post-dosing and at various radioactivity, feces 10% of radioactivity carbonated beverage; Sucrose- successive intervals up to 25-30 days; urine samples within 30 days; subjects dosed with 14C administered @ 400 mg/kg were collected ad libitum for 25-30 days and fecal Sucrose-14C eliminated 50% radioactivity Sucrose-14C; Sucrose-14C and samples collected ad lib. for 5 days post-treatment; in breath, 2.7% radioactivity in urine, unlabeled sucrose (25 or 28 g in negative controls were used <0.3% in radioactivity in feces within 31 200 ml) administered to 2 days; studies were also conducted to subjects examine the effect on elimination of Sucrose Acetate Isobutyrate with various dosing routine changes and results indicated no significant differences in patterns or routes of dose elimination; in humans urinary elimination species are more polar (mostly sugar esters, very little free sucrose) Sucrose Acetate Human Male, n=1 1.18 mg/kg 14C-Sucrose Acetate Single dosage administered; urine samples collected Glucose, fructose, and the esters of 21 Isobutyrate Isobutyrate prior to dosing and at 0 and 6.2 h post-dosing and fructose and sucrose were not detected in assayed; no controls used urine; metabolites (2 unidentified chromatographic peaks) were thought to be principal metabolites of Sucrose Acetate Isobutyrate

Table 10. Acute Toxicity Studies Test Species/ Strain Test Concentration/ Dosage Exposure Procedure Results Reference Substance(s) Population- (Vehicle) Duration Sex ANIMAL Dermal Sucrose Acetate Rat (Sprague- n=5/sex/ 20 ml/kg Sucrose Single Test substance applied to hairless skin, occlusively Skin unaffected by treatment during 14 days 18 Isobutyrate Dawley) dosage Acetate Isobutyrate dosage; 24 wrapped for 24 h, post-application residual material observation; weight gain, clinical signs, gross (vehicle not specified) h washed off with water (followed Organization for pathology unaffected (no evidence of percutaneous Economic Co-operation and Development, OECD, absorption); LD50>20,000 mg/kg for male and Guideline 434, Acute Dermal Tox-Fixed Dose); use female rats of controls not specified Oral

18 Sucrose Acetate Rat (Sprague- n=5/sex/ 5000 mg/kg Sucrose Single Dosage administered orally by gavage, rats observed LD 50>5000 mg/kg for male and female rats; body Isobutyrate Dawley) dosage Acetate Isobutyrate, in dosage for 14 days; use of controls not specified weight and gross pathology unaffected; diarrhea corn oil (likely from corn oil) observed day of dosing (resolved 1-2 days post-dosing); no treatment- related effects at necropsy

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Table 10. Acute Toxicity Studies Test Species/ Strain Test Concentration/ Dosage Exposure Procedure Results Reference Substance(s) Population- (Vehicle) Duration Sex Sucrose Acetate Rat, Mouse Sample size 25.6 g/kg Sucrose Single Dosage administered; use of controls not specified Oral dosages produced no mortality in mice and 60 Isobutyrate details not Acetate Isobutyrate in dosage mortality in 1 of 7 rats specified corn oil (50% solution of Sucrose Acetate Isobutyrate)

18 Sucrose Acetate Monkey n=2 male, 2 1.25, 2.50, 5.00, 10.00, Incremental Dosage administered (by gavage) incrementally (72 h LD 50>20,000 mg/kg for male and female monkeys; Isobutyrate (Cynomolgus) female 20.00 g/kg bw Sucrose with 72 h between) until 20 g/kg reached or toxicity occurred; yellow/ watery emesis or stools observed (at Acetate Isobutyrate in between no controls used dosages 1.25, 2.5, 5.0 g/kg); 24 h post-dosing with (vehicle: orange juice 20.0 g/kg loose stools noted; body weight and gross concentrate) pathology were unaffected; food consumption was slightly less during treatment Sucrose Acetate Squirrel n=3 1 g Sucrose Acetate Single Dosage administered after fasting overnight (method BSP clearance was normal in 2 of 3 monkeys in 21 Isobutyrate monkeys males/group Isobutyrate in 2 ml dosage of administration was not specified); 24 h post- each group (Saimiri (6 total cottonseed oil treatment BSP clearance measured; 7 days rest then sciureus) animals; one treatment for groups was reversed group received treatment and the other group served as a control) Sucrose Acetate Squirrel n=3 2 g Sucrose Acetate Single Dosage administered after fasting overnight (method High plasma BSP detected in 3 controls, however 21 Isobutyrate monkeys males/group Isobutyrate in 4 ml dosage of administration was not specified); 24 h post- authors considered this to be a technical error when (Saimiri (6 total cottonseed oil treatment BSP clearance measured; 7 days rest then BSP clearance after Sucrose Acetate Isobutyrate sciureus) animals; one treatment for groups was reversed treatment was normal in all animals group received treatment and the other group served as a control) Sucrose Acetate Monkey n=10 5 g/kg Sucrose Acetate Single Dosage administered, 30 min bromosulfophthalein BSP and SAP measurements, clinical observations, 21 Isobutyrate, (Cynomolgus) Isobutyrate, 5 g/kg dosage (BSP)* retention and serum alkaline phosphatase and body weight were unaffected by treatment Sucrose Sucrose Octaisobutyrate (SAP)* measured 5 h post-dosing; negative controls (intervals for hepatic function measurements not Octaisobutyrate (corn oil vehicle) were used optimized) Sucrose Acetate Dog (Beagle) Male, n=3 2 g/kg Sucrose Acetate Single Dosage administered (by gavage), BSP clearance Plasma BSP levels increased at all post-dosing 21 Isobutyrate (dosed), n=2 Isobutyrate in corn oil dosage measured 0.5, 2, 4, 6, 10, 12, 18 or 24 h post-dosing; measurements compared to pre-dosing values (5 h (controls) negative controls were used post-dosing was max BSP retention) (delayed BSP clearance rates are indicative of inhibited liver function)

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Table 10. Acute Toxicity Studies Test Species/ Strain Test Concentration/ Dosage Exposure Procedure Results Reference Substance(s) Population- (Vehicle) Duration Sex Sucrose Dog (Beagle) Males, 100-1000 mg/kg Single Dosage administered, BSP and SAP measured; Sucrose Hexaacetate Diisobutyrate increased BSP 21 Hexaacetate Experiments Sucrose Hexaacetate dosage negative controls were used (5-7x) at all dosages tested vs. pretreatment values; Diisobutyrate, 1-3: n=12 Diisobutyrate; 5-1000 Sucrose Octaisobutyrate increased BSP (4-5x) at Sucrose (test mg/kg Sucrose levels of 25 mg/kg and higher; no dose-response Octaisobutyrate; animals), Octaisobutyrate (corn correlation; BSP retention at 5 mg/kg Sucrose both are n=2 (control oil vehicle) Octaisobutyrate showed slight increase vs. control constituent animals); and pretreatment values; SAP, body weight, and esters of Experiment gross clinical observations unaffected Sucrose Acetate 4: n=6 (test Isobutyrate animals), n=1 (control animal) *BSP=bromosulfophthalein; SAP=serum alkaline phosphatase

Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex SHORT-TERM (< 3 MONTHS EXPOSURE) ANIMAL Oral Sucrose Acetate Rat (Wistar) n=5 4% Sucrose Acetate 7 days Dosed daily in diet for 7 days; BSP* measured at 0 BSP clearance unaffected 21 Isobutyrate Isobutyrate (pretreatment) and 24, 48 h following withdrawal from treated feed ; use of controls not specified Sucrose Acetate Dog (Beagle) n=2/sex 0.1, 0.3, 0.5% Sucrose 2 weeks Dosed daily in diet; tested for BSP clearance 24 and 48 h No BSP retention with 0.1%, but reversible BSP 21 Isobutyrate Acetate Isobutyrate post-feeding; rest period of 1 week between dosing levels; retention did occur at 0.3% and 0.5% use of controls not specified Sucrose Acetate Monkey n=1/sex/group 0, 0.5, 1.0, 2.0, 5.0, 10.0 15 days Dosed daily by gavage for 15 days; negative controls Body weight and food consumption unaffected; 21 Isobutyrate (Cynomolgus) (6 groups, 12 g/kg/day; orange juice were used postmortem exam showed no change; no total animals) vehicle alteration in ultrastructural organization of hepatocytes Sucrose Acetate Monkey n=1/sex/group 0, 2.0, 5.0, 10.0 g/kg 15 days Dosed daily by gavage for 15 days; negative controls Body weight, food consumption, and clinical 21 Isobutyrate (Cynomolgus) (4 groups, 8 /day; orange juice were used parameters (including BSP retention) unaffected total animals) vehicle

Sucrose Acetate Rat (Sprague- n=15/sex/ 0, 5000, 50,000 ppm 3 weeks Dosed daily in diet for 3 weeks; 5 rats/sex/group killed No effects on gross necropsy, liver weights, 21 Isobutyrate Dawley) group Sucrose Acetate after 1, 2, and 3 weeks treatment; negative controls were body weight, or food consumption Isobutyrate used

Sucrose Acetate Mouse n=10/sex/ 0, 0.625, 1.25, 2.5, 5.0 4 weeks Dosed daily in diet for 4 weeks; negative controls were Body weights/ weight gains and food 55 Isobutyrate (B6C3F1/ group g/kg bw/day Sucrose used; this study was used for range-finding to be applied consumption were unaffected by treatment; no Cr1BR) Acetate Isobutyrate to a 2-year toxicity (see Chronic Toxicity section of this treatment related effects observed at necropsy; table)/ carcinogenicity study (see Carcinogenicity in-text) treatment was well-tolerated

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Acetate Monkey n=4/sex 0, 500, 1450, 2400 4 weeks For 4 weeks treatment was administered to 1 All monkeys survived to termination, occasional 56 Isobutyrate (Cynomolgus) mg/kg/day Sucrose monkey/sex/dosage/day; negative controls were used; see decreased appetite in all monkeys, no change in Acetate Isobutyrate in chronic toxicity section of this table for 1-yr study body weight except for 1 female (12% loss at corn oil conducted following this preliminary range-finding study 2400 mg/kg/day), hematological values and BSP unaffected (no dose rate dependent effects), low terminal serum phosphorus in 1 female at 2400 mg/kg/day, no lesions, gross changes typical of spontaneous disease Sucrose Acetate Rat (Sprague- n=140/sex 1.0%, 2.0%, 4.0% 28 or 56 280 rats randomly assigned to 14 treatment groups of No toxicological effects were observed 60 Isobutyrate Dawley) days each sex, 10/group; dosed daily in diet for 28 or 56 days

or for 28 days prior to or after which were fed a control diet for 28 days Sucrose Acetate Rat (Sprague- n=not 4% Sucrose Acetate 36 days Dosed daily in diet as indicated for 36 days; ICG* ICG plasma clearance rates no different from 21 Isobutyrate Dawley) specified Isobutyrate + corn oil clearance tested on ≥2 rats/group on days 1, 3, 5, 8, 10, controls 22, 26, and 36; negative controls were used Sucrose Acetate Rat (Sprague- n=not 4.0% Sucrose Acetate 36 days Dosed daily in diet for 36 days to determine ICG No hepatic microsomal activity, slight 60 Isobutyrate Dawley) specified, Isobutyrate + 5.0% corn clearance rates indicating liver functionality depression of G-6-PTase activity males oil/day

Sucrose Acetate Rat (Sprague- n=40/sex/ Group 1 (basal diet); 6 weeks Dose administered daily as indicated; each group divided NOAEC reported at 10% daily in diet; no deaths 54 Isobutyrate Dawley) group Group 2 (basal diet + into 2 subgroups (n=20/subgroup) that were treated for 6 from treatment; mean body weights decreased sodium phenobarbital and 12 weeks (see subchronic section of this table); in in males at all dosage rates for entire study vs. 100 mg/kg/day by each subgroup n=10 rats were used for zoxazolamine test controls potentially due to palatability of gavage); Groups 3- (after which fed basal diet for 4 week withdrawal period treatment; no effect on hepatobiliary function; 5=2.5, 5.0, 10.0% and then zoxazolamine test repeated), n=10/subgroup no microsomal enzyme induction observed; Sucrose Acetate used for clinical chemistry and pathology studies; effects carboxylesterase activity unaffected; urinary Isobutyrate daily in diet, of phenobarbital and Sucrose Acetate Isobutyrate on liver excretion of ascorbic acid and zoxaolamine respectively microsomal enzymes were determined by urinary ascorbic hypnotic activity were unaffected by treatment; acid excretion, zoxazolamine hypnotic activity (Sucrose liver glycogen levels increased in males and Acetate Isobutyrate’s effect on the zoxazolamine females fed 10%; absolute mean heart weights biotransformation rate by liver enzymes may be an decreased in all treated males indication of toxicity), and liver biochemistry; negative controls were used Sucrose Rat (Sprague- Males, 17% (w/w) lipid content 28 days Dosed daily in diet for 28 (some animals in this study NOEC of 15% reported; No toxicity observed; 19,20 Polysoyate Dawley) n=20/group (5 mixed in diet; 0, 4, 8, were dosed for 91 days, see subchronic section of this 8% and 15% groups noted softer feces and groups, 100 15% Sucrose Polysoyate table); 10 rats killed on day 28 and remainder killed on lower growth rates (dose-related); food animals total) (sucrose polyester day 91; negative controls were used consumption increased with dosage increase; no prepared from effects on histopathological findings (Sucrose completely and partially Polysoyate not substantially absorbed from hydrogenated soybean gastrointestinal tract); heart weight decreased oil); 15% Sucrose (dose-dependent) in rats killed day 28 but not Polysoyate (prepared those killed on day 91 (see subchronic section from completely of this table, completely hydrogenated soybean hydrogenated soybean oil treatment led to decreased heart weight); oil) lipid levels unaffected

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Dog (Beagle) Males, n=4/ 17% (w/w) lipid content 28 days Dosed daily in diet for 28 days; animals killed on days 29 NOAEC of 15% reported in male dogs; no 19,20 Polysoyate group (4 mixed in diet; 0, 4, 15% and 30; negative controls were used toxicity observed; food consumption highest groups, 16 Sucrose Polysoyate with 15% groups; hematology, urine, and animals total) (sucrose polyester organs unaffected; lower gastrointestinal tract prepared from contained more material with 15% groups; completely and partially increased heart lipids and liver cholesterol in hydrogenated soybean treated dogs (Sucrose Polysoyate identified in oil); 15% Sucrose liver lipids) Polysoyate (prepared from completely hydrogenated soybean oil) Sucrose Dog (Beagle) n=4/sex/ 17% (w/w) lipid content 28 days Dosed daily in diet for 28 days; animals killed beginning NOEC reported as 15% for male and female 19,20 Polysoyate group (4 mixed in diet; 0, 4, 15% on day 29; negative controls were used dogs; no clinical toxicity observed; higher food groups, 32 Sucrose Polysoyate consumption for treatment group vs. control; animals total) (sucrose polyester hematology, organs, and urine unaffected by prepared from treatment; decrease in cholesterol/lipids in completely and partially treatment groups (dose-related); Sucrose hydrogenated soybean Polysoyate not absorbed from diet oil); 15% Sucrose Polysoyate (prepared from completely hydrogenated soybean oil) HUMAN Oral Sucrose Acetate Human n=10/sex 10 mg/kg /day Sucrose 14 days Dosed daily for 14 days; blood chemistry measured prior Blood chemistry values were unaffected 21 Isobutyrate Acetate Isobutyrate to treatment and on days 7 and 18; negative controls were taken in a bolus used

Sucrose Acetate Human n=12/sex/ 7.0 or 20.0 mg/kg /day 14 days Dosed daily for 14 days (blood chemistry measured prior Blood chemistry and BSP retention were 21 Isobutyrate group (3 Sucrose Acetate to testing and on days 7 and 14); additional preliminary unaffected groups, 24 Isobutyrate dissolved in experiment performed in which 4 men received 20 mg /kg total subjects) a carbonated drink /day for 1 or 3 days only; 45-min BSP retention test performed on all subjects prior to and after completion of Sucrose Acetate Isobutyrate treatment; negative controls were used Sucrose Acetate Human n=27 (13 20 mg/kg/day Sucrose 14 days 7 days prior to treatment served as each subject's control Hematological parameters and blood chemistry 21 Isobutyrate males, 14 Acetate Isobutyrate; with ingestion of placebo orange juice emulsion; dosed (including hepatobiliary function) unaffected females) orange juice vehicle daily for 14 days, blood samples collected on days -6 (pretreatment), 0, 7, and 14; negative controls were used

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex SUBCHRONIC (3 TO 6 MONTHS EXPOSURE) ANIMAL Oral Sucrose Acetate Rat (Sprague- n=40/sex/ Group 1 (basal diet); 12 weeks Dosage administered daily as indicated; each group NOAEC reported at 10% daily in diet; no deaths 54 Isobutyrate Dawley) group Group 2 (basal diet + divided into 2 subgroups (n=20/subgroup) that were from treatment; mean body weights decreased sodium phenobarbital treated for 6 weeks (see short-term section of this table) in males at all dosages for entire study vs. 100 mg/kg/day by and 12 weeks; in each subgroup n=10 rats were used for controls potentially due to palatability of gavage); Groups 3- zoxazolamine test (after which fed basal diet for 4 week treatment; no effect on hepatobiliary function; 5=2.5, 5.0, 10.0% withdrawal period and then zoxazolamine test repeated), no microsomal enzyme induction observed; Sucrose Acetate n=10/subgroup used for clinical chemistry and pathology carboxylesterase activity unaffected; urinary Isobutyrate daily in diet, studies; effects of phenobarbital and Sucrose Acetate excretion of ascorbic acid and zoxaolamine respectively Isobutyrate on liver microsomal enzymes were hypnotic activity were unaffected by treatment; determined by urinary ascorbic acid excretion, liver glycogen levels increased in males and

zoxazolamine hypnotic activity (Sucrose Acetate females fed 10%; absolute mean heart weights Isobutyrate’s effect on the zoxazolamine decreased in all treated males biotransformation rate by liver enzymes may be an indication of toxicity), and liver biochemistry; negative controls were used Sucrose Acetate Dog (Pure- n=68 total Groups 1-5 (n=6 males 12 weeks Dose administered daily as indicated for 12 weeks; No deaths from treatment; no ocular lesions; no 54 Isobutyrate bred Beagle) + 6 females/group) 0, additional dogs n=4/sex fed Sucrose Acetate Isobutyrate impaired growth; hematology and urinalysis 0.5, 1.0, 2.0, and 4.0% at 2.0% in diet for 12 weeks followed by 2 weeks unaffected; statistically significant increase in Sucrose Acetate withdrawal period (basal diet without Sucrose Acetate SAP* (dose- and time-related); serum bilirubin Isobutyrate in diet, Isobutyrate); negative controls were used levels unaffected; 2% for 12 weeks did not respectively affect BSP retention; dilatation of bile canaliculi increased enzyme activity of bile canaliculi;

treatment-induced liver changes were reversible; hepatobiliary effects indicate a pharmacological effect and not toxicity Sucrose Acetate Dog (Beagle) n=4/sex in 0.2, 0.6, 2.0% Sucrose 90 days Dosed daily in diet for 90 days; negative controls were Food intake/weight gain, hematological/ urine 21 Isobutyrate treatment Acetate Isobutyrate in used parameters, organ weights unaffected; serum groups; n= cotton seed oil; fat chemistry showed increase in SAP* in male and 6/sex for content of diet 12% female dogs with 2% group; dose-related control group increase in relative liver weights in 0.6% and 2% groups of male and female dogs compared to controls Sucrose Acetate Dog (Beagle) Males and 0.2, 0.6, 2.0% Sucrose 90 days OECD Guideline 409 (repeated-dose 90-day oral tox in NOAEL male and female dogs>20,000 18 Isobutyrate females, Acetate Isobutyrate, non-rodents) followed (non-GLP); dosed daily in diet for mg/kg/day (2.0%); food consumption, n=4/sex/dose; cottonseed oil vehicle 90 days; negative controls were used hematological parameters, urinary exam, and 6/sex/dose gross pathology/ necropsy unaffected; increase (control in SAP at 2%; increase in liver weight at 0.6% group) and 2% Sucrose Acetate Dog (Beagle) Males n=10 (2 5% Sucrose Acetate 91 days OECD Guideline 409 (repeated-dose 90-day oral tox in Moderate elevation in SAP; prolongation of 18 Isobutyrate groups of 5) Isobutyrate, corn oil non-rodents) followed (non-GLP); dosed daily in diet for ICG cleared by liver; heavier liver weights vs vehicle 91 days; negative controls were used controls; functional effect on liver which was reversed when removed from diet

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Acetate Rat (Sprague- n=10/sex/ 0, 0.3, 1.8, 9.12% 13 weeks Dosed daily in diet for 13 weeks; negative controls were Slight diarrhea at 9.12%; no differences in 21 Isobutyrate Dawley) group Sucrose Acetate used weight gain for test and control groups; organ Isobutyrate in vegetable weight, blood chemistry, and histopathology oil (9.3% oil in diet) unaffected

Sucrose Acetate Rat (Sprague- Males and 0.38, 1.88, 9.38% 13 weeks Non-GLP; dosed daily in diet for 13 weeks; negative No toxic effects observed; at 9.38% no specific 18 Isobutyrate Dawley) females, Sucrose Acetate controls were used tissue changes in various organs, slight n=10/sex/ Isobutyrate (vegetable vacuolization of liver cells (control & treated group; oil vehicle) groups) could be caused by 9.38% vegetable oil n=10/sex for in diet; slight diarrhea for rats at higher doses controls Sucrose Acetate Dog (Beagle) Exp 1: Exp 1 (0.2, 0.6, 2.00% 12 weeks; Exp 1 (36 dogs randomly assigned to each treatment Exp 1 (slight increase in SAP levels at 2%, 60 Isobutyrate n=18/sex Sucrose Acetate 86 days; group; dosed daily in diet for 12 weeks) increase dog liver weights with 0.6% and 2.0%) Isobutyrate in 6% 91 days Exp 2: n=6 Exp 2 (dosed daily in diet for 28 days, switched to control Exp 2 (increase in SAP and prolongation of ICG cottonseed oil) males diet 57 days, on 86th day 4 dogs returned to treatment diet- plasma clearance by liver with 5% for 4 weeks, Exp 2 (5% Sucrose ICG clearance rates/SAP test conducted at 24 and 48 h) after withdrawal of Sucrose Acetate Isobutyrate Exp 3: n=10 Acetate Isobutyrate in effects reversed in 2-5 weeks, when fed 5% males Exp 3 (10 dogs randomly assigned to 2 groups of 5; dosed corn oil) again and tested 24 h post-dosing SAP daily in diet for 91 days); negative controls were used unaffected, ICG clearance prolonged) Exp 3 (5% Sucrose Acetate Isobutyrate + Exp 3 (increase in SAP, prolongation of ICG 5% corn oil) clearance, increase in liver weight, increase in liver glycogen/ phospholipids) Sucrose Acetate Rat n=25/sex/ 0, 1.0, 5.0% Sucrose 95 days Dosed daily in diet for 95 days; negative controls were Slight weight loss in males with 5%; slight 21 Isobutyrate (Holtzman) group Acetate Isobutyrate used increase in liver weight of females fed 5%; (w/w) histopathological changes were unaffected

Sucrose Acetate Rat (Sprague- n=25/sex 0.0%, 1.0%, or 5.0% 95 days 25 rats randomly assigned to each treatment group; dosed With 5% showed lower body weight for males 60 Isobutyrate Dawley) daily in diet for 95 days and slight increase in liver weight for females

Sucrose Rat (Sprague- Males, 17% (w/w) lipid content 91 days Dosed daily in diet for 91 days (some animals in this NOEC of 15% reported; No toxicity observed; 19,20 Polysoyate Dawley) n=20/group (5 mixed in diet; 0, 4, 8, study were also dosed for 28 days, see short-term section 8% and 15% groups noted softer feces and groups, 100 15% Sucrose Polysoyate of this table); negative controls were used lower growth rates (dose-related); food animals total) (sucrose polyester consumption increased with dose increase; no prepared from effects on histopathological findings (Sucrose completely and partially Polysoyate not substantially absorbed from hydrogenated soybean gastrointestinal tract); heart weight decreased oil); 15% Sucrose (dose-dependent) in rats killed day 28 (see Polysoyate (prepared short-term section of this table) but not those from completely killed on day 91 (completely hydrogenated hydrogenated soybean soybean oil treatment led to decreased heart oil) weight); lipid levels unaffected

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Rat (Sprague- n=10/sex/ 16% (w/w) lipid content 90 days Dosed daily in diet for 90 days; animals killed on day 95; NOEC of 15% reported for males and females; 19,20 Polysoyate Dawley) group (5 mixed in diet; 0, 4, 8, negative controls were used no toxicity observed; lower weight gain in 8% groups, 100 15% Sucrose Polysoyate and 15% groups; food consumption highest in animals total) (sucrose polyester pre- groups with highest dose (15%) Sucrose pared from completely Polysoyate prepared from completely and partially hydrogen- hydrogenated soybean oil; organs, clinical ated soybean oil); 15% chemistry, urinalysis, and hematology Sucrose Polysoyate unaffected; Sucrose Polysoyate not substantially (prepared from com- absorbed by gastrointestinal tract and not pletely hydrogenated identified in liver lipids soybean oil) CHRONIC (> 6 MONTHS EXPOSURE) ANIMAL Oral Sucrose Acetate Monkey n=16/sex 0, 500, 1450, 2400 1 year For 1 year, treatment was administered to 4 No effect on hepatobiliary function; NOAEL 56 Isobutyrate (Cynomolgus) mg/kg/day Sucrose monkeys/sex/dosage/day; negative controls were used; reported at 2400 mg/kg/day Acetate Isobutyrate in see short-term toxicity section of this table for the 4-week All dosage rates were well tolerated, corn oil range-finding study conducted prior to this 1-yr study opthalmoscopic exam unremarkable; no lesions;

few gross changes (typical of natural disease) observed in treated and control animals; statistically significant mean corpuscular hemoglobin decrease in males with 2400 mg/kg/day at 6 and12 months; statistically significant increase in prothrombin for all treated groups with 2400 mg/kg/day at 3 and 12 months; statistically significant increase in mean leucocyte count in females with 1450 mg/kg/day; statistically significant increase in mean segmented neutrophil in females with 1450 and 2400 mg/kg/day at 3 months; statistically significant decrease in serum phosphorus in males with 2400 mg/kg/day at 6 months; statistically significant decrease in alanine aminotransferase in males with 2400 mg/kg/day at 9 and 12 months; statistically significant decrease in serum glucose in males with 1450 mg/kg/day at 6 months and statistically significant increase in males with 2400 mg/kg/day at 6 months; statistically significant decrease in aspartate aminotransferase and serum glucose in females with 1450 mg/kg/day at 6 months; at necropsy statistically significant decrease in mean weight thyroid/parathyroid glands in males with 500 mg/kg/day; statistically significant decrease in mean absolute weight of ovaries and ovary/brain weight ratio in females with 2400 mg/kg/day

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Acetate Rat (F344) n=20/sex/ Highest doses fed were 1 year Dosage administered daily in diet for 1 year; hematology NOAEL reported at 2 g/kg/day for males and 55 Isobutyrate dosage rate up to 5% of diet and urine analysis were conducted at 27 and 53 weeks; females; body weight gain decreased likely (beyond which risks negative controls were used from nutritional deficiencies in females with 2 nutritional deficiency); g/kg/day at week 17 and beyond and in males acetone vehicle; 0, 0.5, with 2 g/kg/day at weeks 13 and 54; 1 female 1.0, 2.0 g/kg/day died with 0.5 g/kg/day group, 1 female killed in moribund condition with 2 g/kg/day group, 1 control and 2 treated rats died during blood collection; clinical and ophthalmic observations unaffected; food consumption decreased in females with 2g/kg/day; clinical chemistry, urine analysis, BSP retention unaffected with 2 g/kg/ day; small, but statistically significant hematology differences compared to controls occurred in dosage rates <2g/kg/day at varying times in study but were normal again by 54 weeks; at necropsy absolute organ weights unaffected; no neoplastic or non-neoplastic microscopic changes; no gross or microscopic changes in liver Sucrose Acetate Rat (F344) n=50/sex/ Highest doses fed were 2 year Diet containing Sucrose Acetate Isobutyrate was NOAEL of 2 g/kg/day reported; no treatment- 55 Isobutyrate dosage rate up to 5% of diet administered daily for 2 years; hematology samples were related deaths or clinical effects; food (beyond which risks collected from all surviving animals at study week 104; consumption and hematological parameters nutritional deficiency); negative controls were used; this study also evaluated were unaffected by treatment; occasional acetone vehicle; 0, 0 carcinogenicity (see Carcinogenicity section in-text) decreased mean body weight compared to (two control groups), controls in females up to 61 weeks at 0.5 0.5, 1, 2 g/kg/day g/kg/day and up to 73 weeks at 1 or 2 g/kg/day were observed; there was a decrease in male mean body weight at 2 g/kg/day compared to first control group (but not second control group); gross and microscopic observations were unaffected by treatment; tumors found were typical of those that occur spontaneously in F344 rat (not treatment-related); male survival rates were 46%, 50% 58%, 58% and 60% female survival rates were 74%, 68%, 78%, 62%, and 68% for dosage rates 0, 0, 0.5, 1, and 2 g/kg/day, respectively

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Table 11. Short-Term, Subchronic, and Chronic Toxicity Studies Test Species/ Test Dosage (Vehicle) Exposure Procedure Results Reference Substance(s) Strain Population- Duration Sex Sucrose Acetate Mouse n=50/sex/ Highest doses fed were 2 year Diet containing Sucrose Acetate Isobutyrate was NOAEL of 2.5 g/kg bw/day was reported; no 55 Isobutyrate (B6C3F1) dosage rate up to 5% of diet administered daily for 2 years; hematology samples were treatment-related deaths or clinical effects; food (beyond which risks collected from 15 animals/sex in 5 g/kg/day group and consumption and hematological parameters nutritional deficiency); control groups at 28, 53, 79, and 105 weeks; negative were unaffected by treatment; occasional acetone vehicle; 0, 0 controls were used; this study also evaluated substantially decreased mean body weight in (two control groups), carcinogenicity (see Carcinogenicity section in-text) males at 2.5 g/kg/day compared to both control 1.25, 2.5, 5 g/kg/day groups (not seen with 5 g/kg/day); occasional substantially different body weight in females with 1.25 g/kg/day and 5 g/kg/day (not seen with 2.5 g/kg/day) not thought to be treatment- related; tumors found were typical of those that occur spontaneously in the B6C3F1 mouse and were not treatment-related; there was a treatment-related decrease in mean absolute and relative kidney weights observed at necropsy in males (with 5 g/kg/day) compared to controls; no gross or microscopic kidney changes were observed in males or females; male survival rates were 80%, 80% 80%, 80% and 74% female survival rates were 68%, 68%, 78%, 66%, and 78% for dosage rates 0, 0, 1.25, 2.5, and 5 g/kg/day, respectively Sucrose Acetate Rat (Sprague- n=10/sex/ 0%, 0.38%, 9.38% in 2 year Diet containing Sucrose Acetate Isobutyrate was No substantial body weight differences among 21 Isobutyrate Dawley) dose group diet administered daily for 2 years; negative controls were the groups concluding the first study year; used; this study also evaluated carcinogenicity (see differences in body weight and food Carcinogenicity section in-text) consumption appeared at varying times and doses (no further details provided); males exposed to 0.38% or 9.38% exhibited decreased body weight compared to controls in the second study year; absolute and relative kidney weights in both males and females were noted to have a dose-related increase; organ weight findings were inconclusive because of discrepancies in male body weights compared to controls and low survival numbers (2-3 rats/group; no further details provided); no treatment-related lesions were found upon histological examination; within 10 weeks of the study 4 males died in 9.38% group (with massive hemorrhages in multiple organs, no further information specified as to the cause of these) but was not attributed to treatment * BSP=bromosulfophthalein; ICG=Indocyanine Green plasma clearance rates indicating liver functionality; NOAEC=No Observed Adverse Effect Concentration; NOEC=No Observed Effect Concentration; NOAEL=No Observed Adverse Effect Level; SAP= serum alkaline phosphatase

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Table 12. Developmental and Reproduction Toxicity (DART) Studies for Sucrose Acetate Isobutyrate Species/ Test Population- Dosage (Vehicle) Procedure Results Reference Strain Sex Oral 57 Rat n=30/sex/ dosage 0, 0.5, 1.0, 2.0 g/kg/day F0 generation males fed Sucrose Acetate Isobutyrate for 10 weeks NOAEL 2.0g /kg/day (maternal and developmental); pre-mating (Fischer rate F0 generation Sucrose Acetate and females fed Sucrose Acetate Isobutyrate for 2 weeks prior to period treated males showed decreased food consumption; body 344) (3 generation Isobutyrate; acetone mating (F0 females treated through lactation); F1 generation rats weights lower for treated F0 females during gestation and lactation reproduction vehicle raised on test diet and mated to produce F2a (treated through with 1 and 2g /kg/day and F1 females with 0.5 and 2g /kg/day study; teratology lactation; examined for fertility indices for F3 pregnancy) litters then during lactation; variability in fertility index (# females pregnant/ # study) re-mated to produce F2b litters (treated through day 20; examined for females mated x100) not considered to be treatment related; teratology); F2a females treated until day 14 of gestation; animals reproduction unaffected; negative for teratogenic/ developmental killed day 29 of teratology study; negative controls were used toxic effects Rabbit n=5/dosage rate Range finding-0.6 and 1.2 Range finding: 2x 1.2 g/kg/day or 1x 0.6 g/kg/day for 14 days; NOAEL 1.2 g/kg/day (maternal and developmental); Range finding 57 (New (range finding g /kg/day; for teratology-0, Teratology study: dosed on days 7-19 gestation, animals killed day study-no mortality occurred, corn oil caused soft stools, treatment

Zealand study); n=16/dose 0.5, 0.85, 1.2 g/kg/day; 29 of teratology study; negative controls were used well-tolerated; Teratology study-2 high dosage rate treated rabbits White) level (teratology corn oil vehicle died on day 17 gestation, results indicated no difference in treated studies) vs control rabbits for caesarean section exams, food consumption, weight gain, and gross morphology; negative for teratogenic/ developmental toxic effects Rat n=15 female/5 5% Sucrose Acetate Non-GLP; dosed during the breeding of 2 generations; negative NOAEL reported for maternal toxicity of 1250 mg/kg /day (actual 18 (Holtzman) male in treatment Isobutyrate in diet; acetone controls used dosage rate); 5.0% (w/w) in diet of 2 generations produced no group; n=9 vehicle effect on viability; no observable toxic effects; F1 generation had female/ 7 male in respiratory infection resulting in the death of several young, several control group control rats, and 2 treated rats; none of young weaned in treatment group lived for 2 weeks (deaths attributed to respiratory infection) Rat n=10/sex/ group 0, 0.38, 9.38% (w/w) Dosed in diet daily for 5 weeks; pairs of rats from each dose group At 0.38% reproductive performance was slightly better vs. controls; 21 (Sprague- Sucrose Acetate caged together for 19 days; females allowed to wean young to 21 at 9.38% fewer females became pregnant, fewer pups born and Dawley) Isobutyrate days; parent rats bred 3x in weeks 9-36 with different male per survived to weaning as observed over 3 breedings, this effect mating; negative controls used potentially attributable to compromised nutritive value of feed at high treatment levels

Table 13. Genotoxicity Studies Test Species/ Strain Sample Type/ Test Concentration/ Dosage (Vehicle) Procedure Results Reference Substance(s) Population-Sex IN VITRO Maltitol Laurate Salmonella Not specified Composition of test substance: Ames Test was performed (no further details Negative 58 typhimurium 40% Maltitol Laurate, 50-55% specified) water, 5-10% ethanol Sucrose Acetate Salmonella Histidine 333-10,000 µg/plate Sucrose Ames Test (Salmonella reverse mutation assay): Negative for genotoxicity (as a mutagen, 59 Isobutyrate typhimurium auxotrophs TA98, Acetate Isobutyrate, control- Following preliminary toxicity test with TA100 six clastogen, and DNA-damaging agent); Solubility TA100, TA1535, dimethyl sulfoxide concentrations from 333-10,000 µg/plate were exceeded at 50 µg/ml in dimethyl sulfoxide TA1537, TA1538 selected, with and without metabolic activation; Ames Test: Treatment was not effective at positive and negative control used increasing revertant number per plate; non-toxic; positive control outcomes were as expected

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Table 13. Genotoxicity Studies Test Species/ Strain Sample Type/ Test Concentration/ Dosage (Vehicle) Procedure Results Reference Substance(s) Population-Sex Sucrose Acetate Salmonella Strains: TA 1535, 10, 100, 500, 1000, 1500, 2000 Bacterial Reverse Mutation Assay: This assay was Negative for mutagenic activity 18 Isobutyrate typhimurium TA 1537, TA 98, µg/plate Sucrose Acetate performed with and without metabolic activation; TA 100 Isobutyrate; dimethyl sulfoxide positive controls used vehicle Sucrose Acetate Hamster Chinese Hamster 2.5 to 3350 µg/ml Sucrose CHO/HGPRT Mutation Assay: Preliminary Preliminary Results-Sucrose Acetate Isobutyrate 59 Isobutyrate Ovarian/Hypox- Acetate Isobutyrate in dimethyl cytotoxicity test performed; 6x106 cells/monolayer became toxic between 100-1000 µg/ml; anthine-Guanine sulfoxide (preliminary); 25-1000 exposed to each concentration (25-1000 µg/ml) for metabolic activation had no effect on toxicity; at Phosphoribosyl µg/ml Sucrose Acetate 4 h with and without met activation and assayed; max toxicity 40-50% survival occurred at 1000 Transferase Isobutyrate in Mutation Assay positive and negative controls used µg/ml (3350 µg/ml caused no further increase in (CHO/HGPRT) toxicity); HGPRT Mutation Assay-No increase in

mutant frequency from treatment; positive control outcomes were as expected Sucrose Acetate Rat Rat hepatocytes Sucrose Acetate Isobutyrate Unscheduled DNA Synthesis: Treatment applied Non-toxic to hepatocytes 59 Isobutyrate (Unscheduled DNA dissolved in acetone, solutions to rat primary hepatocytes in 35-mm dishes within Synthesis test) diluted 1:100 into William’s 2 h after attachment to coverslip and assayed (18 h medium E culture medium exposure); positive and negative controls used containing heat-inactivated fetal bovine serum at 1% v/v (Sucrose Acetate Isobutyrate concentrations of 25 ng/ml to 1000 µg/ml) Sucrose Acetate Hamster CHO Preliminary test-Sucrose Acetate CHO Chromosomal Aberration Assay: Cultures In preliminary testing 2000 µg/ml caused 59 Isobutyrate Isobutyrate in dimethyl sulfoxide exposed to treatment for 7.5 h (without metabolic monolayer confluency reduction of 37% (without diluted 1:100 for concentration activation) and 2 h (with metabolic activation) and metabolic activation) to 50% (with activation); range of 1900 µg/ml to 63 ng/ml; assayed; positive and negative controls used 63-1900 µg/ml caused little cell cycle delay; 1200, 1600, 2000 µg/ml Sucrose 2000 µg/ml caused concentration-related

Acetate Isobutyrate in CHO decrease in monolayer confluency and max Chromosomal Aberration Assay reduction in confluency of 33% (without activation) and 67% (with activation) but no increases in aberrations; positive control outcomes were as expected Sucrose Acetate Hamster CHO/HGPRT 10-1000 µg/ml Sucrose Acetate CHO/HGPRT Mutation Assay performed with and Negative for genotoxicity (no further details 21 Isobutyrate Isobutyrate without metabolic activation; use of controls not provided) specified Sucrose Acetate Rat Hepatocyte cells 250 ng/ml-1000 µg/ml Sucrose Unscheduled DNA Synthesis Assay performed; Negative for genotoxicity (no further details 21 Isobutyrate Acetate Isobutyrate use of controls not specified provided) Sucrose Acetate Hamster Chinese Hamster 200-2000 µg/ml Sucrose Acetate Chromosomal Aberration Assay performed with Negative for genotoxicity (no further details 21 Isobutyrate Ovarian Cells Isobutyrate and without metabolic activation; not specified provided) IN VIVO Sucrose Acetate Rat (Sprague- n=20/sex/dosage 20, 200, 2000 mg/kg Sucrose Oral administration by gavage as a single dosage Negative for dominant lethal mutations; positive 18 Isobutyrate Dawley) Acetate Isobutyrate in corn oil to male rats; 2 h post-dosing males mated with control outcomes were as expected untreated females for 1 week; subsequent matings occurred during 3rd (post-meiotic), 5th (meiotic), and 7th (pre-meiotic spermatogenesis) week post- dosing; positive and negative controls used

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Table 14. Cytotoxicity Studies Test Species Sample Type/ Test Concentration (Vehicle) Procedure Results Reference Substance(s) Population IN VITRO 62,79 Sucrose Laurate Hamster Chinese Hamster 10% Sucrose Laurate solution Neutral Red Effective Concentration 50 (NR-EC50): 100 µL Cytotoxicity results: NR-EC50 was Lung cells (prepared from 38% Sucrose suspension of 4x103 cells/ml added to 96-well plates, cells reported to be 290.0 µg/ml or log (NR- Laurate solution) diluted in water incubated at 37°C for 3 days in 5% CO2 incubator, 10% EC50) of 2.46 (no further details Sucrose Laurate added to 5 or 6 wells and incubated for 48 h provided) at which time NR-medium was added and incubated for 2 h, cells assayed and NR-EC50 calculated; negative controls were used This cytotoxicity test measured the number of viable cells in a culture by evaluating the uptake of neutral red dye into Chinese hamster lung cells in Sucrose Laurate treated and untreated cells (the dye is only incorporated into the lysosomes of viable cells); absorbance of the dye in cells was measured and the ratio of treated to non-treated cells determined; NR-EC 50 was calculated based on concentration response curves 62,80 Sucrose Laurate Human Human Skin 10% Sucrose Laurate solution MTT (tetrazolium dye) Effective Concentration50 (MTT- Cytotoxicity results: MTT-EC50 was Fibroblasts Cells (prepared from 38% Sucrose EC50): Treated cells were incubated, after 2 h MTT-formazan reported to be 680.0 µg/ml or log Laurate solution) diluted in water crystals were solubilized in 200 µL isopropanol, cells assayed (MTT-EC50) of 2.83 (no further details and MTT-EC50 calculated; negative controls were used provided) This cytotoxicity test measured the number of viable cells by evaluating the conversion of [3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT)]dye into human skin fibroblast cells both treated with Sucrose Laurate and untreated (mitochondrial dehydrogenses of metabolically active/ viable cells convert MTT to insoluble formazan ); formazan was solubilized with isopropanol and its absorbance measured; the ratio of treated to non-treated cells determined; MTT-EC50 was calculated based on converted dye concentration of response curves Sucrose Laurate Human RPMI 2650 human Variable between 0.01 and 3 Cellular toxicity studies-1-h treatment on cells measured by Cell death in the lactate dehydrogenase 40 and Sucrose nasal epithelial cells mg/ml lactate dehydrogenase release assay; 4-h treatment on cells assay for Sucrose Laurate was <25% Myristate (used to model measured by 3-(4,5-dimethyltiazol-2-yl)-2,5- (0.1 mg/ml) and >75% (0.3 mg/ml) and absorption from the diphenyltetrazolium bromide reduction assay; positive and for Sucrose Myristate was 50%-75% respiratory zone of negative controls used (0.1 to 0.3 mg/ml); cell viability in the human nasal 3-(4,5-dimethyltiazol-2-yl)-2,5- epithelium, diphenyltetrazolium bromide reduction limitations include assay for Sucrose Laurate was near no cilia and no air- 100% (0.1 mg/ml) and <25% (0.3 liquid interface) mg/ml) and for Sucrose Myristate was near 100% (0.03 mg/ml) and 25% (0.3 mg/ml)

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Table 15. Irritation Studies (Dermal) Test Substance(s) Species/ Test Population- Concentration (Vehicle) Procedure Results Reference Strain Sex ANIMAL Sucrose Laurate Mouse 15 week old Sucrose Laurate (unknown Tape-stripping (up to 18x) used to collect The results of the tape-stripping test are located 42 (SKH-1 males, n=not concentration) in hydrogel containing corneocytes from uppermost layer of dorsal skin in Table 8; the authors stated that the treatment hairless specified 5% ibuprofen 30 min post-treatment; negative controls used was non-irritating mice) Sucrose Laurate Rabbit Males, n=9 5% and 15%, w/w Sucrose Laurate Fasted 24 h pre-administration and during Authors of this study stated that there was some 43 (White hydrophilic gels (also containing 60 µg administration; 100 mg gels were applied on days skin irritation potential observed, but that New estradiol and a preservative), pH 6 1 and 7 to 3 x 3 cm shaved skin area; days 2-6 treatment was well-tolerated and emphasized Zealand) placebos applied; blood samples collected from that the irritation effects of surfactants are marginal ear vein 0.5 thru 12 h post- influenced by the application method and administration; skin biopsies (taken from parameters of investigation application site and untreated skin) evaluated for epidermal thickness; negative controls used Sucrose Laurate Rabbit Females, n=6 10% Sucrose Laurate (prepared from a Max Primary Draize Rabbit Skin Irritation Score Max Primary Draize Skin Irritation Score is 3.0 62 (Japanese 38% solution) diluted in water Test: 0.15 ml of solution applied to shaved skin (no further details provided) white) and secured with occlusive patches for 24 h, patches removed 24 h post-treatment and evaluated for erythema and edema; use of controls not specified Sucrose Laurate Guinea Females, n=3 2% Sucrose Laurate solution Skin Irritant Potential Test: 250 ± 10 mg of Skinfold thickness unaffected by repeated 38 Pig solution applied by repeated topical application to applications; non-irritating (Dunkin left and right flanks; skinfold thickness measured Hartley) at 20 min, 8, 24, 32, and 48 h post- challenge (no further details provided); use of controls not specified Sucrose Acetate Guinea n=5 0.5 ml Sucrose Acetate Isobutyrate Irritation test similar to the Acute Dermal Non-irritating; weight gain normal; no 18 Isobutyrate Pig (concentration and vehicle not Irritation/Corrosion test (OECD Guideline 404) percutaneous absorption evident (Hartley specified) was conducted (GLP) by applying treatment to Guinea shaved skin (test material secured by occlusive Pig) wrap) for 24 h; skin observed for 14 days; controls were not used HUMAN Sucrose Palmitate Human Female subjects, Nanoemulsions:-oil phase (drug Irritation Profile Test: 25 µL/cm2 nanoemulsions 3 h after occlusion was removed no cutaneous 46 (80% mono-, 17% n=8 (irritation aceclofenac), 1-2% (w/w) egg lecithin, (nanoemulsions tested on human skin all adverse reactions were visually observed; no di-, 3% tri-) Sucrose profile study) 10% medium chain triglycerides, 10% contained acecofenac; controls used were non- change in erythema index values; Stearate (48% mono- Castor oil, 0.05% butylhydroxy-toluene treated skin both with and without occlusion) transepidermal water loss increased , 34% di-, 14% tri-) -aqueous phase: applied to 3 x 3cm2 forearm surface area; substantially relative to baseline but not 0-2% (w/w) Sucrose Palmitate; 0-2% erythema index, transepidermal water loss, and compared to non-treatment controls; stratum (w/w) Sucrose Stearate stratum corneum hydration evaluated prior to corneum hydration showed substantial decrease testing (to establish a baseline) and 3 h after in all treated sites compared to baselines and removal of 24 h occlusion; negative controls used non-treated control under occlusion; nanoemulsions tested were tolerable to the skin

Sucrose Human n=40 100% Human Patch Test was performed (no further Negative (0% after 24 hours, no further details 58 Pentahydroxystearate details specified) specified)

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Table 15. Irritation Studies (Dermal) Test Substance(s) Species/ Test Population- Concentration (Vehicle) Procedure Results Reference Strain Sex Sucrose Human n=40 100% Human Patch Test was performed (no further Negative (0% after 24 hours, no further details 58 Tetraisostearate details specified) specified) Sucrose Human n=34 subjects, but 4 UV protectant prototypes, 3 Treatment applied each day occlusively (to back Erythema observed (4 subjects) in test group, 20 Polycottonseedate only 27 completed containing 0.5% Sucrose for 24 h) in a 21 day study; negative controls used erythema noted (23 subjects) in control group; study Polycottonseedate and 1 containing 1% slightly irritating Sucrose Polycottonseedate; no vehicle used Sucrose Human n=11 (all subjects Lotion squeezed from cleansing cloths Lotion containing treatment was applied daily at Non-irritating 19,20 Polycottonseedate, completed study) containing 3.18% Sucrose Polybehenate 100%, 50%, and 20% (v/v) occlusively for a 5- Sucrose and 12.73% Sucrose Polycottonseedate; day cumulative study; same dosages were applied Polybehenate water vehicle semi-occlusively to back for 24 h, 4x; negative controls used Sucrose Human n=55 subjects per Two facial cleansing cloths containing Treatment administered 2x/day for 4weeks in a 1 subject discontinued study on day 8 (mild 20 Polycottonseedate product (49 using Sucrose Polycottonseedate at 17.19% single blind study (uncontrolled conditions); use erythema and dryness with 17.19%); at 4 weeks 17.19% Sucrose and 15.79%; no vehicle used of controls not specified 5 subjects had mild to moderate conjunctival Polycottonseedate follicles, mild papillae, mild cysts, mild to cloths and 50 moderate concretions, mild mucous lens using 15.79% deposits and severe blurred vision; 2 subjects Sucrose did not complete due to adverse reactions Polycottonseed (severe itching, moderate erythema, papules, cloths completed tightness, hives and skin dryness, difficulty study) focusing, conjunctival injection); symptoms in 1 subject were reproducible when re-tested 3 weeks later after 4 days of application and determined to be treatment related; 1 subject re-tested on arm 12 days later with no symptoms, but symptoms returned upon facial application; 18 of 50 subjects (using 17.19%) and 12 of 50 subjects (using 15.79%) reported mild skin or eye conditions (dryness, redness, itching, stinging or burning, blurred vision); 4 of 30 reactions >mild but

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Table 16. Irritation and Sensitization Studies (Dermal) Test Substance(s) Species/ Test Population- Concentration (Vehicle) Procedure Results Reference Strain Sex ANIMAL Sucrose Acetate Guinea Unknown Skin Irritation Test: 5-20 ml Skin Irritation Test: Treatment was applied directly to hairless guinea Skin Irritation Test: Slight, transient 60 Isobutyrate Pig of 20% Sucrose Acetate pig skin and held in place by a secured gauze pad for 24 h irritation noted Isobutyrate in acetone + corn Delayed Sensitivity Test: 10 drops of solution (concentration not Delayed Sensitivity Test: No increased oil (9:1) specified) applied to hairless guinea pig skin and examined at 24 and reactivity observed Delayed Sensitivity Test: 48 h post-administration for irritation; 3 more applications Sucrose Acetate Isobutyrate in administered in 5 days followed by 3 week rest period; challenge acetone/ dioxane / guinea pig concentrations (not specified) applied to right shoulder and 1 week fat (7:2:1) later to left shoulder Use of controls not specified Sucrose Acetate Guinea Males, n=10 Induction: 1% Sucrose Acetate Guinea Pig Maximization Test performed, guidelines followed were Light erythema at exposure site for 5 of 10 18 Isobutyrate Pig Isobutyrate in Freund’s similar to OECD 406 (Skin Sensitization), GLP, challenge used Kodak controls and 6of 10 animals previously (Hartley Complete Adjuvant foot pad method) induced with treatment; non-sensitizer Guinea Challenge: 10% Sucrose pig) Induction: Treatment applied to shaved skin and occlusively secured Acetate Isobutyrate; (no further details specified) Vehicle=acetone + dioxane +

guinea pig fat (7:2:1) Challenge: Treatment applied topically; skin observed 24 h post- challenge

Negative (vehicle) controls used HUMAN Sucrose Acetate Human n=203 (40 males, 20% Sucrose Acetate Human Repeat Insult Patch Test (HRIPT) was performed using GLP One subject reported enlarged lymph 18 Isobutyrate 163 females) Isobutyrate (industrial grade) (more specific details not provided); use of controls not specified nodes (cervical area) and was discontinued completed study; in acetone (one of 6 in study (details do not indicate whether 38 additional substances tested, others were this was treatment related); 1 adverse subjects did not plasticizers/lubricants) event related and one possibly related to complete study treatment reported (details not specified); during induction phase isolated reports of slight erythema and 2 reports of mild erythema; at challenge 3 reports of slight erythema at 48 h (resolved by 96 h) post- administration and 1 report slight erythema first appearing at 96 h post- administration; non-irritating, no evidence of sensitization Sucrose Human n=113 (5 88% Sucrose HRIPT protocol followed (occlusive patch, 4 cm2) using undiluted test Staining of skin was observed in one 61 Polycottonseedate discontinued Polycottonseedate in a lipstick material (0.2 g); induction phase was approximately 3 weeks; rest subject during induction phase; no study for personal topcoat matrix period was approximately 2 weeks; use of controls not specified reactions were observed during rest reasons, no period; no reactions at challenge; non- reactions from sensitizing treatment); 108 subjects completed study

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Table 16. Irritation and Sensitization Studies (Dermal) Test Substance(s) Species/ Test Population- Concentration (Vehicle) Procedure Results Reference Strain Sex Sucrose Human n=233 (28 male, 4 UV protectant prototypes, 3 HRIPT was performed by applying treatment occlusively (to back for No subjects discontinued the study due to 20 Polycottonseedate 205 female); 200 containing 0.5% Sucrose 24 h) at 72 h intervals x 9 applications; the rest period was 10-26 days; treatment-related effects; during induction completed the Polycottonseedate and 1 challenge patches similarly applied to a previously untreated area and scattered positive findings for all study; 102- containing 1% Sucrose removed at 24 h post-application; use of controls not specified formulations with up to 8 showing definite normal skin; 98- Polycottonseedate; no vehicle erythema especially in sensitive skin sensitive skin used group; at challenge 1 subject showed definite erythema and 2 subjects had doubtful responses; no sensitization reported since numbers of responses at challenge were no higher than induction period treatment; researchers conducting this study reported that results were non- irritating Sucrose Human n=113 subjects Lotion squeezed from HRIPT was performed by applying treatment occlusively (to back for During induction definite erythema noted 19,20 Polycottonseedate, (24 male and 89 cleansing cloths containing 24 h) at 72 h intervals x 9 applications; the rest period was 10-14 days; in 1 subject; at challenge 4 doubtful Sucrose female); 102 3.18% Sucrose Polybehenate challenge patches similarly applied to a previously untreated area and responses at 24h; no challenge responses Polybehenate completed study and 12.73% Sucrose removed at 24 h post-application; use of controls not specified at 48 h; no sensitization due to responses Polycottonseedate; no vehicle at challenge generally lower than single used induction treatment; researchers conducting this study reported that results were non-irritating Sucrose Human n=108 subjects (7 Two facial cleansing cloths HRIPT was performed by applying treatment occlusively (to back for Up to 1 subject at any observation time for 20 Polycottonseedate male and 101 containing Sucrose 24 h) at 72 h intervals x 9 applications; the rest period was 10-14 days; either product showed definite erythema; female); 107 Polycottonseedate at 17.19% challenge patches similarly applied to a previously untreated area and no challenge responses at 48 h post- completed study and 15.79%; no vehicle used removed at 24 h post-application; use of controls not specified application, at 24 h post-application 2 subjects showed definite erythema; no sensitization since numbers at challenge were lower than after single induction treatment; researchers conducting this study reported that results were non- irritating

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61. Harrison Research Laboratories Inc. 1999. Human repeated insult patch test of a lipstick topcoat containing 88% Sucrose Polycottonseedate.

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64. National Institute of Health-U.S. National Library of Medicine-National Center for Biotechnology Information-PubChem (PubChem). PubChem Open Chemistry Database. http://pubchem.ncbi.nlm.nih.gov. Last Updated 2005. Date Accessed 11-7-2015.

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78. Klang V, Matsko N, RaupachK, El-Hagin N, and Valenta C. Development of sucrose stearate-based nanoemulsions and optimisation through gamma-cyclodextrin. Eur.J Pharm Biopharm. 2011;79(1):58-67.

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VCRP Data For Saccharide Esters-2016

75765490 MALTITOL LAURATE 05F - Shampoos (non-coloring) 1

126136 SUCROSE ACETATE ISOBUTYRATE 03B – Eyeliner 3 126136 SUCROSE ACETATE ISOBUTYRATE 03C - Eye Shadow 10 126136 SUCROSE ACETATE ISOBUTYRATE 03F – Mascara 5 126136 SUCROSE ACETATE ISOBUTYRATE 03G - Other Eye Makeup Preparations 4 126136 SUCROSE ACETATE ISOBUTYRATE 04B – Perfumes 1 126136 SUCROSE ACETATE ISOBUTYRATE 04E - Other Fragrance Preparation 1 126136 SUCROSE ACETATE ISOBUTYRATE 07B - Face Powders 1 126136 SUCROSE ACETATE ISOBUTYRATE 07C – Foundations 3 126136 SUCROSE ACETATE ISOBUTYRATE 07D - Leg and Body Paints 1 126136 SUCROSE ACETATE ISOBUTYRATE 07E – Lipstick 18 126136 SUCROSE ACETATE ISOBUTYRATE 07I - Other Makeup Preparations 15 126136 SUCROSE ACETATE ISOBUTYRATE 08A - Basecoats and Undercoats 7 126136 SUCROSE ACETATE ISOBUTYRATE 08D - Nail Extenders 1 126136 SUCROSE ACETATE ISOBUTYRATE 08E - Nail Polish and Enamel 195 126136 SUCROSE ACETATE ISOBUTYRATE 08F - Nail Polish and Enamel Removers 1 126136 SUCROSE ACETATE ISOBUTYRATE 08G - Other Manicuring Preparations 6 126136 SUCROSE ACETATE ISOBUTYRATE 12D - Body and Hand (exc shave) 1 126136 SUCROSE ACETATE ISOBUTYRATE 12J - Other Skin Care Preps 1

52439697 SUCROSE ACETATE STEARATE 03B – Eyeliner 1 52439697 SUCROSE ACETATE STEARATE 03C - Eye Shadow 1

12738646 SUCROSE BENZOATE 08A - Basecoats and Undercoats 9 12738646 SUCROSE BENZOATE 08E - Nail Polish and Enamel 29 12738646 SUCROSE BENZOATE 08G - Other Manicuring Preparations 10

977010835 SUCROSE COCOATE 01A - Baby Shampoos 1 977010835 SUCROSE COCOATE 03D - Eye Lotion 3 977010835 SUCROSE COCOATE 03E - Eye Makeup Remover 3 977010835 SUCROSE COCOATE 03G - Other Eye Makeup Preparations 2 977010835 SUCROSE COCOATE 05A - Hair Conditioner 2 977010835 SUCROSE COCOATE 05F - Shampoos (non-coloring) 1 977010835 SUCROSE COCOATE 07B - Face Powders 1 977010835 SUCROSE COCOATE 07E – Lipstick 14 977010835 SUCROSE COCOATE 07I - Other Makeup Preparations 15 977010835 SUCROSE COCOATE 10A - Bath Soaps and Detergents 13 977010835 SUCROSE COCOATE 10B - Deodorants (underarm) 11 977010835 SUCROSE COCOATE 10E - Other Personal Cleanliness Products 2 977010835 SUCROSE COCOATE 11A - Aftershave Lotion 1 977010835 SUCROSE COCOATE 11E - Shaving Cream 1 977010835 SUCROSE COCOATE 11G - Other Shaving Preparation Products 1 977010835 SUCROSE COCOATE 12A – Cleansing 23 977010835 SUCROSE COCOATE 12C - Face and Neck (exc shave) 9 977010835 SUCROSE COCOATE 12D - Body and Hand (exc shave) 3 977010835 SUCROSE COCOATE 12F – Moisturizing 21 977010835 SUCROSE COCOATE 12G – Night 8 977010835 SUCROSE COCOATE 12H - Paste Masks (mud packs) 1 977010835 SUCROSE COCOATE 12J - Other Skin Care Preps 2 977010835 SUCROSE COCOATE 13B - Indoor Tanning Preparations 1

25915575 SUCROSE DILAURATE 03B – Eyeliner 2 25915575 SUCROSE DILAURATE 07C – Foundations 2 Distributed for Comment Only -- Do Not Cite or Quote

VCRP Data For Saccharide Esters-2016 (con’t)

25915575 SUCROSE DILAURATE 12A – Cleansing 2 25915575 SUCROSE DILAURATE 12C - Face and Neck (exc shave) 4 25915575 SUCROSE DILAURATE 12D - Body and Hand (exc shave) 2 25915575 SUCROSE DILAURATE 12H - Paste Masks (mud packs) 1

25637972 SUCROSE DIPALMITATE 12A – Cleansing 1

27195160 SUCROSE DISTEARATE 03C - Eye Shadow 7 27195160 SUCROSE DISTEARATE 03F – Mascara 12 27195160 SUCROSE DISTEARATE 03G - Other Eye Makeup Preparations 1 05G - Tonics, Dressings, and Other Hair 27195160 SUCROSE DISTEARATE Grooming Aids 1 27195160 SUCROSE DISTEARATE 07C – Foundations 2 27195160 SUCROSE DISTEARATE 07E – Lipstick 1 27195160 SUCROSE DISTEARATE 08B - Cuticle Softeners 2 27195160 SUCROSE DISTEARATE 10E - Other Personal Cleanliness Products 1 27195160 SUCROSE DISTEARATE 12A – Cleansing 3 27195160 SUCROSE DISTEARATE 12C - Face and Neck (exc shave) 4 27195160 SUCROSE DISTEARATE 12D - Body and Hand (exc shave) 19 27195160 SUCROSE DISTEARATE 12E - Foot Powders and Sprays 2 27195160 SUCROSE DISTEARATE 12F – Moisturizing 8 27195160 SUCROSE DISTEARATE 12G – Night 2 27195160 SUCROSE DISTEARATE 12J - Other Skin Care Preps 2

01B - Baby Lotions, Oils, Powders, and 25339995 SUCROSE LAURATE Creams 1 25339995 SUCROSE LAURATE 01C - Other Baby Products 2 25339995 SUCROSE LAURATE 02D - Other Bath Preparations 2 25339995 SUCROSE LAURATE 03B – Eyeliner 3 25339995 SUCROSE LAURATE 03E - Eye Makeup Remover 1 25339995 SUCROSE LAURATE 04A - Cologne and Toilet waters 1 25339995 SUCROSE LAURATE 05I - Other Hair Preparations 1 25339995 SUCROSE LAURATE 07C – Foundations 2 25339995 SUCROSE LAURATE 07I - Other Makeup Preparations 1 25339995 SUCROSE LAURATE 09C - Other Oral Hygiene Products 1 25339995 SUCROSE LAURATE 10A - Bath Soaps and Detergents 3 25339995 SUCROSE LAURATE 12A – Cleansing 5 25339995 SUCROSE LAURATE 12C - Face and Neck (exc shave) 6 25339995 SUCROSE LAURATE 12D - Body and Hand (exc shave) 6 25339995 SUCROSE LAURATE 12F – Moisturizing 3 25339995 SUCROSE LAURATE 12H - Paste Masks (mud packs) 2 25339995 SUCROSE LAURATE 12J - Other Skin Care Preps 2

27216473 SUCROSE MYRISTATE 03E - Eye Makeup Remover 1 27216473 SUCROSE MYRISTATE 12A – Cleansing 2

01B - Baby Lotions, Oils, Powders, and 39300953 SUCROSE PALMITATE Creams 1 39300953 SUCROSE PALMITATE 01C - Other Baby Products 2 39300953 SUCROSE PALMITATE 03B – Eyeliner 4 39300953 SUCROSE PALMITATE 03D - Eye Lotion 2 39300953 SUCROSE PALMITATE 03G - Other Eye Makeup Preparations 1 39300953 SUCROSE PALMITATE 04A - Cologne and Toilet waters 1 39300953 SUCROSE PALMITATE 05A - Hair Conditioner 2 Distributed for Comment Only -- Do Not Cite or Quote

VCRP Data For Saccharide Esters-2016 (con’t)

39300953 SUCROSE PALMITATE 05F - Shampoos (non-coloring) 2 39300953 SUCROSE PALMITATE 07I - Other Makeup Preparations 1 39300953 SUCROSE PALMITATE 11G - Other Shaving Preparation Products 1 39300953 SUCROSE PALMITATE 12A – Cleansing 4 39300953 SUCROSE PALMITATE 12C - Face and Neck (exc shave) 25 39300953 SUCROSE PALMITATE 12D - Body and Hand (exc shave) 7 39300953 SUCROSE PALMITATE 12F – Moisturizing 8 39300953 SUCROSE PALMITATE 12G – Night 3 39300953 SUCROSE PALMITATE 12H - Paste Masks (mud packs) 5 39300953 SUCROSE PALMITATE 12J - Other Skin Care Preps 5

999003730 SUCROSE PALMITATE/STEARATE 12C - Face and Neck (exc shave) 1

977185004 SUCROSE POLYBEHENATE 03F – Mascara 1 977185004 SUCROSE POLYBEHENATE 07I - Other Makeup Preparations 1

977184987 SUCROSE POLYCOTTONSEEDATE 03D - Eye Lotion 2 977184987 SUCROSE POLYCOTTONSEEDATE 03G - Other Eye Makeup Preparations 1 977184987 SUCROSE POLYCOTTONSEEDATE 07E – Lipstick 4 977184987 SUCROSE POLYCOTTONSEEDATE 12B – Depilatories 1 977184987 SUCROSE POLYCOTTONSEEDATE 12C - Face and Neck (exc shave) 6 977184987 SUCROSE POLYCOTTONSEEDATE 12F – Moisturizing 6 977184987 SUCROSE POLYCOTTONSEEDATE 12G – Night 2 977184987 SUCROSE POLYCOTTONSEEDATE 12J - Other Skin Care Preps 1

999004031 SUCROSE POLYLAURATE 12F – Moisturizing 1

999003912 SUCROSE POLYOLEATE 05A - Hair Conditioner 1

999003120 SUCROSE POLYSOYATE 12C - Face and Neck (exc shave) 2 999003120 SUCROSE POLYSOYATE 12F – Moisturizing 17

999002946 SUCROSE POLYSTEARATE 03F – Mascara 1 999002946 SUCROSE POLYSTEARATE 07B - Face Powders 3 999002946 SUCROSE POLYSTEARATE 07C – Foundations 3 999002946 SUCROSE POLYSTEARATE 07E – Lipstick 3 999002946 SUCROSE POLYSTEARATE 07I - Other Makeup Preparations 1 999002946 SUCROSE POLYSTEARATE 11A - Aftershave Lotion 1 999002946 SUCROSE POLYSTEARATE 12D - Body and Hand (exc shave) 1 999002946 SUCROSE POLYSTEARATE 12F – Moisturizing 3

01B - Baby Lotions, Oils, Powders, and 25168734 SUCROSE STEARATE Creams 1 25168734 SUCROSE STEARATE 01C - Other Baby Products 3 25168734 SUCROSE STEARATE 03C - Eye Shadow 6 25168734 SUCROSE STEARATE 03D - Eye Lotion 7 25168734 SUCROSE STEARATE 03E - Eye Makeup Remover 1 25168734 SUCROSE STEARATE 03F – Mascara 12 25168734 SUCROSE STEARATE 03G - Other Eye Makeup Preparations 6 25168734 SUCROSE STEARATE 04A - Cologne and Toilet waters 1 05G - Tonics, Dressings, and Other Hair 25168734 SUCROSE STEARATE Grooming Aids 3 25168734 SUCROSE STEARATE 07C – Foundations 1 25168734 SUCROSE STEARATE 07E – Lipstick 1 Distributed for Comment Only -- Do Not Cite or Quote

VCRP Data For Saccharide Esters-2016 (con’t)

25168734 SUCROSE STEARATE 07I - Other Makeup Preparations 2 25168734 SUCROSE STEARATE 08B - Cuticle Softeners 2 25168734 SUCROSE STEARATE 08C - Nail Creams and Lotions 1 25168734 SUCROSE STEARATE 10E - Other Personal Cleanliness Products 2 25168734 SUCROSE STEARATE 11A - Aftershave Lotion 1 25168734 SUCROSE STEARATE 12A – Cleansing 25 25168734 SUCROSE STEARATE 12C - Face and Neck (exc shave) 23 25168734 SUCROSE STEARATE 12D - Body and Hand (exc shave) 23 25168734 SUCROSE STEARATE 12E - Foot Powders and Sprays 3 25168734 SUCROSE STEARATE 12F – Moisturizing 16 25168734 SUCROSE STEARATE 12G – Night 7 25168734 SUCROSE STEARATE 12H - Paste Masks (mud packs) 2 25168734 SUCROSE STEARATE 12J - Other Skin Care Preps 4 25168734 SUCROSE STEARATE 13B - Indoor Tanning Preparations 3

SUCROSE STEARATE-PALMITATE 01B - Baby Lotions, Oils, Powders, and 999000716 ESTER Creams 2

999002092 SUCROSE TETRAISOSTEARATE 03F – Mascara 3

SUCROSE TETRASTEARATE 977185628 TRIACETATE 03A - Eyebrow Pencil 9 SUCROSE TETRASTEARATE 977185628 TRIACETATE 03B – Eyeliner 13 SUCROSE TETRASTEARATE 977185628 TRIACETATE 03C - Eye Shadow 9 SUCROSE TETRASTEARATE 977185628 TRIACETATE 03F – Mascara 5 SUCROSE TETRASTEARATE 977185628 TRIACETATE 03G - Other Eye Makeup Preparations 2 SUCROSE TETRASTEARATE 977185628 TRIACETATE 07C – Foundations 1 SUCROSE TETRASTEARATE 977185628 TRIACETATE 07E – Lipstick 7 SUCROSE TETRASTEARATE 977185628 TRIACETATE 07I - Other Makeup Preparations 13 SUCROSE TETRASTEARATE 977185628 TRIACETATE 12F – Moisturizing 2

999003703 SUCROSE TRILAURATE 03B – Eyeliner 2

27923633 SUCROSE TRISTEARATE 07E – Lipstick 1 27923633 SUCROSE TRISTEARATE 12A – Cleansing 2 27923633 SUCROSE TRISTEARATE 12C - Face and Neck (exc shave) 2 27923633 SUCROSE TRISTEARATE 12D - Body and Hand (exc shave) 4 27923633 SUCROSE TRISTEARATE 12F – Moisturizing 9 27923633 SUCROSE TRISTEARATE 12J - Other Skin Care Preps 1

Distributed for Comment Only -- Do Not Cite or Quote Distributed for Comment Only -- Do Not Cite or Quote Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO: Lillian Gill, D.P.A. Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: Beth A. Lange, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: July 8, 2016

SUBJECT: Comments on the Tentative Report: Safety Assessment of Saccharide Esters as Used in Cosmetics (released June 23, 2016)

Chemical and Physical Properties - This section hints at a relationship between water solubility and number of esters. Can more information be provided on how structure relates to solubility? Cosmetic Use - Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate, two names in the VCRP but not in the Dictionary, are listed together in Tables 1 and 2. In the Cosmetic Use section, it is not correct to state that these names “are listed together in the INCI Dictionary”. The concentration of use survey for Sucrose Dipalmitate is not yet complete. Therefore, it is not yet correct to state “but no use concentration data were reported.” ADME Human, Table 9, Summary - Table 9 includes 3 human ADME studies. It is not clear why only the single dose study using radiolabled Sucrose Acetate Isobutryate is presented in the text (both ADME and Summary). The multi-dose study should also be mentioned in the text. Developmental and Reproductive Toxicity - Rather than saying that “Several” studies of Sucrose Acetate Isobutyrate were completed, it would be more precise to state the number of studies completed (four). Irritation - Please state the compound tested in the rabbit study in which irritation was reported, and the compound tested in the guinea pig study that reported slight irritation. Discussion - The meaning of the following sentence is not clear: “The available data on many of the ingredients are sufficient, however, and based on the similarity that exists between structural activity relationships and biologic functions in cosmetic concentrations of use, the data presented here can be extrapolated to support the safety of the entire group.” What are the “biologic functions” of these ingredients? The studies presented in the report are essentially negative at large oral doses. Most of the data in the report are on Sucrose Acetate Isobutyrate. How was a structural activity relationship determined? Distributed for Comment Only -- Do Not Cite or Quote

Because Sucrose Acetate Isobutyrate, one of the smaller compounds, was studied for many endpoints, the data can be extrapolated to larger compounds because they will be less likely to penetrate the skin following dermal exposure. Table 1 - To be consistent with the rest of the ingredients, please include the carbon chain lengths for Sucrose Acetate Isobutyrate (C2, C4 branched). Table 4 - Rather than stating “computational, calculated from a mono-caprylate-substituted Xylityl moiety” multiple times in Table 4, this could be 1 footnote to the table. Table 8 - The description of references 77 and 56 uses “acceptor chambers” and “receptor compartment”. If these are the same compartment, one name should be used to describe it. 14 Table 9, Reference 45 - Please correct “C O2" Table 11, Human, third study reference 50 - Were there negative controls in this study in addition to each subject serving as their own control?

The first study in the subchronic oral section says “(see subchronic section of this table)”. This does not make sense as it is in the subchronic section. Table 12 - If no developmental and reproductive toxicity studies are identified on other compounds, Sucrose Acetate Isobutyrate can be added to the title of the table and the test substance column can be deleted in Table 12 of the final report.

If studies were negative for teratogenic/developmental effects, it does not make sense to state that it was not specified if the NOAEL applied to both parents and offspring. It is not clear what is meant by “respiratory outbreak” Table 15, Sucrose Laurate, reference 61 - Is this the correct reference for this study as the title says: “Evaluation of seven alternative assays on the main ingredients in cosmetics as predictors of draize eye irritation scores” - and the study described concerns potential skin irritation.