Safety Assessment of Saccharide Esters As Used in Cosmetics

Safety Assessment of Saccharide Esters as Used in Cosmetics

Status: Draft Report for Panel Review Release Date: May 13, 2016 Panel Meeting Date: June 6-7, 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.

Commitment & Credibility since 1976

Memorandum

To: CIR Expert Panel Members and Liaisons From: Laura N. Scott Senior Scientific Writer Date: May 13, 2016 Subject: Draft Report of the Safety Assessment of Saccharide Esters as Used in Cosmetics

Enclosed is the Draft Report of the Safety Assessment of Saccharide Esters as Used in Cosmetics (identified as SACEST062016rep in the PDF document). This is the first time the Panel is seeing this safety assessment of 41 synthetic cosmetic ingredients that are the end products of the esterification of simple saccharides with a carboxylic acid. The Scientific Literature Review was issued on March 22, 2016.

The Panel has reviewed the following reports with related or constituent ingredients of the saccharide esters: in 2014, monosaccharides, disaccharides, and related ingredients (safe as used); in 2013, Decyl Glucoside and other alkyl glucosides, which differ from glucose ester only in the number of glucose equivalents (safe as used when formulated to be non-irritating); and multiple safety assessments of various saccharide ester constituent acids with safe as used conclusions (e.g., acetic acid, lauric acid, and stearic acid).

Concentrations of use data were received from the Council and are included in this package (SACEST062016data_1). Sucrose Dipalmitate, Sucrose Palmitate/Stearate, and Sucrose Stearate-Palmitate Ester have not yet been included in a Council industry survey, but when that data become available it will be added to the report. Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate Ester are listed in the Definitions/Functions Table 2 on the same line because they have the same definition; for the ingredient count they are also considered to be the same ingredient. However, they are listed on separate lines in the Use Table because data was recited in the VCRP for each separately.

Also included are VCRP data (SACEST062016FDA). Of the 41 saccharide esters presented in this safety assessment, 24 are reported to be used in a total of 970 cosmetic formulations; Sucrose Acetate Isobutyrate has the highest reported uses (274). Sucrose Polycottonseedate has the highest maximum reported concentration of use in lipstick up to 87.7%. Saccharide esters were reported to be used in cosmetic formulations indicating potential exposure to the eye area and mucous membranes, possible ingestion, as well as, use in baby products.

Additionally, the CIR report history (SACEST062016hist), Process flow chart (SACEST062016flow), Literature search strategy (SACEST062016strat), and Ingredient Data profile (SACEST062016prof) are enclosed for the Panel’s review.

The following unpublished data have been submitted:

1. Harrison Research Laboratories, Inc. (submitted in 2015): HRIPT (from 1999) of a lipstick topcoat containing 88% Sucrose Polycottonseedate (SACEST062016data_2).

______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

Council comments on the SLR (SACEST062016pcpc) were received and have been addressed.

[Note: In this Draft 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.]

If the data included in this report adequately address the safety of the saccharide esters, the Panel should be prepared to formulate a tentative conclusion, provide the rationale to be described in the Discussion, and issue a Tentative Report for public comment. If the data are not sufficient for making a determination of safety, then an Insufficient Data Announcement should be issued that provides a listing of the additional data that are needed.

______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 SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY _____Saccharide Esters______

MEETING _____June 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

Issue TR Tentative Report

Draft FR DRAFT FINAL REPORT

60 day Public comment period

Table

Table Different Conclusion

Issue PUBLISH Final Report FR

Distributed for Comment Only -- Do Not Cite or Quote

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

Saccharide Esters Data Profile for June 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 Cosmetic Cosmetic Reported Available No 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

Safety Data Data Safety

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

Use

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

Safety Data Data Safety

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

Use

Sucrose Tetraisostearate Y X Sucrose Acetate/ Stearate Y X Sucrose Tetrastearate Triacetate Y X Sucrose Palmitate/ Stearate Y X Sucrose Palmitate-Stearate Y X Ester Sucrose Polysoyate Y X Sucrose Hexaoleate/ Y X Hexapalmitate/ Hexastearate Sucrose Cocoate Y X Sucrose Polycottonseedate Y X X Non-Alkyl Esters Sucrose Benzoate Y X Sucrose Disinapate N 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 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* 25637972 - Yes X

Sucrose Disinapate N/A - No ------X

Sucrose Distearate 27195-16-0 - Yes - X - X - - - - X Listed, no X further info Sucrose Hexaerucate N/A - No - 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 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 - Yes - - - X ------X

Sucrose Palmitate- 999000716 Stearate Ester* - Yes -

Sucrose Pentaerucate N/A - No - X ------X

Sucrose N/A Pentahydroxy- - No ------Stearate Sucrose Polybehenate 93571-82-5 - Yes ------X X

Sucrose 93571-82-5 Polycottonseedate - Yes ------X X

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

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

Sucrose Polysoyate 93571-82-5 - Yes ------X CAS# X listed 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

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 above

Saccharide Esters Search Info Distributed for Comment Only -- Do Not Cite or Quote

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 sesqui caprylate) 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: 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 Distributed for Comment Only -- Do Not Cite or Quote

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

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 Distributed for Comment Only -- Do Not Cite or Quote

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)…

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

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:

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

(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)…

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

(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.

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 Distributed for Comment Only -- Do Not Cite or Quote

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

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Safety Assessment of Saccharide Esters as Used in Cosmetics

Status: Draft Report for Panel Review Release Date: May 13, 2016 Panel Meeting Date: June 6-7, 2016

INTRODUCTION

This safety assessment includes the 41 saccharide esters listed below. Maltitol Laurate has been reviewed previously by the Cosmetic Ingredient Review (CIR) Expert Panel (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 Disinapate 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, Sucrose Dipalmitate, and Sucrose Stearate-Palmitate Ester are not found in the International Cosmetic Ingredient Dictionary and Handbook (Dictionary), but they are included in the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP) as ingredients used in cosmetic products. Thus, they are included in this safety assessment. The VCRP also provides data on Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate Ester as individual ingredients, however structurally they are considered to have the same definition; they are combined in the Definitions and Functions Table 2 as one entry. The saccharide esters have various reported functions in cosmetics, including use as emollients, 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 Xylityl, 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 3.1,3-14 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.15 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 3.1,3-14 Sucrose Acetate Isobutyrate is generally recognized as safe (GRAS) for use as a direct food additive in the United States.16 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, on the Australian Government Department of Health’s National Industrial Chemicals Notification and Assessment Scheme (NICNAS) website, and in a report published by the World Health Organization (WHO). 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.

# On the in-text Table references use “Ctrl + left click” in Word, or double (left) click in the PDF version, to link directly to the corresponding Table at the end of the document.

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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 either glucose (monosaccharide), sucrose (disaccharide composed of glucose and fructose), the sugar alcohol maltitol derived from maltose (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 chainlength, 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 range of hydrophilic-lipophilic balance (HLB), which is characteristic of sucrose esters, allows these chemicals to function as oil-in-water (high HLB values) and water-in-oil emulsifiers (low HLB values).17 The hexa-, hepta-, and octa- substituted esters are used as fat replacers in food. The lower 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 higher HLB values. Secondary to that effect 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 listed in order by sub-groups according to chain length in Table 2, along with definitions, structures, and functions in cosmetics, as presented in the Dictionary. Chemical and Physical Properties Sucrose fatty acid esters (e.g., Sucrose Laurate) may be stiff gels, soft solids, or white/slightly gray powders.18 Generally, they are sparingly soluble in water, depending on the percentage of mono esters, and soluble in ethanol. The chemical and physical properties of the saccharide esters evaluated in this safety assessment are listed in Table 4. Method of Manufacture Sucrose fatty acid esters (e.g., Sucrose Laurate) that are used in food may be prepared from sucrose, the methyl and ethyl esters of edible fatty acids, or edible, naturally-occurring vegetable oils, using food-grade solvents such as ethyl acetate, methyl ethyl ketone, dimethyl sulfoxide, or isobutanol.18 Impurities Lead impurities are acceptable at not more than (NMT) 1 mg/kg in Sucrose Acetate Isobutyrate used in food, according to the Food Chemicals Codex.18 The following acceptance criteria apply to sucrose fatty acid esters in food: lead (NMT 2 mg/kg in 10 g sample); dimethyl sulfoxide (NMT 2 mg/kg in a 5 g sample); ethyl acetate (NMT 350 mg/kg), isobutanol (NMT 10 mg/kg), methanol (NMT 10 mg/kg), and methyl ethyl ketone (NMT 10 mg/kg) in a 1 g powdered sample. 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/or pesticide residues.19 In a CIR safety assessment published in 2001 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.

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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 201620 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 21 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. Sucrose Dipalmitate and Sucrose Palmitate/Stearate have not yet been included in the Council’s industry survey; that data will be added to the report when it becomes available. Although in Table 2 Sucrose Palmitate/Stearate and Sucrose Stearate-Palmitate Ester are listed together in the INCI Dictionary, with the same structural definition, they are listed separately in Table 5 because the data for each are presented separately in the VCRP.20 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 the hair non-coloring product category.20 The 15 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, but concentration of use data were not provided. For example, Sucrose Dipalmitate is reported to be used in 1 cosmetic formulation, but no use concentration data were reported.20 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%.21 It should be presumed in these cases that there is at least one use in every category for which a concentration or a frequency of use is reported. Saccharide esters were reported to be used in perfumes, hair sprays, deodorants, and powders, and could possibly be inhaled. As examples, Sucrose Laurate is reportedly used in pump hair sprays at concentrations up to 1.2%; Sucrose Stearate is reportedly used in aerosol deodorant sprays at concentrations up to 0.23%; Sucrose Tristearate is reportedly used in powders at concentrations up to 2%.21 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.22,23,24,25 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.22,23 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.23 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. Conservative estimates of inhalation exposures to respirable particles during the use of loose powder cosmetic products are 400-fold to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace.26-28 Saccharide esters were reported to be used in cosmetic formulations indicating potential eye exposure, possible mucous membrane exposure, and possible ingestion, as well as, use in baby products. 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.29 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 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

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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 in a gelatin coated capsule for oral administration at 30 mg; Sucrose Palmitate in a powder for suspension intended for oral administration at 10 mg/1scoop; Sucrose Stearate/ Sucrose Distearate in a topical emulsion cream at 5%, w/w; Sucrose Stearate in a sustained action capsule or an extended release tablet for oral administration up to 44.5%.30

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.31 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 in size and comprised of 50:50:5; Sucrose Laurate: micelle-forming surfactant PEG-8-L: stabilizer sulfosuccinate) containing Sucrose Laurate (30% mono-, 40% di-, 30% tri-) were evaluated in human subjects (n ≥ 3). In all of the tests performed 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 were 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 occlusion test was performed by applying 100 µL of vesicle formulation, both occlusively and 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 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 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 Penetration enhancement experiments are summarized 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 lidocaine32, and in rat skin Sucrose Laurate (30% aqueous solution) was found to be a penetration enhancer for the drug cyclosporine.33 Experiments in micropig skin, evaluating polyphenols in oil-in-water microemulsions (25:19:5:60, Sucrose Laurate:ethanol:iso-propyl 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.34 Sucrose Laurate and Sucrose Myristate (variable between 0.1-3 mg/mL) showed a dose-dependent enhancement of paracellular permeability of a fluorescein isothiocyanate labelled dextran marker in human nasal epithelial cells.35 In a nanoemulsion, Sucrose Stearate (1%) was a permeation enhancer for progesterone in an in vitro porcine skin test.36

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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 experiment37; 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 oestradiol.38 In a unique 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.39 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.40 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.41 Sucrose Oleate and Sucrose Laurate, both tested at 2% and 10% in human subjects, increased skin penetration of the drug 4-hydroxy-benzonitrile.42 Absorption, Distribution, Metabolism, Excretion (ADME) Absorption, distribution, metabolism, and excretion studies are summarized in Table 9. In Vitro Experiments conducted in vitro showed that a mixture of Sucrose Palmitate and Sucrose Stearate (1 µmol/ml, 14C-labelled) 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.43 Results from another rat test in vitro indicated that Sucrose Acetate Isobutyrate (up to 250 µg/ml, 14C-labelled) was 75% hydrolyzed by intestinal mucosa in 6 hours; little hydrolysis was noted in the stomach and liver.44 In an in vitro study testing human fecal homogenates, 1 mg/ml and 0.1 mg/ml Sucrose Acetate Isobutyrate (14C- labelled) were 40% and 60%, respectively, hydrolyzed in 16 hours.44 Animal Tests conducted in rats (oral exposure) revealed the following: Glucose Pentaacetate (20% aqueous solution) was rapidly absorbed (>90%) in 4 hours45; a mixture of Sucrose Palmitate and Sucrose Stearate (up to 250 mg/kg, 14C-labelled) was excreted in feces (30% to 67% of dose), exhaled (11% to 49% of dose), and not detected in urine or blood at 120 hours post-dosing43; a mixture of sucrose esters (250 mg/kg, 14C-labelled), including Sucrose Hexastearate, were hydrolyzed prior to intestinal absorption (less esterified compounds were better absorbed) and largely excreted in feces (>95% of dose) at 120 hours post-dosing46; 200 mg/kg of 14C-labelled Sucrose Octaisobutyrate (a component of Sucrose Acetate Isobutyrate) was excreted in feces (78% to 93% of dose), excreted as a volatile product (3% to 15% of dose), and eliminated in urine (1% to 2% of dose).47 In dogs and monkeys orally administered 200 mg/kg of 14C-Sucrose Octaisobutyrate no radioactivity was detected in whole blood or plasma and excretion in feces was 77% to 94% of the dose and 62% to 85% of dose, respectively.47 In dogs, 14C-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.47 Human Human subjects administered a single, oral dose of 1.0 to 1.2 mg/kg 14C-Sucrose Acetate Isobutyrate exhaled 41% to 66% of the dose in the breath within 30 days post-administration; 15% to 21% of the dose was eliminated in urine and 10% of the dose was excreted in feces.48

TOXICOLOGICAL STUDIES

Acute Toxicity Studies Acute (single exposure) toxicity studies are summarized in Table 10. 49 The LD50 was reported to be > 20 g/kg in a study in which a single dose of Sucrose Acetate Isobutyrate was dermally applied to rats. For rats and monkeys orally administered single doses of Sucrose Acetate Isobutyrate the LD50 was reported to be > 5 g/kg bw and > 20 g/kg bw, respectively.49 In dogs orally administered a single dose of 2 g/kg bw Sucrose Acetate Isobutyrate an increase in plasma bromosulfophthalein (BSP) levels was reported.50 Short-Term Toxicity Studies Short-term toxicity studies are summarized in Table 11. Animal Repeated dose studies conducted in animals that were orally administered Sucrose Acetate Isobutyrate resulted in the following: Sucrose Acetate Isobutyrate was well tolerated in a 15 day study in monkeys orally administered (gavage) 10 g/kg/day50; in a 4-week study in mice fed 5 g/kg/day in their diet no effects were reported50; in a 12-week study in dogs dosed up to 4%/day in their diet an increase in serum alkaline phosphatase (SAP) levels was observed51; reported in a 90-day study in dogs was a no-observed-adverse-

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effect-level (NOAEL) > 20 g/kg/day (2%), an increase in SAP (with 2% dose), and an increase in liver weights (with 0.6% and 2% doses).49 Studies in which Sucrose Polysoyate was orally administered to dogs and rats in their diets for 28 and 90 days, respectively, reported a no-observed-effect-level (NOEL) of 15%/day for each species and was found not to be absorbed by the gastrointestinal tract in either species.52,53 Human Human subjects orally administered 0.02 g/kg/day of Sucrose Acetate Isobutyrate for 14 days experienced no blood chemistry or hematological abnormalities.50 Chronic Toxicity Chronic toxicity studies are summarized in Table 11.

Reported in a 1 year study in monkeys was a NOAEL of 2.4 g/kg/day54; reported in a 1 year study in rats was a NOAEL of 2 g/kg/day.55

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES

Reproductive and developmental toxicity studies are summarized in Table 12. In animals orally exposed to Sucrose Acetate Isobutyrate test results showed the following: in a 3-generation study in rats (dosed daily in the diet for 10 weeks-males and 2 weeks-females, prior to mating) teratogenic and developmental toxic effects were not observed and a NOAEL of 2 g/kg/day, the highest dose rate tested, was reported (not specified as to whether the NOAEL applies to parents only or also includes offspring)56; 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 (not specified as to whether this applies to parents only or also includes offspring), 2 of 16 rabbits dosed at this level died on day 17 of gestation, and teratogenic or developmental toxic effects were not observed37; rats fed 9.38% in their diet for 5 weeks (rats bred 3x in 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.50

GENOTOXICITY STUDIES

Summary data from genotoxicity studies are presented in Table 13.

In Vitro Sucrose Acetate Isobutyrate was evaluated in vitro. An Ames test conducted in Salmonella typhimurium cells showed that the ingredient (Sucrose Acetate Isobutyrate) was non-toxic at concentrations up to 10,000 µg/plate.57 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. A chromosomal aberration assay in CHO cells showed no increase in aberrations up to 2000 µg/ml. An unscheduled DNA synthesis assay in rat hepatocytes was non-toxic for test substance Sucrose Acetate Isobutyrate at concentrations upto 10,000 µg/ml. In Vivo A study in which male rats were administered a single dose (2000 mg/kg) of Sucrose Acetate Isobutyrate by gavage and subsequently mated with untreated females yielded negative results for dominant lethal mutations.49

CARCINOGENICITY STUDIES

Animal Sucrose Acetate Isobutyrate In a 2-year carcinogenicity study, F344 rats (n=50/sex/dose group) were fed a diet containing Sucrose Acetate Isobutyrate (available ad lib.). The nominal dose rates were 0 (control group 1), 0 (control group 2), 0.5, 1.0, and 2.0 g/kg/day .55 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. Hematology samples were collected from all surviving animals at study week 4. Results of the 2-year study were: no Sucrose Acetate Isobutyrate treatment-related deaths or clinical effects; food consumption and hematological parameters were unaffected by treatment; occasional decreased mean body weight compared to controls in females up to 61 weeks at 0.5 g/kg/day and up to 73 weeks at 1.0 or 2.0 g/kg/day were observed; there was a decrease in male mean body weight at 2.0 g/kg/day compared to the first control group (but not to the second control group); gross and microscopic observations were unaffected by treatment; tumors found were typical of those that occur spontaneously in the F344 rat and were not treatment-related; organ weights of treated animals were similar to controls.55 For 0, 0, 0.5, 1.0 and 2.0 g/ kg/day, the survival rates of males were 46%,

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50%, 58%, 58%, and 60%, respectively, and of females 74%, 68%, 78%, 62%, and 68%, respectively. A NOAEL of 2 g/kg/day Sucrose Acetate Isobutyrate was reported. 55 A 2-year carcinogenicity study was also conducted in B6C3F1 mice (n=50/sex/dose group). A range finding study was conducted at 0, 0.625, 1.25, 2.5, and 5.0 g/kg/day Sucrose Acetate Isobutyrate (n=10/sex/dose) for 4 weeks. Results indicated that Sucrose Acetate Isobutyrate was well tolerated. Dose 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%). Hematology samples were collected from 15 animals/sex in the 5.0 g/kg/day group and the control groups during weeks 28, 53, 79, and 105 of the study. Results of the 2-year experiment in mice were: no Sucrose Acetate Isobutyrate treatment-related deaths or clinical effects; food consumption and hematological parameters unaffected by treatment; occasional substantially decreased mean body weight in males at 2.5 g/kg/day compared to both control groups (not observed at 5.0 g/kg/day); occasional substantially different body weights in females with 1.25 g/kg/day and 5.0 g/kg/day (not found at 2.5 g/kg/day), which did not appear to be treatment related (there was no dose-response trend); tumors found typical of those that occur spontaneously in the B6C3F1 mouse and not treatment-related; Sucrose Acetate Isobutyrate treatment-related decrease in mean absolute and relative kidney weights were noted at necropsy in males (not at all in females) fed 5.0 g/kg/day compared to controls; no gross or microscopic kidney changes observed in males or females; microscopic findings not caused by treatment.55 For 0, 0, 1.25, 2.5 and 5.0 g/kg/day, the survival rates of males were 80%, 80%, 80%, 80%, and 74%, respectively, and 68%, 68%, 78%, 66%, and 78% for females, respectively. A NOAEL of 2.5 g/kg/day Sucrose Acetate Isobutyrate was reported for males and females. 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 104 weeks.50 Although in the 9.38% treatment group 4 males died (with massive hemorrhages in multiple organs; no further information specified as to the cause of these) within 10 weeks of the study, this was not attributed to Sucrose Acetate Isobutyrate treatment. There were no substantial body weight differences among the groups at the end of the first year. However, differences in body weight and food consumption appeared at varying times and doses (no further details provided). Males exposed to 0.38% or 9.38% Sucrose Acetate Isobutyrate exhibited decreased body weight compared to controls in the second year of the study. Absolute and relative kidney weights in both males and females were noted at study termination. However, 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 Sucrose Acetate Isobutyrate treatment-related lesions were found upon histological examination.

OTHER RELEVANT STUDIES

Cytotoxicity Studies Cytotoxicity studies are summarized in Table 14. In Vitro Unique 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 testing Sucrose Laurate was <25% at 0.1 mg/ml and for 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% for 0.03 mg/ml for Sucrose Myristate.35

DERMAL IRRITATION AND SENSITIZATION STUDIES

Irritation Dermal irritation studies are summarized in Table 15. Animal The 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 skin37; 5% and 15% hydrophilic gel formulations (also containing drug estradiol) yielded increased epidermal thickness and some irritation potential when tested in rabbits38; a 2% solution was non-irritating when tested in guinea pigs33. 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, but was tolerable to the skin.41 Sucrose Polycottonseedate (up to 1% formulation) was slightly irritating in a 21 day occlusive patch test in human subjects.52 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.52,53 Sensitization Dermal sensitization studies are summarized in Table 16.

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Animal In a Guinea Pig Maximization Test evaluating Sucrose Acetate Isobutyrate (1% solution at induction; 10% solution at challenge), no sensitization was observed.49 Human Sucrose Acetate Isobutyrate (20% solution) in a human repeat insult patch test (HRIPT) was non-irritating and non-sensitizing.49 Sucrose Polycottonseedate (16-17% in facial cleansing cloths) was non-irritating and non-sensitizing in a HRIPT.52 In a HRIPT, Sucrose Polycottonseedate (88% in a lipstick topcoat matrix) was non-sensitizing in human subjects.58

OCULAR IRRITATION

Animal Sucrose Laurate A study in Japanese white female rabbits was conducted to evaluate the effects of Sucrose Laurate on rabbit eyes.59 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 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.49 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 41 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 uses (274) with the next highest reported uses 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). Sucrose Dipalmitate and Sucrose Palmitate/ Stearate have not yet been included in a Council industry survey, but when that data becomes available it will be added to the report. Saccharide esters are known to be 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 Sucrose Laurate (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

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mg/mL) showed a dose-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 (oestradiol) bioavailability by 15%; Sucrose Laurate was a percutaneous absorption enhancer in single dose drug (oestradiol) 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. Toxicokinetics studies in vitro showed that Sucrose Palmitate, Sucrose Stearate, and Sucrose Acetate Isobutyrate were hydrolyzed in the intestinal mucosa of rats. Toxicokinetics studies conducted in rats orally exposed to saccharide esters showed that: 90% of Glucose Pentaacetate (20% Glucose Pentaacetate dose) was absorbed in the gastrointestinal tract rapidly over 4 hours; 120 hours post-dosing, 30%-67% of Sucrose Palmitate (100-250 mg/kg doses) and Sucrose Stearate (100-250 mg/kg doses) were excreted in feces; 78-93% of Sucrose Octaisobutyrate, a constituent of Sucrose Acetate Isobutyrate (200 mg/kg dose), was excreted in feces; >90% Sucrose Acetate Isobutyrate remained in the intestinal tract 6 hours post-dosing (50 mg/kg dose) with evidence of hydrolysis in the intestinal tract prior to absorption; lower doses of Sucrose Acetate Isobutyrate (27 mg/kg) were better absorbed than higher doses (100 mg/kg). For monkeys and dogs orally administered Sucrose Octaisobutyrate (200 mg/kg dose) 62%-85% and 77%-94% were excreted in feces, respectively. Generally in rats, dogs, and monkeys, sucrose esters were not found in whole blood or plasma following oral administration. Toxicokinetic studies in human subjects orally administered Sucrose Acetate Isobutyrate (0.1-1.0 g) showed partially hydrolyzed Sucrose Acetate Isobutyrate in urine. In another experiment (oral dose of 1.0-1.2 mg Sucrose Acetate Isobutyrate), the following excretions were observed in percentages of the applied doses: 41%-66% in breath, 15%-21% in urine, and 10% in feces within 30 days of dosing.

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 bw 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 bw 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 bw for oral administration of Sucrose Acetate Isobutyrate. Short-term toxicity studies evaluating Sucrose Acetate Isobutyrate showed the following results: 10 g/kg/day (oral gavage) for 15 days was well tolerated in monkeys; NOAEL 20 g/kg/day in diet for 90 days in dogs; mice were unaffected by 5 g /kg/day for 4 weeks in diet. Experiments in rats (for 90 days) and in dogs (for 28 days) orally exposed to Sucrose Polysoyate revealed a NOEL of 15%/day. A study in which Sucrose Acetate Isobutyrate was orally administered up to 0.020 g/kg/day for 14 days to human subjects reported that blood chemistry, hematological parameters, and BSP retention were unaffected by treatment. Chronic toxicity studies testing Sucrose Acetate Isobutyrate in animals reported a NOAEL of 2 g/kg/day for 1 year in rats and a NOAEL of 2.4 g/kg/day for 1 year in monkeys. Developmental and reproductive toxicity studies reported a NOAEL of 2 g Sucrose Acetate Isobutyrate/kg/day in rats (dosed daily in the diet for 10 weeks-males and 2 weeks-females, prior to mating) and a NOAEL of 1.2 g Sucrose Acetate Isobutyrate/kg/day in rabbits (dosed on days 7-19 of gestation by gavage); in neither study is it specified as to whether the NOAEL applies to parents only or also includes offspring. 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. Bacterial reverse mutation assay experiments (in vitro) in S. typhimurium up to 2000 µg Sucrose Acetate Isobutyrate/plate showed no mutagenic activity; an unscheduled DNA synthesis assay was negative for genotoxicity in rat hepatocyte cells up to 1000 µg Sucrose Acetate Isobutyrate/ml; an animal study in rats tested for dominant lethal mutations showed negative results up to 2000 mg Sucrose Acetate Isobutyrate/kg (male rats dosed once by gavage 2 hours prior to mating with untreated females). An Ames test in Chinese Hamster Ovarian/Hypoxanthine-Guanine Phosphoribosyl Transferase cells treated with up to 10,000 µg Sucrose Acetate Isobutyrate/plate yielded negative results for genotoxicity.

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Carcinogenicity bioassays were conducted in rats and mice; study results were negative for carcinogenicity. These studies reported oral NOAELs of 2 g/kg/day Sucrose Acetate Isobutyrate and 2.5 g/kg/day Sucrose Acetate Isobutyrate, for rats and mice respectively (5 g/kg/day was associated with a decrease in kidney weights and body weights in male mice). 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% was moderately irritating, but 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; Sucrose Polycottonseedate at 0.5-1.0% was slightly irritating. A 1% solution (at inductions) 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; Sucrose Polybehenate (~3%) and Sucrose Polycottonseedate (13%) were non-irritating and non-sensitizing; Sucrose Polycottonseedate (88% in a lipstick topcoat matrix) in a HRIPT was found to be non-sensitizing. A 10% Sucrose Laurate solution and a 50% Sucrose Acetate Isobutyrate solution were slightly irritating to rabbit eyes.

DISCUSSION

To be determined…

CONCLUSION

To be determined…

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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 Sucrose Acetate Isobutyrate Sucrose Benzoate Sucrose Octaacetate Xylityl Sesquicaprylate (C8) Sucrose Disinapate Trehalose Undecylenoate (C11:1) Sucrose Polylaurate (C12) Maltitol Laurate (C12) Sucrose Polystearate (C18) Sucrose Laurate (C12) Sucrose Polyoleate (C18:1) Sucrose Dilaurate 2(C12) Sucrose Polylinoleate (C18:2) Sucrose Trilaurate 3(C12) Sucrose Tetraisostearate (C18 branched) Sucrose Myristate (C14) Sucrose Acetate/Stearate (C2, C18) Raffinose Myristate (C14) Sucrose Tetrastearate Triacetate (C18, C2) Sucrose Palmitate (C16) Sucrose Palmitate/ Stearate or Sucrose Palmitate-Stearate Ester** Sucrose Dipalmitate (C16) (C16, C18) Raffinose Isostearate (C16 branched) Sucrose Polysoyate (Soybean Oil fatty acid distribution: Oleic Acid, Sucrose Hexapalmitate 6(C16) C18:1, 11.5-60.0%; Linoleic Acid, C18:3, 2.9- Sucrose Stearate (C18) 12.1%)13 Sucrose Oleate (C18:1) Sucrose Hexaoleate/ Hexapalmitate/ Hexastearate (C16, C18, C18:1) Trehalose Isostearate Esters (C18 branched) Sucrose Cocoate (Coconut Oil fatty acid distribution: Caproic Acid, Raffinose Oleate (C18) C6, 0-1%; Caprylic Acid, C8, 5-9%; Capric Acid, Sucrose Distearate 2(C18) C10, 6-10%; Lauric Acid, C12, 44-52%; Myristic Sucrose Tristearate 3(C18) Acid, C14, 13-19%; Palmitic Acid, C16, 8-11%; Sucrose Tetrahydroxystearate 4(C18:OH) Palmitoleic Acid, C16:1, 0-1%; Stearic Acid, C18, 1 Sucrose Pentahydroxy-Stearate 5(C18:OH) -3%; Oleic Acid, C18:1, 5-8%; Linoleic Acid, Sucrose Polybehenate (C22) C18:2, trace-2.5%)13 Sucrose Tribehenate 3(C22) Sucrose Polycottonseedate (Cottonseed Oil fatty acid distribution: Sucrose Pentaerucate 5(C22:1) Myristic Acid, C14, 2%; Palmitic Acid, Sucrose Hexaerucate 6(C22:1) C16, 21%; Oleic Acid, C18:1, 30%; Linoleic Acid, C18:2, 45%; Stearic Acid, C18, trace; Arachidic Acid, C20, trace)13 *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

where R represents the Acetic Acid radical.

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

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

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

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]

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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 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]

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]

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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 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

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

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 residue of Palmitic (C16) Acid]

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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 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 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]

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)]

Raffinose Oleate Raffinose Oleate is the ester of Raffinose and Oleic Acid. Skin-Conditioning Agents- Emollient; Surfactants- 96352-58-8 Emulsifying Agents

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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 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 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]

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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 Polybehenate Sucrose Polybehenate is a mixture of esters of behenic acid and Skin-Conditioning Agents- Sucrose. 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]

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)

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 Isobutyrate Sucrose Acetate Isobutyrate is the mixed ester of Sucrose and Acetic Plasticizers and isobutyric Acids. 126-13-6

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]

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 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 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)]

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]

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]

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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 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 three 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 Palmitic Acid or Stearic N/A Sucrose Palmitate-Stearate Ester] Acid, and Sucrose.

***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]

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]

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 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 cases 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 Plasticizers Sucrose] that conforms generally to the formula: 12738-64-6

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 Disinapate Sucrose Disinapate is the diester of Sucrose and sinapic acid Skin-Conditioning Agents- Miscellaneous

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

[sinapic acid]

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) 14 Maltitol (sugar alcohol derived from the sugar Maltitol: Safe as used (2008; 8% in leave-ons; 15% in rinse-offs) 1,14 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) 14 Trehalose Safe as used (2014; 2% in leave-ons; 1% in rinse-offs) 14 Xylose (Xylityl* is derived from the sugar alcohol Safe as used (2014; 0.11% in leave-ons; 1% in rinse-offs) 14 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) 12 Benzoic Acid Safe as used (2011; 5% in leave-ons; 5% in rinse-offs) 10,11 Coconut Acid Safe as used (2011; not reported in leave-ons; 14% in rinse-offs) 9,13,60 Cottonseed Acid Safe as used (2011; no reported use) 13,19 Hydroxystearic Acid Safe as used (1999; 10% in leave-ons; not reported in rinse-offs) 8 Isostearic Acid Safe as used (1983; 10% leave-ons; 5% rinse-offs); Reaffirmed in 2005 6,7 Lauric Acid Safe as used (1987; 1% in leave-ons; 25% in rinse-offs); Reaffirmed 2006 4,5 Myristic Acid Safe as used (2010; 10% in leave-ons; 19% in rinse-offs) 3-5 Oleic Acid Safe as used (1987; 25% in leave-ons; 50% in rinse-offs); Reaffirmed in 2006 4,5 Palmitic Acid Safe as used (1987; 25% in leave-ons; 25% in rinse-offs); Reaffirmed in 2006 4,5 Soy Acid Safe as used (2011; no reported use) 13 Stearic Acid Safe as used (1987; 50% in leave-ons; 50% in rinse-offs); Reaffirmed in 2006 4,5 *Not previously reviewed by the Panel

Distributed for Comment Only -- Do Not Cite or Quote

Table 4. Chemical and Physical Properties Property Value Reference Glucose Pentaacetate Molecular Weight 390.34 g/mol61; 390 g/mol (computational)62 61,62 61 Density 1.30±0.1 g/ml (computational) Melting Point 130-131.5 °C (measured) 63 Water Solubility Slightly soluble in water @ pH 7, 25 °C 61 Log P 0.634±0.488 (computational) 61

Maltitol Laurate Molecular Weight 527 g/mol (computational) 62

Raffinose Isostearate Molecular Weight 3435 g/mol (computational) 62

Raffinose Myristate Molecular Weight 687 g/mol (computational) 62

Raffinose Oleate Molecular Weight 785.89 g/mol64; 769 g/mol (computational)62 62,64

Sucrose Acetate Isobutyrate Physical Form Clear, pale yellow, viscous liquid 18 Molecular Weight 846.91 g/mol64; 847 g/mol62 (computational) 62,64 Density 1.22±0.1 g/ml (computational) 61 Water Solubility Slightly soluble 18 Other Solubility Very soluble in essential oils (orange); soluble in ethanol, ethyl acetate 18 Log P 6.619±0.825 (computational) 61

Sucrose Acetate/ Stearate Molecular Weight 651 g/mol (computational) 62

Sucrose Benzoate Molecular Weight 446 g/mol (computational) 62 Melting Point 98 °C (from patent) 65

Sucrose Dilaurate Molecular Weight 706.90 g/mol64; 707 g/mol62 (computational) 62,64

Sucrose Dipalmitate Molecular Weight 819 g/mol (computational) 62

Sucrose Disinapate Molecular Weight 755 g/mol (computational) 62

Sucrose Distearate Molecular Weight 875.22 g/mol64; 875 g/mol62 (computational) 62,64 Melting Point 76-78 °C (measured) 66

Sucrose Hexaerucate Molecular Weight 2265 g/mol (computational) 62

Sucrose Hexapalmitate Molecular Weight 1772.75 g/mol64; 1773 g/mol62 (computational) 62,64

Sucrose Laurate Molecular Weight 524.60 g/mol64; 524 g/mol62 (computational) 62,64

Sucrose Myristate Molecular Weight 569.66 g/mol64; 496 g/mol62 (computational) 62,64 Melting Point 180-186 °C (measured) 67

Sucrose Octaacetate Molecular Weight 678.59 g/mol64; 679 g/mol62 (computational) 62,64 Density 1.37±0.1 g/ml (computational) 61 Melting Point 89-93 °C (measured) 68 Water Solubility 0.909 g/L (hygroscopic) 69 Other Solubility Very soluble in methanol, chloroform; soluble in ether 69 Log P 1.440±0.812 (computational) 61

Sucrose Oleate Molecular Weight 607 g/mol (computational) 62 Melting Point 54-56 °C (measured) 66

Distributed for Comment Only -- Do Not Cite or Quote

Table 4. Chemical and Physical Properties Property Value Reference Sucrose Palmitate Molecular Weight 552 g/mol (computational) 62

Sucrose Pentaerucate Molecular Weight 1945 g/mol (computational) 62

Sucrose Pentahydroxystearate Molecular Weight 2039 g/mol (computational) 62

Sucrose Polybehenate Physical Form White waxy solid @ 20°C, 760 mmHg 53 Density 900-950 g/ml@72°C 53 Melting Point 72°C 53 Water Solubility ≤ 4.26 x 10-5 g/L @ 24°C 53 Log Pow (n-octanol/water) 3.55±0.16 @ 20°C 53

Sucrose Polycottonseedate Physical Form Amber, viscous liquid 52 Density 900-950 g/L at 71°C 52 Water Solubility 4.96 x 10-6 to 4.26x10-5 g/L @ 24°C 52 Log Pow (n-octanol/water) 3.55±0.16 @20°C 52

Sucrose Stearate Molecular Weight 608.76 g/mol64; 609 g/mol62 (computational) 62,64 Melting Point 67-71 °C (measured) 70

Sucrose Tetrahydroxystearate Molecular Weight 1472 g/mol (computational) 62

Sucrose Tetraisostearate Molecular Weight 1408 g/mol (computational) 62

Sucrose Tetrastearate Triacetate Molecular Weight 1534 g/mol (computational) 62

Sucrose Tribehenate Molecular Weight 1310 g/mol (computational) 62

Sucrose Trilaurate Molecular Weight 889.20 g/mol64; 889 g/mol62 62,64

Sucrose Tristearate Molecular Weight 1141.68 g/mol64; 1142 g/mol62 (computational) 62,64

Trehalose Undecylenoate Molecular Weight 509 g/mol (computational) 62

Xylityl Sesquicaprylate Molecular Weight 278.34 g/mol (computational) 61 Density 1.170±0.06 g/ml (computational) 61 Water Solubility Slightly soluble @ pH 7, 25 °C (computational) 61 Log P 1.387±0.735 (computational) 61 Dissociation Constant (pka) 13.02±0.20 (computational) 61

Distributed for Comment Only -- Do Not Cite or Quote

Table 5. Current frequency and concentration of use of saccharide esters according to duration and exposure20,21

# 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/ Hexastearte Totals* 1 67 0.0003-5.5 NR 5 Duration of Use Leave-On NR 63 0.0003-5.5 NR 5 Rinse-Off 1 4 1.1 NR NR Diluted for (Bath) Use NR NR 0.011 NR NR Exposure Type Eye Area NR 20 1-5.5 NR NR Incidental Ingestion NR 1 0.57-1.8 NR NR Incidental Inhalation-Spray NR possible: 11a; 25b possible: 1.2a NR NR Incidental Inhalation-Powder NR possible: 25b powder: 0.015 NR NR possible: 0.5-2c Dermal Contact 1 51 0.0003-2 NR 5 Deodorant (underarm) NR NR NR NR NR Hair - Non-Coloring NR 1 1.2 NR NR Hair-Coloring NR NR 1.1 NR NR Nail NR 2 NR NR NR Mucous Membrane NR 2 0.011-1.8 NR NR Baby Products 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 exposure20,21

# 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 2 1-6 23 0.5-87.7 Duration of Use Leave-On 1 2 1-6 22 0.5-87.7 Rinse-Off NR NR NR 1 2.8 Diluted for (Bath) Use NR NR NR NR NR Exposure Type Eye Area NR 1 4 3 1-1.5 Incidental Ingestion NR NR 6 4 87.7 Incidental Inhalation-Spray possible: 1b NR spray: 1 possible: 8a; 6b NR Incidental Inhalation-Powder possible: 1b NR NR possible: 6b possible: 1c Dermal Contact 1 1 1 19 0.5-2.8 Deodorant (underarm) NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR Hair-Coloring NR NR NR NR NR Nail NR NR NR NR NR Mucous Membrane NR NR 6 4 87.7 Baby Products 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

Distributed for Comment Only -- Do Not Cite or Quote

Table 5. Current frequency and concentration of use of saccharide esters according to duration and exposure20,21

# 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 Duration of Use Leave-On 16 1-6 126 0.0001-6 2 Rinse-Off NR 0.7 30 0.04-3 NR Diluted for (Bath) Use NR NR NR 0.069 NR Exposure Type Eye Area 1 1-6 32 0.0003-6 NR Incidental Ingestion 3 1-2.5 1 0.079-0.2 NR Incidental Inhalation-Spray possible: 3a; 1b NR spray: 1 possible: 0.2-2.2a NR possible: 29a; 49b Incidental Inhalation-Powder powder: 3 possible: 1.7c powder: 1 possible: 0.013- powder: 2 possible: 1b possible: 49b 3.9c

Dermal Contact 12 1-1.7 137 0.0003-6 2 Deodorant (underarm) NR NR NR spray: 0.23 NR not spray: 0.45 Hair - Non-Coloring NR NR 3 0.3-2.2 NR Hair-Coloring NR 0.7 NR NR NR Nail NR NR 3 0.0001 NR Mucous Membrane 3 1-2.5 3 0.069-0.2 NR Baby Products NR NR 4 NR 2 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 these 2 ingredients have the same definition they are listed separately here because VCRP data for each is individually recited # These ingredients have not yet been included in a Council industry survey, but when that data becomes available it will be added to the report 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

Distributed for Comment Only -- Do Not Cite or Quote

Table 6. Ingredients not currently reported to be in use20 Glucose Pentaacetate Sucrose Hexaerucate Sucrose Pentahydroxystearate Raffinose Isostearate Sucrose Hexapalmitate Sucrose Polylinoleate Raffinose Myristate Sucrose Octaacetate Sucrose Tetrahydroxystearate Raffinose Oleate Sucrose Oleate Sucrose Tribehenate Sucrose Disinapate Sucrose Pentaerucate Xylityl Sesquicaprylate

Table 7. Non-Cosmetic Uses Ingredient Non-Cosmetic Use References Glucose Pentaacetate Direct food additive, synthetic flavoring substance 21CFR172.515; 71 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; 16; 72; 73 300 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; 74 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- 71; 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 Vehicle/ Exposure Procedure Results Reference Type/Test Concentration Route Population- Gender 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, 32 (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 Yucatan Micropig oil-in-water Skin (0.83 cm2 Skin was exposed to microemulsion Sucrose Laurate (surfactant component in 34 Micropig skin 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 hr Laurate used for drug Franz-type hr then assayed; no controls without in epidermis and at 20 and 40 hr in dermis; delivery; diffusion (37°C Sucrose Laurate were used hydrophilic polyphenol distributed slightly composition ratio water jacket), 2- more in epidermis, and hydrophobic (small 25:19:5:60, Sucrose h pretreatment molecular weight) polyphenol distributed Laurate:ethanol:iso- with 150 mM 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 33 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 SL is an effective dermal 0.35 mm penetration enhancer for hydrophilic substances

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Table 8. Penetration Enhancement Studies Test Substance(s) Species Sample Vehicle/ Exposure Procedure Results Reference Type/Test Concentration Route Population- Gender Sucrose Laurate and Human RPMI 2650 Variable between Cells cultured Cells treated and transepithelial electrical Sucrose Laurate and Sucrose Myristate 35 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 Porcine skin Nanoemulsions (used Hair-free Receptor compartment filled with Sucrose Stearate was shown to be an 75 for dermal drug porcine skin phosphate buffer; diffusion cells at 32°C for emulsifier with physical and chemical delivery); 2.5% w/w (area 1.13 cm2) 24 h then 0.6 g of nanoemulsion (mixture of stability; pH decreased with increasing Sucrose Stearate in treated with aqueous and oil phase described) placed on Sucrose Stearate concentrations due to aqueous phase dermatome (1.2 skin in donor chamber; 200 µL samples residual, non-esterified fatty acids (up to w/hydrophilic drugs mm), frozen, removed from the acceptor chamber at 10%, based on manufacturer supplied info); (fluconazole and thawed; skin intervals for analysis (of drug content) and drug permeation enhancement comparable minoxidil); lecithin patches replaced by fresh receptor medium; lecithin to that of lecithin-based emulsions in oil-phase clamped emulsions were used as a comparison to w/lipophilic drugs between donor Sucrose Stearate emulsions; controls (fludrocortisone and acceptor without drugs were used, but no controls acetate and chambers of without Sucrose Stearate were used flufenamic acid) Franz-type diffusion cells Sucrose Stearate Pig Porcine abdominal Nanoemulsions (used Hair-free Receptor compartment filled with propylene Sucrose Stearate was a skin permeation 36 skin 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 acceptor 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 acceptor chambers of Franz-type diffusion cells ANIMAL

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Table 8. Penetration Enhancement Studies Test Substance(s) Species Sample Vehicle/ Exposure Procedure Results Reference Type/Test Concentration Route Population- Gender Sucrose Laurate Mouse 15-wk old male Sucrose Laurate Dermal Tape stripping (up to 18x) used to collect Minimal changes in lipid and protein 37 (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 38 (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 39 (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 Vehicle/ Exposure Procedure Results Reference Type/Test Concentration Route Population- Gender Sucrose Cocoate, Rat Male, For nasal Nasal, Ocular Dos was administered for nasal exposure sucrose monodecanoate was found to be the 40 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% 41 (80% mono-, 17% subjects, n=4 (tape phase- (drug µL/cm2) applied to 4 cm2 forearm surface Sucrose Stearate (intermediate di-, 3% tri-), Sucrose stripping study) aceclofenac), 1-2% area for 2 h, after which residual test lipophilicity), and 1.5% egg lecithin were Stearate (48% mono- (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

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Table 8. Penetration Enhancement Studies Test Substance(s) Species Sample Vehicle/ Exposure Procedure Results Reference Type/Test Concentration Route Population- Gender Sucrose Oleate, Human Healthy, female 2% or 10% Sucrose Dermal Test formulation (1.5ml) applied via filter Sucrose Oleate and Sucrose Laurate 42 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 hr); 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 Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender IN VITRO Sucrose Palmitate Rat (Wistar) Male rats, three 1 µmol/ml 14C-Sucrose Ester Intestinal absorption studies- bicarbonate buffer No transport of 14C-labelled sucrose esters 43 (mono-) and 10-cm segments (intestinal absorption studies); solutions were incubated for 1 h; serosal fluid, from mucosal to serosal solution via Sucrose Stearate of rat small 2mM 14C-Sucrose Ester mucosal fluid and tissue were assayed for intestinal tissues; enzymes in intestinal (mono-, di-); intestine used to (pancreatic fluid hydrolysis); 20 radioactivity; no controls used mucosal more important in hydrolysis of >95% purity prepare everted mM 14C-Sucrose Ester (liver and sucrose esters than enzymes in digestive 14 Artificial Pancreatic Fluid Hydrolysis-artificial sacs; also used in mucosa hydrolysis); 5 mM C- fluid; rate of hydrolysis by mucosal pancreatic fluid aliquots were removed at 0, 0.5, 1, 2, this study were sucrose esters (whole blood homogenates (10% of Sucrose Mono- and 4 h and assayed; no controls used rat liver hydrolysis) Stearate, 30% of Sucrose Mono-Palmitate) homogenates, Hydrolysis by Liver Homogenates and Intestinal considerably faster than by artificial intestinal mucosa Mucosa- incubation for up to 4 h for liver pancreatic juice (9% of Sucrose Mono- homogenates, homogenates and 1 h for mucosal homogenates; no Stearate, 15% of Sucrose Mono- artificial controls used Palmitate); liver homogenates hydrolyzed pancreatic fluids, 20% of Sucrose Mono-Stearate or Sucrose Hydrolysis by Whole Blood-performed by adding 1 and whole blood 14 Mono-Palmitate; hydrolysis of sucrose ml of 5 mM C-sucrose esters to buffered solution of esters in whole blood showed 10% blood and incubated up to 1 h and assayed; no hydrolysis of Sucrose Mono-Palmitate and controls used 2.4% of Sucrose Mono-Stearate 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 44 Isobutyrate homogenates of Isobutyrate (gut content intestinal mucosa were prepared and assayed; hydrolyzed in intestinal mucosa (75% in 6 gut contents, homogenates); 25 or 250 negative controls used h) by non-specific esterases, but little liver, and µg/ml 14C-Sucrose Acetate hydrolysis in stomach and liver intestinal mucosa Isobutyrate (liver/ intestinal mucosa homogenates) Sucrose Acetate Human fecal homogenate 0.1 or 1 mg/ml 14C-Sucrose Human fecal homogenates were prepared and 40% of 1 mg/ml in fecal homogenates was 44 Isobutyrate Acetate Isobutyrate (fecal assayed; human feces bacteria cultured, hydrolysis hydrolyzed by 16 h (<2% hydrolyzed homogenates); 100 µg/ml 14C- was measured; negative controls used completely to sucrose); 60% of 0.1 mg/ml Sucrose Acetate Isobutyrate in fecal homogenates was hydrolyzed (5% (bacteria isolated from human completely de-esterified) by 16 h; only 2 feces) strains each of E. coli, Streptococcus and Bacteroides and 1 strain of bifidobacteria resulted in > 15% degradation of 14C- Sucrose Acetate Isobutyrate in 20 h (many E. coli and Lactobacillus strains yielded <5% hydrolysis) ANIMAL Oral

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species Sample Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender Glucose Rat (Wistar) Male rats, Aqueous non-radioactive 20% Intestinal Absorption Study-rats were dosed (2-ml, Gastrointestinal tract absorption is rapid 45 Pentaacetate fasted prior to Glucose Pentaacetate (intestinal single) and at time intervals of ½, 1, 2, and 4 h were (>90% in 4 h); 2% recovered from feces at dosing; n=37 absorption study); 10% killed and gastrointestinal tract analyzed; negative 48 h; radioactive equilibrium by 7days; total for all radioactive Glucose Pentaacetate controls used rats exposed to 10% Glucose Pentaacetate studies (repeated dose study); 10% for 2 yr excreted 76% as CO compared to Repeated Dose Retention Study-rats were dosed (1- 2 radioactive Glucose Pentaacetate rats not previously exposed to Glucose ml) daily for 2, 7, or 14 days then were killed and (metabolism study) Pentaacetate (excreted 65% as CO ); carcass assayed for radioactivity; no controls used 2 Glucose Pentaacetate is hydrolyzed to Metabolism Study-rats were dosed (2-ml, single) and lesser acetylated metabolites which are placed in a metabolic chamber where a continuous detected in urine radioactive gas analyzer recorded specific activity and 14 integrated total C O2 for 48 h post-dosing; urine and feces collect during this 48 h period; no controls used

14 14 14 43 Sucrose Palmitate Rat (Wistar) Male rats fasted 100 or 250 mg/kg C-sucrose Excretion Study-single dose, CO2, urine, feces were Within 120 h post-dosing 30%-67% C- (mono-) and prior to dosing esters (excretion study); 250 analyzed for radioactivity; negative controls used sucrose esters were excreted in feces and Sucrose Stearate mg/kg 14C-sucrose esters (lymph 11%-49% exhaled; urinary excretion of 14 Absorption Via Mesenteric Lymphatic System- (mono-, di-); >95% evaluation); 250 mg/kg C- radioactivity was 0.7%-4.9% of the dose; performed by cannulating thoracic ducts of purity sucrose esters (portal system no intact Sucrose Ester was found in the anaesthetized rats, fasting then dosing (single) rats, study) urine; very little intact Sucrose Stearate lymph collected at 2, 4, 6, 10, 24 h; negative controls was transported from the intestinal tract to used lymph; sucrose esters were hydrolyzed to Absorption Via Portal System-single dose, blood yield sucrose and fatty acids that were samples from portal and femoral veins taken at 1, 2, transferred from the intestine to lymph; no and 4 h then assayed for radioactivity; no controls intact sucrose esters were detected in used blood

Sucrose Rat (Fischer Male rats, n=3 200 mg/kg 14C-Sucrose Animals fasted prior to dosing; single dose (by 3%-15% excreted as volatile products, 47 Octaisobutyrate-(a 344) (metabolism Octaisobutyrate gavage); rats placed in metabolism cages for 5 days 1%-2% in urine, 78%-93% in feces; peak component of studies) and post-dosing; food available ad lib.; collections from CO2 radioactivity 24-36 h post-dosing Sucrose Acetate n=3 (blood expired air traps to measure CO2 were made at 2, 4, 6, suggested delayed absorption, <0.2% Isobutyrate) study) 8, 10, 12, and 24 hr and at successive 12 hr intervals excreted in bile, evidence of extensive gut for 5 days post-dosing; urine and feces were collected hydrolysis; no radioactivity found in at 4, 8, 12, 24 hr intervals for 5 days post-dosing; bile whole blood or plasma post-dosing collected (through catheter) 2-6 hr intervals for 48 hr post-dosing, and blood analysis (collected from abdominal aorta) was performed 2, 4, 8, 12, and 24 hr post-dosing; no controls used

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species Sample Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender

14 14 47 Sucrose Dog (Beagle) male dogs, n=3 200 mg/kg C-Sucrose Animals fasted prior to dosing; single dose (by C recovered 1% in CO2, <2% in urine, Octaisobutyrate-(a Octaisobutyrate gavage); dogs placed in metabolism cages for 5 days 77%-94% in feces, 2%-10% in bile; no component of 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 hr and at successive 12 hr 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 hr intervals for 5 days post-dosing; bile radioactivity found in whole blood or collected (through catheter) 2-6 hr intervals for 48 hr plasma post-dosing post-dosing, and blood analysis (collected from a saphenous vein) was performed 2, 4, 8, 12 hr and longer intervals post-dosing; no controls used Sucrose Monkey male monkeys, 200 mg/kg 14C-Sucrose Animals fasted prior to dosing; single dose (by 62%-85% excreted in feces, <2% 47 Octaisobutyrate-(a (Cynomolgus) n=3 Octaisobutyrate gavage); monkeys placed in metabolism cages for 5 eliminated in CO2,1% or less in urine, not component of days post-dosing and fed 2x/day; collections from hydrolyzed in gut or absorbed, 0.1%-0.2% Sucrose Acetate expired air traps to measure CO2 were made at 2, 4, 6, excreted in bile, little intestinal Isobutyrate) 8, 10, 12, and 24 hr and at successive 12 hr intervals metabolism occurred; no radioactivity for 5 days post-dosing; urine and feces were collected found in whole blood or plasma post- at 4, 8, 12, 24 hr intervals for 5 days post-dosing; bile dosing collected (through catheter) 2-6 hr intervals for 48 hr post-dosing, and blood analysis (collected from a saphenous or radial vein) was performed 4, 8, 12, 24, 36, and 48 hr 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 44 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 hr 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 hr; Sucrose / 5-cm length of small and fructose at 2.4% of dose; 90% this was a negative control intestines radioactivity excreted by 24 h (<8% in Dose administered directly into caecum (to evaluate gastro-intestinal tract); 50% excreted 14 14 absorption and hydrolysis of C-Sucrose Acetate radioactivity from CO2; fecal excretion Isobutyrate) of anaesthetized male rats; rats placed in was 33% of dose; 87% of dose in small metabolism cage and killed at 3 or 6 hr post-dosing; intestine remained after 1 h whereas negative controls used control (14C-sucrose) <30% after 30 min; 14C-Sucrose Acetate Isobutyrate Intestinal absorption studies were conducted in hydrolyzed in gastrointestinal tract prior to anaesthetized male rats by administering dose absorption; hydrolysis decreases from through 3 separate 5-cm sections of small intestine duodenum to caecum (less hydrolysis in loops (absorptive durations post-dosing were up to 1 caecum with direct administration vs. hr); after dosing loops were excised, washed with small intestine after oral dosing); end saline and wall homogenates and washings were result of orally administered 14C-Sucrose assayed for radioactivity; negative controls used Acetate Isobutyrate similar to that of 14C- Sucrose

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species Sample Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender

14 14 14 48 Sucrose Acetate Rat For C-Sucrose 26, 28, 89, 98 mg/kg C- Metabolic parameters (CO2, urine, feces) were For 5.8 and 11.2 mg/kg C-Sucrose Isobutyrate Acetate Sucrose Acetate Isobutyrate in evaluated after a single dose; post-dosing the rats Acetate Isobutyrate 59% and 52% Isobutyrate corn oil; 5.8 and 11.2 mg/kg 14C- were placed in metabolic cages for 3 days (rats fed an detected in breath, 11% and 13% in urine, treatments n=6 Sucrose Acetate Isobutyrate in aqueous emulsion of 14C-Sucrose Acetate Isobutyrate) 23% and 27% in feces within 3 days post- aqueous emulsion; 400 or 4 days (rats fed 14C Sucrose Acetate Isobutyrate in dosing; 6.0% and 6.6% in carcass after 3 mg/kg 14C-Sucrose and 112 mg corn oil); for rats housed 3 days samples to measure days post-dosing; 14C-Sucrose rapidly 14 Sucrose/4 ml by stomach tube metabolic parameters were collected every 24 hr; for absorbed and metabolized to CO2 rats housed 4 days samples to measure metabolic parameters were collected every 1.5 hr for the first 15 hr and then successively at 8-16 hr intervals; negative controls used

14 48 Sucrose Acetate Dog n=2 4.8 and 3.0 mg/kg C-Sucrose Metabolic parameters (CO2, urine, feces) were 28% and 27% detected in breath, 7% and Isobutyrate Acetate Isobutyrate in aqueous evaluated after a single dose; post-dosing the dogs 5% in urine, 53% and 46% in feces within emulsion were placed in metabolic cages; samples to measure 7 days post-dosing metabolic parameters were collected every 1.5 hr for the first 15 hr and then successively at 8-16 hr intervals; negative controls used 14C-Sucrose Acetate Rat n=3 Oral doses: 19.8 (rat 1), 41.5 (rat Non-Good Laboratory Practice (GLP) study; Single Material passed slowly through 49 Isobutyrate 2), or 50.6 (rat 3) mg/kg; no oral dose; rat bile ducts cannulated and bile collected gastrointestinal tract (no feces) for rat 1 dose specified for intragastric (after intragastric intubation) continuously for 65 h (78% in intestines 3 days post dose); rapid intubation (rat 1) and 2-3 days (rats 2 and 3); no controls used peak in bile elimination 1-2 h post dose, falling off 3-4 h post dose for rats 2 and 3; 12.4% and 35.1% dose 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 14C-Sucrose Acetate Non-GLP study; test animals were fed unlabeled Dog: 67-75% Sucrose Acetate 49 nd Isobutyrate (Beagle) male n=1 Isobutyrate Sucrose Acetate Isobutyrate for 7 days (2 trial) and Isobutyrate eliminated in feces within 7.5- 4 days (3rd trial) before dosing with 14C-Sucrose 9 h; 2%-6% 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 dose; 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 Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender Sucrose Acetate Rat Rat-male, corn Unlabeled 2.5, 5 g/kg (prelim Non-GLP study; unlabeled Sucrose Acetate Rats fed unlabeled Sucrose Acetate 49 Isobutyrate (Holtzman) oil study); 14C-Sucrose Acetate Isobutyrate administered in preliminary study; single Isobutyrate eliminated ethanol-extractable administration Isobutyrate in corn oil doses administered; post-dosing (corn oil) acetate and isobutyrate 16%-60% of dose n=2/dose level; 26,28,89,98 mg/kg ; 14C-Sucrose metabolism parameters monitored for 4 days; post- within 6 days, at 2.5 mg/kg increased aqueous Acetate Isobutyrate in aqueous dosing (aqueous emulsion) parameters monitored for urinary excretion of combined acetic acid emulsion n=2 emulsion 5.8,11.2 mg/kg; 371, 3 days; no controls used equivalent to 36%-46% of dose; Rats-corn for 14C-Sucrose 405 mg/kg 14C-Sucrose oil dosed showed 45%-50% absorbed at Acetate higher doses, 74%-82% at lower doses Isobutyrate; from intestinal tract; Sucrose Acetate n=2 for 14C- Isobutyrate rapidly eliminated at all doses, Sucrose 90%-93% eliminated within 4 days with 97% of the total elimination occurring within 2 days; 55-67% metabolized 14 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 in gut; aqueous emulsion dose Sucrose Acetate Isobutyrate largely absorbed from gut; unabsorbed material in feces was highly acylated sucrose; >73% excreted as CO2 in exhaled air in 3 days; 14%-18% eliminated in urine; no fat incorporation of Sucrose Acetate Isobutyrate detected 14 50 Sucrose Acetate Rat Male, n=? 27 or 100 mg/kg C-Sucrose Single dose administered and CO2 in exhaled air, Gastrointestinal tract absorption was Isobutyrate (Holtzman) Acetate Isobutyrate urine, feces, blood, liver, and kidney evaluated; use of 74%-82% (27 mg/kg) and 45%-50% (100 controls not specified mg/kg); eliminated 88%-90% by 48 h; 100 mg/kg dose eliminated 54%-56% as CO2 and 26%-28% in urine; 27 mg/kg dose eliminated 63%-67% as CO2 and 23%- 25% in urine; <1% 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 dose administered and metabolic parameters 3-3.5 h post administration: 78%-84% 50 Isobutyrate (Holtzman) Isobutyrate monitored; use of controls not specified recovered from gastrointestinal tract; 7%- 9% from stomach, intestinal, caecal tissues; <4% excreted in breath, urine, feces; gastrointestinal tract + organ extracts contained sucrose, partially- acylated sucrose esters, and unchanged Sucrose Acetate Isobutyrate

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Table 9. Toxicokinetic Studies-Absorption, Distribution, Metabolism, Excretion (ADME) Test Substance(s) Species Sample Vehicle/ Concentration Procedure Results Reference Type/Test Population- Gender Sucrose Acetate Rat Not specified 14C-Sucrose Acetate Isobutyrate, Single dose administered; use of controls not Eliminated 7%-10% in urine within 30-46 50 Isobutyrate no further details provided specified 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 dose administered; use of controls not Eliminated 2.8%-5.2% in urine within 29- 50 Isobutyrate no further details provided specified 30 h post-dosing; 14C molecules larger than sucrose not detected in urine (sucrose, glucose, and fructose absent) 14 46 sucrose Rat (Wistar) Male rats, n=3 250 mg/kg C-sucrose esters 24 h fast, rats dosed (single); expired CO2, urine, >95% of the dose of sucrose esters was tetrastearate, per formulation (sucrose tetrastearate, Sucrose feces collected 120 h post-dosing; blood, tissue, and found in feces; lesser esterification Sucrose Hexastearate, sucrose lymph analyzed; use of controls not specified compounds were better absorbed; sucrose Hexastearate, octastearate) esters were hydrolyzed before absorbed in sucrose octastearate the intestines; by 120 h post-dosing 14C sucrose esters were found in fat, lymph node, liver, and blood samples 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% excreted in 44 Isobutyrate dose); Males n=2 dissolved in butter: Single dose single dose study urine was assayed for sucrose, free urine as parent compound or metabolites (multi-dose); n=1 of 0.1 or 1.0 g ; 1g x7 days and esterified; For 7 days 24 h urine sample collected w/disaccharide moiety; with 1 g x 7 days, (fecal excretion (multi-dose study); 0.1g x7 days (in the multi-dose study urine was assayed for total similar result as above; with 0.1 g in 1 study); n=2 (sucrose (fecal excretion study); 100, 250, sucrose); For 3 days feces collected post-dosing and subject x 7 days, no unchanged Sucrose clearance study) and 500 mg sucrose iv as 10% assayed for glucose; Urine collected at 3, 12, and 24 h Acetate Isobutyrate or metabolite detected (w/v) and assayed for glucose after acid hydrolysis (sucrose in fecal samples; urinary excretion clearance study); negative controls were used following iv showed 50% sucrose recovered in urine after 3 h at all three dose levels; partially hydrolyzed Sucrose Acetate Isobutyrate in urine; absorption of partially esterified sucrose molecules from intestinal tract is insignificant Sucrose Acetate Human n=7 subjects total 1.0-1.2 mg/kg 14C-Sucrose Human subjects were administered a single dose; Subjects eliminated in breath 41-66%, 48 Isobutyrate Acetate Isobutyrate (n=6) and breath samples were collected at 1-1.5 hr intervals urine 15-21%, feces 10% of dose within 0.2 mg/kg (n=1) in non- from 0.5 to 16 hr post-dosing and at various 30 days; subjects dosed 14C-Sucrose carbonated beverage; 14C- successive intervals up to 25-30 days; urine samples eliminated 50% in breath, 2.7% in urine, Sucrose administered @ 400 were collected ad libitum for 25-30 days and fecal <0.3% in feces within 31 days; studies mg/kg 14C-Sucrose; 14C-Sucrose samples collected ad lib. for 5 days post-treatment; were also conducted to examine the effect and unlabeled sucrose (25 or 28 negative controls were used on elimination of Sucrose Acetate g in 200 ml) administered to 2 Isobutyrate with various dosing routine subjects 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)

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Table 10. Acute Toxicity Studies Test Species Sample Vehicle/ Dose Procedure Results Reference Substance(s) Type/ Test Concentration Duration Population- Gender ANIMAL Dermal Sucrose Acetate Rat (Sprague- n=5/sex/dose 20 ml/kg Sucrose Single Dose applied to hairless skin, occlusively wrapped Skin unaffected by treatment during 14 days 49 Isobutyrate Dawley) Acetate Isobutyrate dose; 24 h for 24 h, post-dose residual material washed off with observation; weight gain, clinical signs, gross (vehicle not specified) water (followed Organization for Economic Co- pathology unaffected (no evidence of percutaneous operation and Development, OECD, Guideline 434, absorption); LD50>20,000 mg/kg for male and Acute Dermal Tox-Fixed Dose); use of controls not female rats specified Oral 49 Sucrose Acetate Rat (Sprague- n=5/sex/dose 5000 mg/kg bw Sucrose Single dose Dose administered orally by gavage, rats observed LD 50>5000 mg/kg for male and female rats; body Isobutyrate Dawley) Acetate Isobutyrate, in 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 Sucrose Acetate Rat, Mouse Sample size 25.6 g/kg Sucrose Single dose Dose administered; use of controls not specified Oral doses produced no mortality in mice and 76 Isobutyrate details not Acetate Isobutyrate in mortality in 1 of 7 rats specified corn oil (50% solution of Sucrose Acetate Isobutyrate)

49 Sucrose Acetate Monkey n=2 male, 2 1.25, 2.50, 5.00, 10.00, Incremental Doses 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 doses Acetate Isobutyrate in between no controls used 1.25, 2.5, 5.0 g/kg); 24 h post-dosing with 20.0 g/kg (vehicle: orange juice loose stools noted; body weight and gross concentrate) pathology were unaffected; food consumption was slightly less during treatment Sucrose Acetate Monkey n=10 5 g/kg Sucrose Acetate Single dose Dose administered, 30 min bromosulfophthalein BSP and SAP measurements, clinical observations, 50 Isobutyrate, (Cynomolgus) Isobutyrate, 5 g/kg (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)

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Table 10. Acute Toxicity Studies Test Species Sample Vehicle/ Dose Procedure Results Reference Substance(s) Type/ Test Concentration Duration Population- Gender Sucrose Acetate Dog (Beagle) Male, n=3 2 g/kg bw Sucrose Single dose Dose administered (by gavage), BSP clearance Plasma BSP levels increased at all post-dosing 50 Isobutyrate (dosed), n=2 Acetate Isobutyrate in measured 0.5, 2, 4, 6, 10, 12, 18 or 24 h post-dosing; measurements compared to pre-dosing values (5 h (controls) corn oil negative controls were used post-dosing was max BSP retention) (delayed BSP clearance rates are indicative of inhibited liver function) Sucrose Dog (Beagle) Males, 100-1000 mg/kg Single dose Dose administered, BSP and SAP measured; Sucrose Hexaacetate Diisobutyrate increased BSP 50 Hexaacetate Experiments Sucrose Hexaacetate negative controls were used (5-7x) at all doses 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 and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender SHORT-TERM (0-3 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 50 Isobutyrate Isobutyrate (pretreatment) and 24, 48 h following withdrawal from treated feed ; use of controls not specified Sucrose Acetate Squirrel n=3 1 g Sucrose Acetate 1 week Dosed daily in diet; 24 h post-treatment BSP clearance BSP clearance was normal in 2 of 3 monkeys in 50 Isobutyrate monkeys males/group Isobutyrate in 2 ml measured; 7 days rest then treatment for groups reversed; each group (Saimiri (6 total cottonseed oil negative controls were used sciureus) animals) Sucrose Acetate Squirrel n=3 2 g Sucrose Acetate 1 week Dosed daily in diet; 24 h post-treatment BSP clearance High plasma BSP detected in 3 controls, 50 Isobutyrate monkeys males/group Isobutyrate in 4 ml measured; 7 days rest then treatment for groups reversed; however authors considered this to be a (Saimiri (6 total cottonseed oil negative controls were used technical error when BSP clearance following sciureus) animals) Sucrose Acetate Isobutyrate treatment was normal in all animals

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Table 11. Short-Term and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender 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 50 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; 50 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 50 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, 50 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 g 4 weeks Dosed daily in diet for 4 weeks; negative controls were No effect on biological performance; no 50 Isobutyrate (B6C3F1/ group kg/bw/day Sucrose used treatment related effects observed at necropsy Cr1BR) Acetate Isobutyrate

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 50 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- Rats Group 1 (basal diet); 6 and 12 Dose administered daily as indicated; each group divided NOAEL reported at 10%/day in diet; no deaths 51 Isobutyrate Dawley) n=40/sex/ Group 2 (basal diet + weeks into 2 subgroups (n=20/subgroup) that were treated for 6 from treatment; mean body weights decreased group sodium phenobarbital and 12 weeks; in each subgroup n=10 rats were used for in males at all dose levels for entire study vs. 100 mg/kg/day by zoxazolamine test (after which fed basal diet for 4 week controls potentially due to palatability of gavage); Groups 3- withdrawal period and then zoxazolamine test repeated), treatment; no effect on hepatobiliary function; 5=2.5, 5.0, 10.0%/day n=10/subgroup used for clinical chemistry and pathology no microsomal enzyme induction observed; Sucrose Acetate studies; effects of phenobarbital and Sucrose Acetate carboxylesterase activity unaffected; urinary Isobutyrate in diet, Isobutyrate on liver microsomal enzymes were excretion of ascorbic acid and zoxaolamine respectively determined by urinary ascorbic acid excretion, hypnotic activity were unaffected by treatment; zoxazolamine hypnotic activity (Sucrose Acetate liver glycogen levels increased in males and Isobutyrate’s effect on the zoxazolamine females fed 10%/day; absolute mean heart biotransformation rate by liver enzymes may be an weights decreased in all treated males 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 51 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 at 2.0% in diet for 12 weeks followed by 2 weeks unaffected; statistically significant increase in 4.0%/day Sucrose withdrawal period (basal diet without Sucrose Acetate SAP* (dose- and time-related); serum bilirubin Acetate Isobutyrate in Isobutyrate); negative controls were used levels unaffected; 2%/day for 12 weeks did not diet, 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

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Table 11. Short-Term and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender 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 50 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, 2.00%/day 90 days OECD Guideline 409 (repeated dose 90-day oral tox in NOAEL male and female dogs>20,000 49 Isobutyrate females, Sucrose Acetate non-rodents) followed (non-GLP); dosed daily in diet for mg/kg/day (2.00%); food consumption, n=4/sex/dose; Isobutyrate in diet, 90 days; negative controls were used hematological parameters, urinary exam, and 6/sex/dose cottonseed oil vehicle 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%/day Sucrose Acetate 91 days OECD Guideline 409 (repeated dose 90-day oral tox in Moderate elevation in SAP; prolongation of 49 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 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 50 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% /day 13 weeks Non-GLP; dosed daily in diet for 13 weeks; negative No toxic effects observed; at 9.38% no specific 49 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, 12 weeks; Exp 1 (36 dogs randomly assigned to each treatment Exp 1 (slight increase in SAP levels at 2%/day, 76 Isobutyrate n=18/sex; 2.00%/day Sucrose 86 days; group; dosed daily in diet for 12 weeks); Exp 2 (dosed increase dog liver weights with 0.6%/day and Acetate Isobutyrate in 91 days daily in diet for 28 days, switched to control diet 57 days, 2.0%/day); Exp 2 (increase in SAP and Exp 2 n=6 th 6% cottonseed oil); Exp on 86 day 4 dogs returned to treatment diet-ICG prolongation of ICG plasma clearance by liver males; 2 (5%/day Sucrose clearance rates/SAP test conducted at 24 and 48 h); Exp 3 with 5%/day for 4 weeks, after withdrawal of Exp 3 n=10 Acetate Isobutyrate in (10 dogs randomly assigned to 2 groups of 5; dosed daily Sucrose Acetate Isobutyrate effects reversed in males corn oil); Exp 3 in diet for 91 days); negative controls were used 2-5 weeks, when fed 5%/day again and tested (5%/day Sucrose 24 h post-dosing SAP unaffected, ICG Acetate Isobutyrate + clearance prolonged); Exp 3 (increase in SAP, 5% corn oil) prolongation of ICG 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 50 Isobutyrate (Holtzman) group Acetate Isobutyrate used increase in liver weight of females fed 5%; (w/w) histopathological changes were unaffected

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Table 11. Short-Term and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender Sucrose Acetate Rat (Sprague- Rats: Exp 1 Exp 1 (0.0, 1.0, 95 days; Exp 1 (25 rats randomly assigned to each treatment Exp 1 (with 5%/day showed lower body weight 76 Isobutyrate Dawley) n=25/sex; 5.0%/day Sucrose 28 or 56 group; dosed daily in diet for 95 days); Exp 2 (280 rats for males and slight increase in liver weight for Acetate Isobutyrate); days; 36 randomly assigned to 14 treatment groups of each sex, females); Exp 2 (no toxicological effects); Exp Exp 2 Exp 2 (1.0, 2.0, days 10/group; dosed daily in diet for 28 or 56 days or for 28 3 (no hepatic microsomal activity, slight n=140/sex; 4.0%/day Sucrose days prior to or after which were fed a control diet for 28 depression of G-6-PTase activity) Exp 3 n=not Acetate Isobutyrate); days); Exp 3 (dosed daily in diet for 36 days to determine

specified, Exp 3 (4.0% Sucrose ICG clearance rates indicating liver functionality); males Acetate Isobutyrate + controls were used 5.0% corn oil/day)

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 NOAEL of 15% reported in male dogs; no 52,53 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, 17% (w/w) lipid content 28 days Dosed daily in diet for 28 days; animals killed beginning NOEL reported as 15% for male and female 52,53 Polysoyate n=4/sex/ mixed in diet; 0, 4, 15% on day 29; negative controls were used dogs; no clinical toxicity observed; higher food group (4 Sucrose Polysoyate consumption for treatment group vs. control; groups, 32 (sucrose polyester hematology, organs, and urine unaffected by animals total) 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) Sucrose Rat (Sprague- Males, 17% (w/w) lipid content 28 or 91 Dosed daily in diet for 28 or 91 days; 10 rats killed on day NOEL of 15% reported; No toxicity observed; 52,53 Polysoyate Dawley) n=20/group (5 mixed in diet; 0, 4, 8, days 28 and remainder killed on day 91; negative controls were 8% and 15% groups noted softer feces and groups, 100 15% Sucrose Polysoyate 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 but not Polysoyate (prepared those killed on day 91 (completely from completely hydrogenated soybean oil treatment led to hydrogenated soybean decreased heart weight); lipid levels unaffected oil)

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Table 11. Short-Term and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender 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; NOEL of 15% reported for males and females; 52,53 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 groups with highest dose (15%) Sucrose prepared from Polysoyate prepared from completely completely and partially hydrogenated soybean oil; organs, clinical hydrogenated soybean chemistry, urinalysis, and hematology oil); 15% Sucrose unaffected; Sucrose Polysoyate not substantially Polysoyate (prepared absorbed by gastrointestinal tract and not from completely identified in liver lipids 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 50 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 50 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 50 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 CHRONIC (> 6 MONTHS EXPOSURE) ANIMAL Oral

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Table 11. Short-Term and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender Sucrose Acetate Monkey Range finding For Range finding and 4 weeks; For 4 weeks (range-finding study) treatment was No effect on hepatobiliary function; No 54 Isobutyrate (Cynomolgus) study n=4/sex; 1-yr Toxicological 1 year administered to 1 monkey/sex/dose/day; For 1 year Observed Adverse Effect Level (NOAEL) 1yr study: 0, 500, 1450, (Toxicological study) treatment was administered to 4 reported at 2400 mg/kg/day Toxicological 2400 mg/kg/day monkeys/sex/dose/day; negative controls were used Range finding study (4 wks): all monkeys Study Sucrose Acetate survived to termination, occasional decreased n=16/sex Isobutyrate in corn oil appetite in all monkeys, no change in body

weight except for 1 female (12% loss at 2400 mg/kg/day), hematological values and BSP unaffected (no dose dependent effects), low terminal serum phosphorus in 1 female at 2400 mg/kg/day, no lesions, gross changes typical of spontaneous disease 1 Year Toxicological study: all doses were well tolerated, 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 and Chronic Toxicity Studies Test Species Sample Vehicle/ Concentration Dose Procedure Results Reference Substance(s) Type/ Test Duration Population- Gender Sucrose Acetate Rat (F344) n=20/sex/dose Highest doses fed were 1 year Dose administered daily in diet for 1 year; negative NOAEL reported at 2 g/kg/day for males and 55 Isobutyrate level up to 5% of diet controls were used females; body weight gain decreased likely (beyond which risks from nutritional deficiencies in females with 2 nutritional deficiency); g/kg/day at week 17 and beyond and in males acetone vehicle, 1 Year with 2 g/kg/day at weeks 13 and 54; 1 female study: 0, 0 (two control died with 0.5 g/kg/day group, 1 female killed in groups), 0.5, 1.0, 2.0 moribund condition with 2 g/kg/day group, 1 g/kg/day Sucrose control and 2 treated rats died during blood Acetate Isobutyrate collection; clinical and ophthalmic observations unaffected; food consumption decreased in females with 2g/kg/day; clinical chemistry, urine analysis, BSP retention unaffected with 2g/kg/day; statistically significant hematology values occurred in doses <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 * BSP=bromosulfophthalein; ICG=Indocyanine Green plasma clearance rates indicating liver functionality; SAP= serum alkaline phosphatase

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Table 12. Developmental and Reproduction Toxicity (DART) Studies Test Species Sample Type/ Vehicle/ Concentration Procedure Results Reference Substance(s) Test Population- Gender Oral

56 Sucrose Acetate Rat n=30/sex/dose 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 (not specified as to Isobutyrate (Fischer level F0 generation Sucrose Acetate and females fed Sucrose Acetate Isobutyrate for 2 weeks prior to whether the NOAEL applies to parents only or 344) (3 generation Isobutyrate; acetone mating (F0 females treated through lactation); F1 generation rats also includes offspring); pre-mating period reproduction vehicle raised on test diet and mated to produce F2a (treated through treated males showed decreased food study; teratology lactation; examined for fertility indices for F3 pregnancy) litters then consumption; body weights lower for treated F0 study) re-mated to produce F2b litters (treated through day 20; examined for females during gestation and lactation with 1 teratology); F2a females treated until day 14 of gestation; animals and 2g /kg/day and F1 females with 0.5 and 2g killed day 29 of teratology study; negative controls were used /kg/day during lactation; variability in fertility index (# females pregnant/ # females mated x100) not considered to be treatment related; reproduction unaffected; negative for teratogenic/ developmental toxic effects Sucrose Acetate Rabbit n=5/dose level 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 (not specified as to 56 Isobutyrate (New (range finding g /kg/day; for teratology-0, Teratology study: dosed on days 7-19 gestation, animals killed day whether the NOAEL applies to parents only or

Zealand study); n=16/dose 0.5, 0.85, 1.2 g/kg/day; 29 of teratology study; negative controls were used also includes offspring); Range finding study-no White) level (teratology corn oil vehicle mortality occurred, corn oil caused soft stools, studies) treatment well-tolerated; Teratology study-2 high dose treated rabbits died on day 17 gestation, results indicated no difference in treated vs control rabbits for caesarean section exams, food consumption, weight gain, and gross morphology; negative for teratogenic/ developmental toxic effects Sucrose Acetate 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 49 Isobutyrate (Holtzman) male in treatment Isobutyrate in diet; acetone controls used mg/kg /day (actual dose received); 5.0% (w/w) group; n=9 vehicle in diet of 2 generations produced no effect on female/ 7 male in viability; no observable toxic effects; F1 control group generation had respiratory outbreak resulting in the death of several young, several control rats, and 2 treated rats; none of young weaned in treatment group lived for 2 weeks (deaths attributed to respiratory outbreak) Sucrose Acetate 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 50 Isobutyrate (Sprague- Sucrose Acetate caged together for 19 days; females allowed to wean young to 21 slightly better vs. controls; at 9.38% fewer Dawley) Isobutyrate days; parent rats bred 3x in weeks 9-36 with different male per females became pregnant, fewer pups born and mating; negative controls used survived to weaning as observed over 3 breedings, this effect potentially attributable to compromised nutritive value of feed at high treatment levels

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Table 13. Genotoxicity Studies Test Species Sample Type/ Test Vehicle/ Concentration Procedure Results Reference Substance(s) Population IN VITRO Sucrose Acetate Salmonella Histidine 333-10,000 µg/plate Sucrose Ames Test (Salmonella reverse mutation assay): Negative for genotoxicity (as a mutagen, 57 Isobutyrate typhimurium auxotrophs TA98, Acetate Isobutyrate, control- Following preliminary toxicity test with TA100 six clastogen, and DNA-damaging agent); Solubility TA100, TA1535, dimethyl sulfoxide doses from 333-10,000 µg/plate were selected, exceeded at 50 µg/ml in dimethyl sulfoxide TA1537, TA1538 with and without metabolic activation; positive and Ames Test: Treatment was not effective at negative control used increasing revertant number per plate; non-toxic; positive control outcomes were as expected Sucrose Acetate Hamster Chinese Hamster 2.5 to 3350 µg/ml Sucrose CHO/HGPRT Mutation Assay: Preliminary Preliminary Results-Sucrose Acetate Isobutyrate 57 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 57 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 57 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 dose-related decrease in

Acetate Isobutyrate in CHO monolayer confluency and max reduction in Chromosomal Aberration Assay confluency of 33% (without activation) and 67% (with activation) but no increases in aberrations; positive control outcomes were as expected Sucrose Acetate Salmonella Strains: TA 1535, 10, 100, 500, 1000, 1500, 2000 Bacterial Reverse Mutation Assay: This assay was Negative for mutagenic activity 49 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 CHO/HGPRT 10-1000 µg/ml Sucrose Acetate CHO/HGPRT Mutation Assay performed with and Negative for genotoxicity (no further details 50 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 50 Isobutyrate Acetate Isobutyrate use of controls not specified provided)

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Table 13. Genotoxicity Studies Test Species Sample Type/ Test Vehicle/ Concentration Procedure Results Reference Substance(s) Population Sucrose Acetate Hamster Chinese Hamster 200-2000 µg/ml Sucrose Acetate Chromosomal Aberration Assay performed with Negative for genotoxicity (no further details 50 Isobutyrate Ovarian Cells Isobutyrate and without metabolic activation; not specified provided) IN VIVO Sucrose Acetate Rat (Sprague- n=20/sex/dose 20, 200, 2000 mg/kg Sucrose Oral administration by gavage as a single dose to Negative for dominant lethal mutations; positive 49 Isobutyrate Dawley) Acetate Isobutyrate in corn oil 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 Vehicle/ Concentration Procedure Results Reference Substance(s) Population IN VITRO 59,77 Sucrose Laurate Hamster Chinese Hamster 10% Sucrose Laurate solution Neutral Red Effective Concentration50 (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 59,78 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 35 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 Sample Type/ Vehicle/ Concentration Procedure Results Reference Test Population- Gender 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 37 (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 stated that there was some skin 38 (White hydrophilic gels (also containing 60 µg administration; 100 mg gels were applied on days irritation potential observed, but that treatment New estradiol and a preservative), pH 6 1 and 7 to 3 x 3 cm shaved skin area; days 2-6 was well-tolerated and emphasized that the Zealand) placebos applied; blood samples collected from irritation effects of surfactants are influenced by marginal ear vein 0.5 thru 12 h post- the application method and parameters of administration; skin biopsies (taken from 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 59 (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 33 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 49 Isobutyrate Pig (concentration and vehicle not specified) Irritation/Corrosion test (OECD Guideline 404) percutaneous absorption evident (Hartley 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 41 (80% mono-, 17% n=8 (irritation aceclofenac), 1-2% (w/w) egg lecithin, (nanoemulsions tested on human skin all contained adverse reactions were visually observed; no di-, 3% tri-) profile study) 10% medium chain triglycerides, 10% acecofenac; controls used were non-treated skin change in erythema index values; Sucrose Stearate Castor oil, 0.05% butylhydroxy-toluene both with and without occlusion) applied to 3 x transepidermal water loss increased (48% mono-, 34% -aqueous phase: 3cm2 forearm surface area; erythema index, substantially relative to baseline but not di-, 14% tri-) 0-2% (w/w) Sucrose Palmitate; 0-2% transepidermal water loss, and stratum corneum compared to non-treatment controls; stratum (w/w) Sucrose Stearate hydration evaluated prior to testing (to establish a corneum hydration showed substantial decrease baseline) and 3 h after removal of 24 h occlusion; in all treated sites compared to baselines and negative controls used non-treated control under occlusion; nanoemulsions tested were tolerable to the skin

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Table 15. Irritation Studies (Dermal) Test Substance(s) Species Sample Type/ Vehicle/ Concentration Procedure Results Reference Test Population- Gender Sucrose Human N=34 subjects, but 4 UV protectant prototypes, 3 containing Treatment applied each day occlusively (to back Erythema observed (4 subjects) in test group, 52 Polycottonseedate only 27 completed 0.5% Sucrose Polycottonseedate and 1 for 24 h) in a 21 day study; negative controls used erythema noted (23 subjects) in control group; study containing 1% Sucrose slightly irritating Polycottonseedate; no vehicle used Sucrose Human N=11 (all subjects Lotion squeezed from cleansing cloths Lotion containing treatment was applied daily at Non-irritating 52,53 Polycottonseedate, completed study) containing 3.18% Sucrose Polybehenate 100%, 50%, and 20% (v/v) occlusively for a 5-day Sucrose and 12.73% Sucrose Polycottonseedate; 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 52 Polycottonseedate product (49 using Sucrose Polycottonseedate at 17.19% single blind study (uncontrolled conditions); use of erythema and dryness with 17.19%); at 4 weeks 17.19% Sucrose and 15.79%; no vehicle used 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. Sensitization Studies (Dermal) Test Substance(s) Species Sample Type/ Vehicle/ Concentration Procedure Results Reference Test Population- Gender ANIMAL Sucrose Acetate Guinea Skin Skin Irritation Test: 5-20 ml Skin Irritation Test: Treatment was applied directly to hairless guinea Skin Irritation Test: Slight, transient 76 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; challenging acetone/ dioxane / guinea pig doses (not specified) applied to right shoulder and 1 week later to left fat (7:2:1) 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 49 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 49 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 58 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. Sensitization Studies (Dermal) Test Substance(s) Species Sample Type/ Vehicle/ Concentration Procedure Results Reference Test Population- Gender 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 52 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; 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 52,53 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; non-irritating Sucrose Human N=108 subjects Two facial cleansing cloths HRIPT was performed by applying treatment occlusively (to back for Up to 1 subject at any observation time for 52 Polycottonseedate (7 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; non-irritating

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Distributed for Comment Only -- Do Not Cite or Quote

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

Concentration of Use by FDA Product Category – Saccharide Esters*

Sucrose Acetate Isobutyrate Sucrose Palmitate/Stearate Glucose Pentaacetate Sucrose Pentaerucate Maltitol Laurate Sucrose Pentahydroxystearate Raffinose Isostearate Sucrose Polybehenate Raffinose Myristate Sucrose Polycottonseedate Raffinose Oleate Sucrose Polylaurate Sucrose Acetate/Stearate Sucrose Polylinoleate Sucrose Benzoate Sucrose Polyoleate Sucrose Cocoate Sucrose Polysoyate Sucrose Dilaurate Sucrose Polystearate Sucrose Disinapate Sucrose Stearate Sucrose Distearate Sucrose Tetrahydroxystearate Sucrose Hexaerucate Sucrose Tetraisostearate Sucrose Sucrose Tetrastearate Triacetate 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 Ingredient Product Category Maximum Concentration of Use Sucrose Acetate Isobutyrate Eyebrow pencils 1.8% Sucrose Acetate Isobutyrate Eyeliners 10-11% Sucrose Acetate Isobutyrate Eye shadows 0.77-31% Sucrose Acetate Isobutyrate Mascara 4.8% Sucrose Acetate Isobutyrate Other eye makeup preparations 0.5% Sucrose Acetate Isobutyrate Foundations 2.4-31% Sucrose Acetate Isobutyrate Lipstick 0.41-27% Sucrose Acetate Isobutyrate Other makeup preparations 1.6-24% Sucrose Acetate Isobutyrate Basecoats and undercoats 0.07-0.9% (manicuring preparations) Sucrose Acetate Isobutyrate Nail polish and enamel 0.1-9% Sucrose Acetate Isobutyrate Nail polish and enamel removers 0.1% Sucrose Acetate Isobutyrate Other manicuring preparations 0.0084-4.5% Sucrose Acetate Isobutyrate Moisturizing products Not spray 0.5% Sucrose Acetate Isobutyrate Other skin care preparations Temporary tattoo 6.6% Sucrose Acetate/Stearate Face and neck products

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Not spray 0.3% Sucrose Benzoate Basecoats and undercoats 1.4-2.5% (manicuring preparations) Sucrose Benzoate Nail polish and enamel 2-14.3% Sucrose Benzoate Other manicuring preparations 8% Sucrose Benzoate Skin cleansing (cold creams, 0.21% cleansing lotions, liquids and pads) Sucrose Cocoate Hair conditioners 0.05% Sucrose Cocoate Shampoos (noncoloring) 0.05% Sucrose Cocoate Tonics, dressings and other hair 0.12% grooming aids Sucrose Cocoate Foundations 1% Sucrose Cocoate Lipstick 0.0001-0.98% Sucrose Cocoate Bath soaps and detergents 1.3% Sucrose Cocoate Deodorants Not spray 0.49% Sucrose Cocoate Shaving soap 20.6% Sucrose Cocoate Skin cleansing (cold creams, 0.2-4% cleansing lotions, liquids and pads) Sucrose Cocoate Face and neck products Not spray 0.05-4% Sucrose Cocoate Body and hand products Not spray 0.05-1% Sucrose Cocoate Moisturizing products Not spray 0.12-0.2% Sucrose Cocoate Night products Not spray 1.2-2.2% Sucrose Cocoate Pastes masks and mud packs 4.3% Sucrose Cocoate Suntan products Not spray 0.12% Sucrose Dilaurate Eyeliners 0.00000004% Sucrose Dilaurate Lipstick 0.013% Sucrose Dilaurate Face and neck products Not spray 0.17-0.45% Sucrose Dilaurate Paste masks and mud packs 0.18% Sucrose Distearate Bath oils, tablets and salts 0.011% Sucrose Distearate Eye lotions 1% Sucrose Distearate Mascara 1-5.5% Sucrose Distearate Tonics, dressings and other hair 1.2% grooming aids Sucrose Distearate Other hair coloring preparations 1.1% Sucrose Distearate Face powders 0.015% Sucrose Distearate Foundations 0.003% Sucrose Distearate Lipstick 0.57-1.8% Sucrose Distearate Other makeup preparations 0.0003% Sucrose Distearate Face and neck products

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Not spray 2% Sucrose Distearate Body and hand products Not spray 0.5% Sucrose Distearate Other skin care preparations 1% Sucrose Rouges 5% Hexaoleate/Hexapalmitate/Hexastearate Sucrose Laurate Eyeliners 0.0003% Sucrose Laurate Eye lotions 0.12% Sucrose Laurate Eye makeup removers 3% Sucrose Laurate Hair conditioners 0.05-0.5% Sucrose Laurate Hair sprays Pump spray 1.2% Sucrose Laurate Shampoos (noncoloring) 0.05-1.5% Sucrose Laurate Lipstick 0.063% Sucrose Laurate Dentifrices 0.1% Sucrose Laurate Mouth washes and breath 0.05% fresheners Sucrose Laurate Bath soaps and detergents 1% Sucrose Laurate Skin cleansing (cold creams, 0.57-1% cleansing lotions, liquids and pads) Sucrose Laurate Face and neck products Not spray 0.05-1.5% Spray 0.6% Sucrose Laurate Body and hand products Not spray 0.05-3% Sucrose Laurate Moisturizing products Not spray 0.4% Sucrose Myristate Shampoos (noncoloring) 0.3% Sucrose Myristate Mouth washes and breath 0.1% fresheners Sucrose Myristate Moisturizing products Not spray 6% Sucrose Palmitate Bath oils, tablets and salts 0.008% Sucrose Palmitate Eyeliners 0.000012-0.000048% Sucrose Palmitate Eye makeup removers 3% Sucrose Palmitate Hair conditioners 0.00004-0.05% Sucrose Palmitate Shampoos (noncoloring) 0.00004-0.05% Sucrose Palmitate Face powders 0.008% Sucrose Palmitate Foundations 0.008% Sucrose Palmitate Lipstick 0.02% Sucrose Palmitate Other makeup preparations 3% Sucrose Palmitate Nail polish and enamel 0.00002% Sucrose Palmitate Skin cleansing (cold creams, 0.00004-1.3% cleansing lotions, liquids and pads) Sucrose Palmitate Face and neck products Not spray 0.0008-1.5%

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Sucrose Palmitate Body and hand products Not spray 0.05-0.31% Sucrose Palmitate Night products Not spray 0.49% Sucrose Palmitate Skin fresheners 0.0004% Sucrose Polybehenate Mascara 4% Sucrose Polybehenate Lipstick 6% Sucrose Polybehenate Suntan products Not spray 1% Aerosol 1% Sucrose Polycottonseedate Eye lotions 1-1.5% Sucrose Polycottonseedate Foundations 0.5% Sucrose Polycottonseedate Lipstick 87.7% Sucrose Polycottonseedate Skin cleansing (cold creams, 2.8% cleansing lotions, liquids and pads) Sucrose Polycottonseedate Face and neck products Not spray 1% Sucrose Polycottonseedate Moisturizing products Not spray 2.5% Sucrose Polycottonseedate Night products Not spray 1.4% Sucrose Polycottonseedate Other skin care preparations 2% Sucrose Polylaurate Face and neck products Not spray 0.01% Sucrose Polylaurate Body and hand products Not spray 0.039% Sucrose Polysoyate Lipstick 4.9% Sucrose Polysoyate Moisturizing products Not spray 1% Sucrose Polysoyate Night products Not spray 0.51% Sucrose Polystearate Eye shadows 1-1.4% Sucrose Polystearate Eye lotions 1% Sucrose Polystearate Mascara 4-6% Sucrose Polystearate Hair tints 0.7% Sucrose Polystearate Lipstick 1-2.5% Sucrose Polystearate Face and neck products Not spray 1.7% Sucrose Stearate Bath oils, tablets and salts 0.069% Sucrose Stearate Eyebrow pencils 4.4% Sucrose Stearate Eyeliners 0.0003% Sucrose Stearate Eye lotions 0.28-0.75% Sucrose Stearate Eye makeup removers 0.79-3% Sucrose Stearate Mascara 0.5-6% Sucrose Stearate Other eye makeup preparations 6% Sucrose Stearate Shampoos (noncoloring) 0.3%

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Sucrose Stearate Tonics, dressings and other hair 1.8-2.2% grooming aids Sucrose Stearate Wave sets 2% Sucrose Stearate Foundations 3% Sucrose Stearate Lipstick 0.079% Sucrose Stearate Makeup bases 2% Sucrose Stearate Nail polish and enamel 0.0001% Sucrose Stearate Mouth washes and breath 0.2% fresheners Sucrose Stearate Deodorants Not spray 0.45% Aerosol 0.23% Sucrose Stearate Shaving cream 0.04% Sucrose Stearate Skin cleansing (cold creams, 1-3% cleansing lotions, liquids and pads) Sucrose Stearate Face and neck products Not spray 0.013-2% Sucrose Stearate Body and hand products Not spray 0.2-3.9% Sucrose Stearate Moisturizing products Not spray 2% Sucrose Stearate Night products Not spray 0.04% Sucrose Stearate Paste masks and mud packs 3% Sucrose Stearate Other skin care preparations 3.3% Sucrose Tetraisostearate Eyebrow pencils 5% Sucrose Tetraisostearate Eye shadows 0.01% Sucrose Tetraisostearate Mascara 1% Sucrose Tetraisostearate Lipstick 1% Sucrose Tetrastearate Triacetate Eyebrow pencils 4.4-7% Sucrose Tetrastearate Triacetate Eyeliners 2.6-7% Sucrose Tetrastearate Triacetate Eye shadows 0.55-5% Sucrose Tetrastearate Triacetate Eye makeup removers 10% Sucrose Tetrastearate Triacetate Mascara 15% Sucrose Tetrastearate Triacetate Blushers 0.65% Sucrose Tetrastearate Triacetate Foundations 0.5-5% Sucrose Tetrastearate Triacetate Lipstick 0.0086-10% Sucrose Tetrastearate Triacetate Makeup bases 3% Sucrose Tetrastearate Triacetate Other makeup preparations 3.3% Sucrose Tetrastearate Triacetate Face and neck products Not spray 1% Sucrose Tetrastearate Triacetate Body and hand products Not spray 2% Sucrose Trilaurate Lipstick 0.004% Sucrose Tristearate Face powders 2% Sucrose Tristearate Foundations 2%

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Sucrose Tristearate Lipstick 0.38-0.75% Sucrose Tristearate Body and hand products Not spray 2% Sucrose Tristearate Suntan products Not spray 0.5% Trehalose Isostearate Esters Foundations 0.5% Trehalose Undecylenate Hair conditioners 0.05% Trehalose Undecylenate Shampoos (noncoloring) 0.25% Trehalose Undecylenate Tonics, dressings and other hair 0.05% grooming aids Trehalose Undecylenate Bath soaps and detergents 0.0005% Trehalose Undecylenate Skin cleansing (cold creams, 0.0005% cleansing lotions, liquids and pads) *Ingredients included in the title of the table but not found in the table were included in the concentration of use survey, but no uses were reported.

Information collected in 2015-2016 Table prepared February 12, 2016

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Persona I Core Products Council Committed to Safety, Quality & Innovation

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: April 14, 2016

SUBJECT: Comments on the Scientific Literature Review: Safety Assessment of Saccharide Esters as Used in Cosmetics (SLR posted on CIR's website March 22, 2016)

The Council has no suppliers listed for the following ingredients: Raffinose Myristate Raffinose Oleate Sucrose Polylinoleate

Key Issues When tables are used to summarize information, it would be helpful if the text provided a synthesis of the information in the table, rather than a briefer listing of the results that can be found in the table. If there are multiple similar studies, the number of similar studies could be stated. In the toxicology section, it would be helpful to state if a target organ was identified and to state the lowest dose that resulted in an effect and whether or not the observed effect was adverse. If a column for controls is included in a table, "Yes" is not sufficient information. How the controls were treated should be stated. Generally, controls are not needed for metabolism studies. Therefore, if they were comparing the metabolism of one compound to another compound, the names of both compounds should be stated. In Table 8 reference 33 (human study) it states that the controls were not specified, but the study description indicates that they compared the metabolism of Sucrose Acetate Isobutyrate to Sucrose. For other types of studies, it should at least state if the controls were positive or negative.

Additional Considerations Introduction, Table 2 - Although the FDA VCRP may include both Sucrose Palmitate/Stearate and Sucrose Palmitate-Stearate Esters, the descriptions given for these ingredients in Table 2 are the same. Therefore, these names should not be counted as separate ingredients. It should be stated that they appear to be two names for the same material.

1620 L Street, N.W., Suite 1200 IWashington, D.C. 20036,202.331.1770 I 202.331.1969 (fax) Iwww.personalcarecoundl.org Distributed for Comment Only -- Do Not Cite or Quote

Impurities - In the sentence "Impurities known to be toxic that may be found in these ingredients include ... ", it is not clear what "these ingredients" represents. Cosmetic Use- Please state the specific product category in which Maltitol Laurate was reported to be used.

Sucrose dipalmitate has not yet been included in a Council concentration of use survey. Therefore, stating that "no use concentration data were reported" is misleading - of course no use data were reported because companies were not asked to provide any concentration of use information on sucrose dipalmitate.

Please state the specific leave-on product category for which a 0.5% use concentration was reported for Trehalose Undecylenoate. Non-Cosmetic Use- Because Sucrose Octaacetate is not safe and effective for use in nail-biting and thumb-sucking deterrents, in the United States it should not be used in those products. Therefore, it is not appropriate to state that Sucrose Octaacetate is used in OTC drug products. Absorption, Distribution, Metabolism and Excretion- Please state the route(s) of exposure used in the "Tests conducted in rats:" Penetration Enhancement - The word "enhancement" is missing from the sentence describing the information in Table 9. Toxicological Studies- Generally, there are at least two subheadings, acute and repeated dose, in the toxicology section.

Was the 5 g/kg/day a dose (mg/kg bw) or a dietary concentration of Sucrose Acetate Isobutyrate? Toxicological Studies, Table 10- It is not clear what is meant by "no NOAEL was reported". The summary of this study provided in the table suggests that the effects observed were considered pharmacological effects rather than adverse effects. Did the study authors state that they did not identify a NOAEL? Or did they just not label any of the doses as a NOAEL? Reproductive and Developmental Toxicity- For developmental toxicity studies, it should state if the NOAELs were for maternal or developmental toxicity, or for both maternal and developmental toxicity. Genotoxicity - This section needs to be revised. The current sentence structures states that the tests (rather than the compounds) were non-non toxic. Irritation and Sensitization- What was the induction concentration used in the guinea pig maximization test of Sucrose Acetate Isobutyrate? Irritation and Sensitization, Table 13, Summary - Rather than stating that 88% Sucrose Polycottonseedate was tested, it would be more accurate to state that a lipstick topcoat containing 88% Sucrose Polycottonseedate was tested in an HRIPT. Summary- The micropig experiments were not presented in the text earlier. If they are important enough to be in the Summary, they should also be mentioned in the text ofthe report in addition to the tables.

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The timing of dosing in relation to gestation also needs to be stated in the descriptions of the developmental toxicity studies in the Summary.

The descriptions of the carcinogenicity studies in the Summary should clearly state that they were negative. If "vehicle" is included in a column heading, then the vehicle should be stated in that column, not in another column. Table 4 - If molecular weight can be "predicted" for Xylityl Sesquicaprylate, it should be possible to estimate molecular (formula) weight from the structures for all of the ingredients with a defined chain length. Table 5- Sucrose dipalmitate and sucrose stearate-palmitate were not included in the Council concentration of use survey. Therefore, it is not appropriate to indicate that concentrations of use were "not reported". Table 7- FDA does not use the terminology "Generally Recognized as Safe" for OTC drug actives. 21 CFR31 0 indicates ingredients that lack data to support safety and effectiveness. Table 8 - The first study in Table 8 is a cytotoxicity study (reference 29). It does not belong in Table 8.

The description of ADME studies should always indicate when after dosing samples were taken and the time frame of the results also need to be indicated. This is not done for a number of studies from reference 32, 28 and 33.

The study concerning absorption of insulin following nasal exposure to Sucrose Cocoate (reference 67) needs to be moved to Table 9, Penetration Enhancement, as it appears that absorption of insulin not the absorption of Sucrose Cocoate was studied. Table 9- Rather than stating that the tested sites were hairless, it would be better to indicate how the hair was removed from the rabbits (shaved or depilatated) (reference 39). Table 10- Was the 15 day study of Sucrose Acetate !sobutyrate a gavage study or a dietary study (reference 43)? One column says (gavage), another column says dosed daily in the diet.

Were the doses stated in the mouse dietary study (reference 43) mg/kg bw or mglkg diet?

At the bottom of Table 10, please define the acronyms used in this table, such as ICG and SAP.

Please check to see if the 1 year rat (F344) studies described in reference 46 and reference 26 are the actually the same study. Table 11 -In the rabbit study (reference 49) did they really use 2x1200 mglkg/day doses (total2400 mglkg/day) or was it 2x600 mglkg/day for a total dose of 1200 mg/kg/day. In the description of this study, please use units of glkg/day or mglkg/day throughout the description of this study, not both units. Table 12- The first two studies in this table are cytotoxicity studies not genotoxicity studies. 1 References - Please update the Dictionary reference to the 16 h (20 16) edition.