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SAFETY REPORT/ SAFETY ASSESSMENT

Product Name: simplehuman Moisturizing Liquid Hand Soap

PART A, SAFETY REPORT

The following Safety Assessment is carried out according to the Council Directive 76/768/EEC, on the Safety of Cosmetic Products and as amended by Commission Directives 2003/15/EC (7th Amendment), 2003/83/EC (30th Amendment), and 2003/80/EC (31st Amendment)

The Assessment is conducted in accordance with the principles of Good Laboratory Practice referred to in Article 1 of Council Directive 2004/10/EC on the applications of the principles of good laboratory practice and the verification of their application for tests on chemical substances.

This assessment takes account of: a) the general toxicological profile of each ingredient used: b) the chemical structure of each ingredient: c) the level of exposure of each ingredient; d) the specific exposure characteristics of the areas on which the cosmetic product will be applied; e) the specific exposure characteristics of the class of individuals for whom the cosmetic product is intended.

Review of Ingredients.

All of the ingredients have a history of use in cosmetic and toiletry products. Ingredients that are: • Prohibited under the Cosmetics Directive • Restricted when used beyond the allowed authorised conditions • With toxicological data incompatible with the intended concentration and use • Which have insufficient toxicological data nor safety in use experience • Which are not properly characterised with regard to purity and analytical composition

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Are excluded.

ASSESSMENT

Assessment is based on ingredient safety review and information on the final formulations, including the intended and reasonably foreseeable use, the physico-chemical and microbiological specifications of the raw materials and the finished product, stability and a history and record of any reported undesirable effects linked to the use of the product.

DESCRIPTION OF THE PRODUCT

This is a rinse-off product for application to the hands. It is for use by the whole family above age 3 years. The product may typically be used 1-5 times daily.

QUANTITATIVE COMPOSITION OF THE PRODUCT

Ingredients are listed below. Detailed information on the safety and toxicology of ingredients is appended.

Ingredient INCI names %w/w (as 100% Supplier/Trade Name active)

Aqua 85.1529 Sodium Laureth Sulphate 6.75 Stepan, Steol CS-230 PCK Cocoamidopropyl betaine 3 Pilot, Caltaine C-35 Sodium Lauryl Sulfate 2.9 Stepan, Stepanol WA-Extra PCK Glycerin 1 Univar, Glycerin 99.7% Sodium Chloride 0.6 Univar Lavandula Angustifolia Oil 0.22 ING Soutions, Lavender Oil Trisodium Ethylenediamine 0.037 Innospec-Argan, Natriquest E30 Disuccinate Panthenol 0.05 DSM, DL Panthenol 50L Tocopheryl Acetate 0.0001 DL-Alpha Tocopheryl Acetate Benzophenone-4 0.05 BASF, Uvinul MS-40

*Methylchloroisothiazolinone 0.07** Thor, Microcare ITL *Methylisothiazolinone Thor, Microcare ITL Sodium PCA 0.005 Ajinimoto, Ajidew NL 50 CI 60730 (0.1% solution) 0.15 Sensient, Ext D&C Violet No 2 CI 14700 (0.1% solution) 0.015 Sensient, FD&C Red No 4

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EU Ingredients Labelling

Aqua Sodium Laureth Sulfate Cocoamidopropyl betaine Sodium Lauryl Sulfate Glycerin Sodium Chloride Panthenol Tocopheryl Acetate Lavandula Angustifolia oil Benzophenone-4 Trisodium Ethylenediamine Disuccinate Sodium PCA Methylchloroisothiazolinone Methylisothiazolinone CI 60730 CI 14700 Linalool

PHYSICAL/CHEMICAL CHARACTERISTICS

The raw material Specifications and the Finished Product Specifications are to be available.

RAW MATERIAL QUALITY/ PURITY

All raw materials are from reputable sources of supply and are considered to meet current standards of purity and quality. The physical and chemical properties and microbiological of the raw materials have been reviewed. It is noted that all are to current standards and there are no banned or restricted materials present. The raw materials meet current good standards for quality and purity. Manufacturers Material data sheets/ Certificates are to be available.

STABILITY

The product is stable under normal and foreseeable conditions of use.

MICROBIAL QUALITY

INGREDIENTS

It is a requirement that all raw materials/ ingredients meet a microbial quality of < 1000 cfu/ gram for Adult products

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FINSHED PRODUCT

It is a requirement that the Finished Product meets a microbial quality of < 1000 cfu/ gram for Adult products and zero harmfuls.

CHALLENGE TEST DATA

The product passes a Microbial Challenge Test

PACKAGING

The product is packaged as described below: a. POUCH (1 litre refill pouch) Country of Origin: South Korea Stand Up Pouch / 3 SIDE SEAL/ / SPOUT(10mm I.D.DIA) / ROUND CORNER Pouch Composition: MATTCOAT/PET(12)/PRN(4)/ADH/ONY(15)/ADH/WHITE OCTENE- LLDPE(135) Spout Composition: HDPE Size: 177mm x 245mm + 90mm (7.0'' x 9.6'' + 3.5'') Gauge: 162 mic ( 6.4 mil) Print: 4 Colors

Give away 0.2 litre sample pouches. Description: Stand Up Pouch / NO ZIPLOCK/3 SIDE SEAL/ / TEAR NOTCH / ROUND CORNER / Composition: MATT-COAT/PET(12)/PRN(4)/ADH/ONY(15)/ADH/WHITE OCTENE-LLDPE(95) Size: 110mm x 170mm + 50mm (4.3'' x 6.7'' + 2.0'') Gauge: 122 mic ( 4.8 mil) Print: 4 Colors

b. PET BOTTLE Country of Origin: China Pump (stem/ stem guide/SS spring/spring guide/bottle cap/piston seal/ glass ball/pump housing/foam washer/ straw/ polypropylene cover) Metal cap (stainless steel/ polypropylene) Collar lock (polypropylene)

The packaging material is to meet an acceptable standard of purity. Consideration has been given to interaction between the product and the packaging. It is considered there is no adverse interaction between product and packaging as regards safety to the consumer.

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DESCRIPTION OF INTENDED AND REASONABLY FORESEEABLE USE

The product may reasonably be typically used 1-5 times daily.

EXPOSURE TO THE PRODUCT & MARGINS OF SAFETY

Based on the available toxicological literature or on “read-across” data Margins of Safety have been calculated for both topical and systemic effects. The procedure is as described in: THE SCCS NOTES OF GUIDANCE, FOR THE TESTING OF COSMETIC INGREDIENTS AND THEIR SAFETY EVALUATION, 7th REVISION, 2010.

Dermal Absorption reported as a % of the substance applied:

The calculation of the SED is as follows:

SED = A (g/day) x 1000mg/g x C (%)/100 x DAp (%)/100 60 kg

SED (mg/kg bw/day) = Systemic Exposure Dosage A (g/day) = Amount of the cosmetic product applied daily: see the daily exposure values for different cosmetic product types C (%) = the Concentration of the ingredient under study in the finished cosmetic product on the application site DAp (%) = Dermal Absorption expressed as a percentage of the test dose assumed to be applied in real life conditions 60 kg = default human body weight

The calculation of Margin of Safety (MOS): NOAEL SED

NOAEL data is derived from published literature where available.

Estimated Daily Exposure Levels:

Data for Estimated daily exposure levels is taken from the current Colipa data as presented in THE SCCS NOTES OF GUIDANCE, FOR THE TESTING OF COSMETIC INGREDIENTS AND THEIR SAFETY EVALUATION, 7th REVISION, 2010.

Estimated daily exposure levels for different cosmetic product types according to Colipa data [SCCNFP/0321/02; Hall et al. 2007, 2011].

Product type Estimated Relative Retention Calculated Calculated daily amount factor 1 daily relative daily amount applied exposure exposure applied (mg/kg (g/day) (mg/kg bw/day bw/day)

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Bathing, showering Shower gel 18.67 g 279.20 0.01 0.19 2.79 Hand wash soap 20.00 g 0.01 0.20 3 3.33 2 - Hair care Shampoo 10.46 g 150.49 0.01 0.11 1.51 Hair conditioner 3.92 g - 0.01 0.04 0.60 Hair styling 4.00 g 57.40 0.1 0.04 5.74 products Semi-permanent 35 ml - 0.1 Not - hair (per calculated dyes (and application) lotions) 2 Oxidative/perma 100 ml - 0.1 Not - nent (per calculated 4 hair dyes 2 application) Skin care Body lotion 7.82 g 123.20 1.0 7.82 123.20 Face cream 1.54 g 24.14 1.0 1.54 24.14 Hand cream 2.16 g 32.70 1.0 2.16 32.70 Make-up Liquid foundation 0.51 g 7.90 1.0 0.51 7.90 Make-up 5.00 g - 0.1 0.50 8.33 remover 2 Eye shadow 2 0.02 g - 1.0 0.02 0.33 Mascara 2 0.025 g - 1.0 0.025 0.42 Eyeliner 2 0.005 g - 1.0 0.005 0.08 Lipstick, lip salve 0.057 g 0.90 1.0 0.057 0.90 Deodorant Deodorant non- 1.50 g 22.08 1.0 1.50 22.08 spray Deodorant 1.43 g 20.63 1.0 1.43 20.63 aerosol spray (ethanol-based) 5 Deodorant spray 0.69 g 10.00 1.0 0.69 10.00 (not ethanol- based) Oral hygiene Toothpaste 2.75 g 43.29 0.05 0.138 2.16 (adult) Mouthwash 21.62 g 325.40 0.10 2.16 32.54

1 The retention factor was introduced by the SCCNFP to take into account rinsing off and dilution of finished products by application on wet skin or hair (e.g. shower gels, shampoos, …) [SCCNFP/0321/00] 2 Product types not covered by the Colipa studies: existing daily application amounts are divided by the mean human body weight of 60 kg. 3 Danish Ministry of the Environment, Environmental Protection Agency: Survey of liquid hand soaps, including health and environmental assessments. 4 Daily exposure value not calculated due to the low frequency of exposure (see also 3-8.3.1). 5 Steiling et al. (publication in preparation); results presented to the SCCS. ‘Ethanol-based’ are products containing ethanol as principal ingredient.

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It was concluded that all ingredients, when considered both individually and in combination have an adequate Margin of Safety, ie > 100.

GOOD MANUFACTURING PRACTICE

The product is manufactured to adequate standards of Good Manufacturing Practice and there are adequate controls in regards to Microbial quality.

FINISHED PRODUCT SAFETY

The above formulation is based on known ingredients with history of safe use in cosmetic products. The product is considered to be protected from microbial growth.

It is a requirement that all raw materials met EU standards for purity and regulatory compliance. It is noted that all ingredients are used within limits as specified in the cosmetics Directive.

The use of the preservative blend methylchloroisothiazolinone/ methylisothiazolinone (10.5 ppm active isothiazolinones) is within the requirements of Annex 6 of the EU Cosmetics Directive. The use of the colours is within the requirements of Annex 4 of the EU Cosmetics Directive The microbial content (Total Viable Count) at time of manufacture must be within recognised limits (nmt 1000cfu and zero harmfuls /gm).

This Safety Assessment has taken account of: 1. The Quantitative/Qualitative composition of the product, 2. The intended and reasonably foreseeable use of the product, 3. Margins of Safety for all ingredients considered both individually and in combination. 4. A review of raw material specifications for purity. 5. Standards of good manufacturing practice 6. A consideration of potential interactions of substances in the formulation. 7. A consideration of the stability of the formulation.

TOXICOLOGY PROFILE OF THE INGREDIENTS

SODIUM LAURETH SULFATE

CAS: 9004-82-4; 1335-72-4; 3088-31-1

7 Sodium Laureth Sulfate SLES has been reviewed in the Cosmetic Ingredient Review. The CIR summarises and concluded that SLES is safe as presently used in cosmetics (1) A full toxicological review of the safety of SLES was published in JACT 1983 (2). The review details acute toxicity by the oral and dermal routes in rodents. At typical in-use levels there is zero or very minimal skin irritation and acute toxicity. In sub chronic dosing SLES was fed to rats for 13 weeks. There were minor but not significant changes and no evidence of pathological changes at necropsy. In chronic feeding studies in rats for 105 weeks there were no adverse effects of significance recorded. In reproduction studies, SLES caused no effects on fertility, lactation or other reproductive parameters. In skin tumorogenicity studies, SLES applied at 0.1ml of a 5% solution did not cause tumors. In human clinical studies, SLES was applied dermally to test for acute irritation, subchronic dermal irritation and contact sensitisation. Moderate irritation occurred on repeat contact, but there was no evidence of contact sensitisation. Products containing SLES have been evaluated in human clinical studies and have not shown potential for sensitisation, photo-allergy or photo-toxicity. Carcinogenic, Mutagenic and Teratogenic properties have been reviewed in the literature(3,4). In a range of anionic surfactants studied of chemical structures similar to SLES there were no reports of carcinogenic activity considered to be due to product. A variety of genotoxicity studies have been conducted with several anionic surfactants of similar chemistry to SLES. Tests including recombination assays, in-vivo and in-vitro cytogenetics and host- mediated assays demonstrated no evidence of mutagenic activity. Teratogenicity studies gave no evidence of effects at doses likely to be encountered in normal use. In summary SLES is considered safe at amounts typically used in rinse-off skincare products and as used in the current formulation. A NOAEL of 225 mg/kg is reported in suppliers literature (5).

REFERENCES 1 CIR Compendium 2004. 2 JACT 2, 1983. 1-33 3 Surfactants in Cosmetics, Eds Rieger & Rhein. Marcel Dekker Inc NY. 1999. Chapter 25, pp557-571. 4 Anionic Surfactants – Biochemistry, Toxicology, Dermatology. Ed Gloxhuber. Marcel Dekker Inc. NY. 1980. Chapter 27 pp 327- 399. 5. SODIUM SULPHATE (SODIUM LAURETH SULFATE; CAS NO. 3088-3 l-l) Submitted to the US Environmental Protection Agency Company .DATE: May 2006

COCAMIDOPROPYL BETAINE

CAS: 61789-40-0

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Cocamidopropyl betaine (CAPB), is the subject of a CIR monograph (2004) and of a review in JACT (1991), in addition there is a BIBRA Toxicity Profile (1999). The oral LD50 in rats is 4.9g/kg for a 30% strength material. In skin irritation studies a 30% solution of CAPB was rated as “ moderately irritant” in a 24hr patch test, but only mild irritant effects were seen with a similar test a 4 hrs. In rabbit eye studies a 2-3 % solution is rated as moderately irritant. In human skin patch tests a 10% solution was reported as “non irritant” in 20 eczema patients, while no irritant reactions were seen in 22 healthy volunteers patch tested for 48 hrs at 1% in petrolatum. It is known that impurities especially the amido-amine content can affect irritation and sensitisation results. There are clinical reports of sensitisation to CAPB from use of products containing this ingredient. It is now considered that a major contributor to such effects is the presence of impurities and that pure grade will have less irritant/ sensitising potential. In human volunteer studies there were neither sensitising nor photosensitising nor photo-toxic responses. In mutagenicity studies CAPB was non mutagenic in 4 assay systems, ie Ames test and mouse lymphoma cells. In carcinogenicity studies of a hair dye containing CAPB (0.3%) applied to mice 3 x per week for 20 months there was no difference from controls, although this dose is very low for sensitivity for carcinogen detection. There is no data available for reproductive toxicity. In summary CAPB as used in the current formulation is considered safe. A NOAEL of 250mg/kg for a 30% solution is reported (5).

REFERENCES 1. Cosmetic Ingredient Review 2004 2. BIBRA Toxicity Profile 1999 3. JACT 1991 10 (1) 33-52 4. Manufacturer’s Data on file, Innovant Research 5. File No: STD/1363 January 2011 NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME (NICNAS) FULL PUBLIC REPORT

SODIUM LAURYL SULFATE

CAS: 151-21-3

The safety and toxicity profile has been reviewed in JACT (1983). The acute oral toxicity in rats is moderate with an LD 50 of approx.1g/kg. In acute ocular irritation tests a 10% SLS solution caused corneal damage to rabbit eyes. A dermal patch test in rabbits with SLS at 5.1% caused mild irritation, with a level of 21% there was severe irritancy in the absence of rinsing, and mild irritancy with rinsing.

9 A chronic toxicity study, feeding SLS to rats for 2 years at 0.25%, 0.5%,and 1.0% produced no abnormalities, except for moderate to severe dermal effects. There were neither chromosomal aberrations nor any clastogenic effects in rats given 1.13% and 0.56% SLS in the diet when compared to controls. In human clinical studies, there was no UV sensitisation seen in applications of 0.1% to 10% SLS. A summary of the toxicology profile is given below (4). Acute oral toxicity rat LD50 = 1200 mg/kg acute dermal toxicity rabbit LD50 = ca. 600 mg/kg guinea pig LD50 = >1200 mg/kg

Repeated dose toxicity rat NOAEL= 100 mg/kg/day (hepatotoxicity)

Genetic toxicity in vitro bacterial test (gene mutation)S. typhimurium Ames test, negative (with and without metabolic activation)

Non-bacterial test (gene-mutation) mice Lymphoma cell forward mutation assay, negative (with and without metabolic activation) Non-bacterial test, (indicator test for gene and/or chromosome mutation) Chinese hamster Sister chromatid exchange, negative (with and without metabolic activation)

Genetic toxicity in vivo (chromosome aberration) rat Micronucleus assay negative

Toxicity to reproduction mice NOAEL = 1000mg/kg/day (male fertility)

Developmental toxicity / teratogenicity mice rabbits NOAEL 300 mg/kg/day (maternal toxicity) NOAEL = 400 mg/kg/day (resorption/litter loss) NOAEL =600 mg/kg/day (foetal malformation)

Experience with human exposure. In experimental ulcer treatment up to 80 mg/kg/day (highest dose tested) were tolerated without adverse side effects.

As with other anionic surfactants, the evidence indicates that there is no potential for carcinogenicity, teratogenicity nor for genotoxicity (Sterzel, 1997). In summary, it is concluded that when used in rinse-off products at low concentrations as in the current formulation, sodium lauryl sulfate is safe. The lowest NOAEL is set at 100mg/kg/day (4).

REFERENCES

1 JACT 2(7) 127-181, (1983) 2 Sterzel, W. Toxicology of Surfactants used in Cosmetics,

10 2nd Edit. Eds. Rieger, MM & Rhein, LD. pub. Dekker NY 1997. 4. Sodium dodecyl sulfate, SIDS Assessment profile. OECD/SIDS, www.chem.unep.ch/irptc/sids/oecdsids/151213.htm

GLYCERIN

CAS: 56-81-5

The full toxicity status of glycerin has been reviewed in a BIBRA profile (1). Oral exposure in rats, mice, guinea pigs and rabbits gave LD50 values of 7.75 – 38.1 gm/kg. The intravenous LD50 for rat and mouse is 4.25 – 6.3 gm/kg. Skin contact with 2.52 gm of neat liquid (12.9gm/kg) for 20 minutes resulted in excretion of haemoglobin in male rats indicating red blood cell damage. Oral exposure in humans gave only evidence of headache, nausea and increased urine output at high dose levels ie greater than 700mg /kg bodyweight. Skin irritancy testing in humans showed no evidence of irritancy with a 50% solution in several thousand dermatitis patients. Formulations containing glycerin have been tested in human volunteers and shown not to have sensitisation, photo-sensitisation nor photo-toxic potential. There is no evidence of reproductive effects in rats treated orally or dermally. Tests for mutagenicity have generally given negative results Carcinogenicity studies in a 2 year rat study indicated no increase in tumors compared to control when rats were dosed at 5 or 10 mg / kg for 2 years. Chronic studies in animals at high doses indicate a very low order of toxicity with possible target organs of stomach and kidneys. In man repeat topical application is a rare cause of sensitisation, but with a low irritation potential to eyes and skin. In summary, glycerin is considered to be safe as used in the current formulation. Repeated oral exposure to glycerol does not induce adverse effects other than local irritation of the gastro-intestinal tract. The 2-year study of Hine (1953) was chosen to establish the overall NOEL after prolonged treatment with glycerol of 10,000 mg/kg bw/day (20% in diet), which is in agreement with the findings in other studies. At this dose level no systemic or local effects were observed. For inhalation exposure to aerosols, the NOAEC for local irritant effects to the upper respiratory tract is 165 mg/m3 and 662 mg/m3 for systemic effects. No effects on fertility and reproductive performance were observed in a two generation study with glycerol administered by gavage (NOAEL 2000 mg/kg bw/day). No maternal toxicity or teratogenic effects were seen in the rat, mouse or rabbit at the highest dose levels tested in a guideline comparable

11 teratogenicity study (NOEL 1180 mg/kg bw/day). (2)

The NOAEL was considered as 10,000mg/kg.

REFERENCES

1. Toxicity Profile, Glycerin. BIBRA 1987. 2. OECD SIDS, SIDS Initial Assessment Report Paris, France, 26-28 March 2002

SODIUM CHLORIDE

CAS: 7647-14-5

Sodium chloride is a naturally occurring material, and is a normal part of the human body. At low concentrations as used in bathing, or at higher amounts in salt scrub products, there is no skin irritation. It is considered that sodium chloride is safe as used in the current application.

REFERENCE

1. Data on file Innovant Research Ltd

LAVANDULA ANGUSTIFOLIA (LAVENDER) OIL

CAS: 8000-28-0

This essential oil has a history of safe usage in cosmetics and skin care. Lavender oil has a long history of safe use topically and has been used in medicine as a carminative. It also has a function as an insect repellent in several commercial products. There have been occasional reports of contact dermatitis due to sensitisation from essential oils. However this is in fact very rare and this oil can be considered safe in the current application. The components of lavender oil, including one of the major ingredients linalool, are approved for intake with an acceptable daily intake (ADI) of 500 microgram/day. A review of the published dermatological literature indicates a good level of tolerance to the skin.

A NOAEL is not applicable as the material is used in accordance with IFRA Guidelines.

The material is not IFRA restricted in rinse off products.

Based on the above and a long history of safe use lavender oil is considered safe in the current application.

12 REFERENCES

1. Data on file Innovant Research Ltd.

TRISODIUM ETHYLENEDIAMINE DISUCCINATE

CAS: 20846-91-7, 178949-82-1

This is a chelating agent that acts similarly to EDTA and EDTA salts. However unlike EDTA salts trisodium ethylenediamine disuccinate is readily biodegradable. Manufacturer’s data indicates low toxicity with no evidence of irritation or sensitisation at typical in use amounts. A review of the safety and toxicology of EDTA and its salts is applicable to this material since there are some structural similarities. EDTA and its sodium, potassium and ammonium salts are reviewed in CIR (3) and in IJT (2). Sodium salts of ethylene diamine tetra acetic acid (EDTA) are used in most cosmetic skin care formulations. Di-sodium, tri-sodium and tetra-sodium salts of EDTA are typically used at up to 2% concentrations (3) in cosmetic products. Sodium salts of EDTA are used in medicine as chelating agents (1).

The safety of sodium and other salts of EDTA is the subject of a recent literature review (2). Human and rat studies indicated that Calcium Disodium EDTA and Disodium EDTA were poorly absorbed via oral routes of administration. A study that dosed human males both IV and IM determined that a majority of the dose of EDTA was excreted entirely through the kidneys by glomerular filtration and tubular excretion. Rats dosed IV, IM, and IP with Calcium C14 EDTA eliminated a majority of the chelate in their urine. Most of the chelate was eliminated through the feces after oral administration. A clinical study using male subjects reported almost no absorption of Calcium Disodium EDTA following dermal exposure. However, rat studies on denuded and abraded skin provided evidence of dermal absorption.

In all available toxicology studies (rodent and nonrodent species), the lowest dose reported to the FDA that caused toxicological effects was 750 mg/kg/day of either Tetrasodium EDTA, Calcium Disodium EDTA, or Disodium EDTA.

EDTA is classified as a weak mutagen in microbial systems. In a variety of studies using bacteria, mammalian cell lines, and mammals EDTA and its salts gave both positive and negative results. Irradiation of cells prior to exposure to EDTA produced both an increase and a decrease in chromosomal aberrations. In a number of studies using mammalian test systems, EDTA inhibited DNA synthesis. However, in a number of cell lines inhibition was not observed. Trisodium EDTA Trihydrate was not carcinogenic

13 to rats or mice fed 7500 ppm for 103 weeks. Disodium EDTA does not inhibit metabolic cooperation.

Exposure to 0.2 g of Disodium EDTA for 4 hours in a human patch test did not produce any signs of reactivity. In various studies, Calcium Disodium EDTA demonstrated either no contact sensitization or weak sensitization. Products that contained Disodium EDTA did not produce sensitization in an RIPT at concentrations of 0.02% to 0.2%. Calcium Disodium EDTA injected IV at 20 mg/kg for 6 and 10 weeks significantly increased serum concentrations of immunoglobulins. Administration of Calcium Disodium EDTA to patients in an aerosol form produced no ill-effects during and after treatment, as the therapy was well tolerated, with no changes in the respiratory organs observed. Absorption was determined to be 10% to 30% of the dose. Stippled cell counts were somewhat irregular; however, no other changes occurred in the blood analysis as a result of Calcium Disodium EDTA inhalation.

In a review of the data as applied to skin care/cosmetic use (3), the Cosmetic Ingredient Review (CIR) Expert Panel in the United States recognized that oral exposures to EDTA produced reproductive/ developmental toxicity in test animals; an effect related to zinc deficiency. The CIR Panel concluded that dermal exposures to EDTA in cosmetic products, however, would result in very little EDTA penetrating the skin, resulting in systemic levels well below those shown to produce adverse effects in the oral dosing studies.

Sodium salts of EDTA are commonly used at up to 2% concentrations in skin creams/lotions and have been reported to be used at higher amounts (3).

Based on the structural similarity of the molecule to sodium salts of EDTA, it is considered that trisodium ethylenediamine disuccinate is safe as used in the current application. A NOAEL of 500 mg/kg/day is established for trisodium EDTA, which is considered applicable in the current review (4).

REFERENCES

1. Martindale, The Extra Pharmacopoia 29th Ed (1989) Pharmaceutical Press, London. 2. Lanigan RS, Yamarik TA (2002). Final Report on the Safety of EDTA, calcium disodium EDTA, diammonium EDTA. Dipotassium EDTA, Disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA and trisodium HEDTA. Int. J. Toxicol. 21 suppl 2: 95-142. 3. CIR Compendium 2004, pub by CTFA, Washington DC. 4. European Commission, Scientific Commission on Toxicity, Tetrasodium EDTA, EDTA, Brussels, C7/GF/csteeop/edta-hh/100903 D(03) 39th Plenary Meeting, Sept 2003

14 PANTHENOL

CAS: 81-13-0 EINECS: 240-540-6

D-Panthenol is the subject of extensive toxicological studies. This ingredient is related to vitamin B5 and is a food/dietary requirement. Panthenol and pantothenic acid is the subject of a CIR monograph (2004) and a review in JACT (1987) The acute oral toxicity is low with an LD50 in both the rat and mouse of >10g/kg. In rabbit primary skin irritation tests panthenol is rated as “non-irritant” at doses of 0.5% with some irritation at 2%. Nappy creams containing up to 5% panthenol are shown to be well tolerated and have been sold in EU for several decades (Roche B-Pantene). In ocular irritation tests in rabbits at up to 2% there were at most only slight signs of conjunctival redness. In a human skin sensitisation study there was no sensitising potential at 0.5%.A survey of the published dermatological literature indicates clinical reports of allergic contact dermatitits are extremely rare. Photo-toxicity and photo-sensitising studies in the Guinea pig indicated no photo toxic or photo allergic potential. No toxicological effects were associated with the subchronic and/or chronic oral administration of Panthenol to rats at doses of 2 -200mg/kg/day It is reported that neither teratogenic nor foetotoxic effects were seen in the offspring when rats were fed calcium pantothenate prior to mating and throughout gestation. Although mutagenicity and carcinogenicity data are not available the amount obtained in the diet exceeds normal cosmetic use and such effects are considered unlikely.

In summary panthenol can be considered safe as used in this formulation. A NOAEL is conservatively estimated as 2 mg/kg/day.

REFERENCES

1 Cosmetic Ingredient Review 2004 2 JACT (1987) 6(1) 139-162 3 Manufacturer’s Data on file Innovant Research

TOCOPHERYL ACETATE

CAS: 7695-91-2 / 58-95-7

This is the acetate salt of vitamin E, a naturally occurring food ingredient. The oral LD 50 in the rat is low at >5g/kg. Skin irritation data for primary irritation in the rabbit is rated as “non-irritant” as also is rabbit eye irritation data. In a Guinea pig maximisation study for sensitisation, no sensitising potential was seen at a 20% dilution.

15 Clinical published data has found tocopheryl acetate to have a low-grade sensitisation potential in use, although this is probably concentration dependent and not likely to occur at the low concentrations used in this formulation. No photo allergy or photo toxicity data is available, although formulations containing this ingredient have been tested and shown not to have photo- reactive potential. In several genotoxicity tests, tocopheryl acetate was found not to be genotoxic. In a 4-week systemic toxicity study to both dogs and rats dosed orally at up to 20,000 ppm in the diet there were no adverse effects seen. Reproductive and developmental tests in animals were all negative. A NOAEL level for adults has been set at an upper limit (UL) as 300mg/day (ie 5 mg/kg) (4) In summary this ingredient may be regarded as safe in skin care products as currently used.

REFERENCES

1. CIR Compendium 2004. 2. IJT,21 (S3):51-116,2002 3. Data on file Innovant Research. 4. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin E (expressed on 4 April 2003) SCF/CS/NUT/UPPLEV/31 Final 23 April 2003

BENZOPHENONE-4 CAS: 4065-45-6

Benzophenone-4 is a substituted derivative of 2-hydroxybenzophenone and has a long-established history of use in toiletries as a photo-stabiliser. Benzophenone-4 is the subject of a safety review in CIR (2004) and a review in JACT (1983). This ingredient has a low order of acute toxicity with an oral LD50 in the rat of 6.4g/kg. It was rated as irritant in the rabbit eye test at 100% concentration. Rabbit primary skin testing for irritation gave a rating of mildly irritant at concentrations up to 100%. When tested at 5% in man there was no evidence of dermal irritation or sensitisation. The chemically similar benzophenone-3 was not a sensitiser or a photo-toxic in Guinea pigs and rabbits and it can be extrapolated that this will apply also to benzophenone-4.

16 Sub-chronic feeding studies in rats gave a toxic effect at 600mg/kg bodyweight. However this dose gives a very adequate safety factor for the typical use of this ingredient. There was no evidence of photo-mutagenicity in a E coli gene mutation assay and in an in vitro chromosomal aberration assay in CHO cells in the presence of UV light. Skin permeation was minimal at a level of 0.01-0.03% in human skin in-vitro. Benzophenone-4 has been tested in an Ames test for mutagenicity and found to be non- genotoxic. Based on this evidence it is considered that benzophenone-4 is not a carcinogen, nor a reproductive toxin. Based on read-across of studies from benzophenone-3 a NOAEL of 200mg/kg is established (4).

In summary benzophenone-4 is considered safe as used in the current formulation.

REFERENCES

1 Cosmetic Ingredient Review 2004. 2 JACT 2(5) 35-77 (1983) 3 Manufacturer’s data on file Innovant Research Ltd. 4. SCCP Opinion on Benzophenone-3, SCCP/1069/06, 19th Dec 2006.

METHYLCHLOROISOTHIAZOLINONE/ METHYLISOTHIAZOLINONE

CAS: 2682-20-4; 26172-55-4

The acute toxicity is rated as high, with an LD50 in the rat of 60mg/kg. MI/MCI blend is rated as moderately toxic when applied dermally to rabbits. The LD50 of a 14% solution was 660mg/g, while the LD50 of a 1.5% solution was >5g/kg The MI/MCI blend is regarded as an irritant and corrosive to skin, eyes and mucous membranes at concentrations >1.5%.

MI/MCI is rated as a sensitizer at higher concentrations. Its use in cosmetic applications is restricted to concentrations that are considered to be non- sensitizing or having very little sensitising potential. In studies of repeat dose toxicity, no treatment effects were seen in rats receiving an MI/MCI blend orally for 2 weeks at doses of 24.4mg/kg. Dermal application of MI/MCI at up to 2.8 mg/kg/day (5 days per week), for 3 weeks to rabbits produced moderate local irritation, but no systemic toxicity.

Dermal application of MI/MCI up to 0.4mg/kg for 3 months to rabbits produced no systemic toxicity. Similarly there were no toxicological effects in rats and dogs.

Results for genotoxicity studies have been variable. In data submitted to CIR panel, there were positive effects in 2 out of 8 mutagenicity assays. However

17 there is scientific opinion that the two methods where there were positive results (Ames test with TA100 and Mouse lymphoma assay) are not applicable to biocides. It is concluded by CIR that there was no genotoxic risk.

When MI/MCI was administered at up to 13.3 mg/kg/day, by gavage to pregnant rabbits and rats, there were no teratogenic effects. However there was toxicity to the dam embryo and fetus.

The MI/MCI blend is poorly absorbed from the skin. Up to 62% of a percutaneous dose was bound to the site of application 24 hr after exposure. The MI/MCI bound to the skin has a half-life of 13.1 days. In an in-vitro assay using a Franz Cell, there was 67% absorption at a dose of 25ppm.

MI/MCI was absorbed after oral administration and excreted in the urine and feces, with only minimal storage in tissues. In a study of radio-labelled MI alone, dosed orally to mice, there was activity in all tissues. Bone marrow concentrations decreased from 39ppm (males) and 29 ppm (females) to 1.1ppm and 1.0 ppm respectively after 48 hr. In studies for carcinogenicity, dermal application of 400ppm of the blend, 3 times per week for 30 months had no local or systemic tumorigenic effects in mice.

It is concluded that the blend of methylchloroisothiazolinone and methylisothiazolinone is safe as used in the current formulation.

REFERENCE

1. Data on file Innovant Research Ltd

SODIUM PCA

CAS: 28874-51-3

This is sodium DL-2-pyrrolidone-5-carboxylate. The acute toxicity is low, with an oral LD50 in the mouse of 10.4g/kg. In a rabbit dermal irritation test sodium PCA was rated as “non-irritant” when tested at 4%. In a Guinea pig test the dermal irritancy was considered not irritating. Eye irritation testing in the rabbit at 4% was not irritating. This ingredient has a long history of use in skin care and is considered safe as used in the current formulation.

REFERENCE

1 Manufacturer's Data on file Innovant Research Ltd.

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COLORS Ref: CI 60730, CI 14700

The above colors are listed as permitted in Annex 4 of the Cosmetics Directive for application in all cosmetic products. All are considered safe as used in the current formulation. It is a requirement that colors meet EU standards for purity.

SAFETY REPORT SUMMARY

In reviewing the safety and toxicity profile of the ingredients used and their history of safe use, it is concluded that there are no likely safety hazards from normal use of this product and when used as directed or from foreseeable conditions of misuse.

The product is considered safe for sale in EU Countries.

Dated: March 24th 2012.

Dr. JOHN HOPKINS BSc. PhD. MSB. C Biol.

Safety Assessor

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