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Abstract

The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6 dialkyl malate compounds used in cosmetics. These ingredients function mostly as skin-conditioning agents—emollients. The Panel reviewed relevant animal and human data related to the ingredients along with a previous safety assessment of malic acid. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Panel concluded that these dialkyl maleate compounds are safe in the present practices of use and concentration as given in this safety assessment.

Keywords

dialkyl malates safety cosmetics

Introduction

As given in the International Cosmetic Ingredient Dictionary and Handbook (INCI),¹ these 6 dialkyl malates mostly function as skin-conditioning agents—emollients (Table 1). The ingredients included in this report are:

Table 1.

The CAS Numbers, Definitions, and Functions of the Ingredients in This Safety Assessment.^a

Ingredient CAS No.	Definition	Function
Monohydroxysuccinates, free acid, and salt
Diisostearyl malate 67763-18-2 81230-05-9	Diisostearyl malate is the diester of isostearyl alcohol and malic acid; diisostearyl malate is a four carbon, hydroxy-diacid, esterified at each acid with a branched, eighteen carbon alkyl chain.	Skin-conditioning agent—emollient
Dibutyloctyl malate 399551-19-0	Dibutyloctyl malate is defined structurally; the diester of 2-butyloctanol and malic acid; dibutyloctyl malate is a four carbon, hydroxy-diacid, esterified at each acid with a branched, twelve carbon alkyl chain (an eight carbon chain substituted at the two position with a four carbon alkyl chain).	Plasticizer; skin-conditioning agent—emollient; solvent
Di-C12-13 Alkyl malate	Di-C12-13 alkyl malate is the diester of C12-13 alcohols and malic acid; di-C12-13 alkyl malate is a mixture of diesters of C12 and C13 alcohols with malic acid; Di-C12-13 alkyl malate is a four carbon, hydroxy-diacid, esterified at each acid with either a twelve or thirteen carbon alkyl chain.	Skin-conditioning agent—emollient
Diethylhexyl malate 56235-92-8	Diethylhexyl malate is the diester of malic acid and 2-ethylhexanol; diethylhexyl malate is the diester of malic acid and 2-ethylhexanol; diethylhexyl malate is a four carbon, hydroxy-diacid, esterified at each acid with a branched, eight carbon alkyl chain (a six carbon chain substituted at the two position with a two carbon alkyl chain).	Skin-conditioning agent—emollient
Diisoamyl malate [1587-19-5] (per CAS)	Diisoamyl malate is defined structurally; diisoamyl malate is the diester of isoamyl alcohol and malic acid; diisoamyl malate is a four carbon, hydroxy-diacid, esterified at each acid with a branched, five carbon alkyl chain.	Plasticizer; skin-conditioning agent—emollient; slip modifier; solvent
Dioctyldodecyl malate	Dioctyldodecyl malate is defined structurally; dioctyldodecyl malate is the diester of octyldodecyl alcohol and malic acid; dioctyldodecyl malate is a four carbon, hydroxy-diacid, esterified at each acid with a branched, twenty carbon alkyl chain (a twelve carbon chain substituted at the two position with an eight carbon alkyl chain).	Skin-conditioning agent—miscellaneous

Abbreviation: CIR, Cosmetic Ingredient Review.

^a The First Definition is provided by the International Cosmetic Ingredient Dictionary and Handbook; the Definition in Italics was Developed by the CIR Staff.⁵⁴

diisostearyl malate,

dibutyloctyl malate,

di-C12-13 alkyl malate,

diethylhexyl malate,

diisoamyl malate, and

dioctyldodecyl malate

The similar chemical structures, physicochemical properties, and functions and concentrations used in cosmetics enable grouping these ingredients and reading across the available toxicological data to support the safety assessment of the entire group. Dibutyl malate is not a cosmetic ingredient, however, it is a dialkyl malate and data regarding this chemical were considered relevant to the entire group.

Because these ingredients are diesters, esterases in the skin may metabolize them to the monoester and/or possibly to the free acid as well as the corresponding alcohol. For example, diisostearyl malate may result in isostearyl malate (the monoester), malic acid, and isostearyl alcohol, which may penetrate into the dermis. Summary data for malic acid are provided where appropriate in the main document and the toxicity data on the corresponding alcohols are included in Appendix A.

Chemistry

Definition, Structure, and Manufacture

Dialkyl malate ingredients have at their core succinic acid (a 4-carbon, alkyl diacid), that is, monohydroxy substituted. Malic acid (a dicarboxylic acid) is a monohydroxy succinic acid. Because of this diacid structure, these ingredients may be esterified with an alkyl group at each end of the molecule. For instance, diisostearyl malate is monohydroxy-substituted succinic acid, which is esterified at each end with a branched, 18 carbon alkyl chain (ie, isostearyl chain; Figures 1 and 2).

Figure 1.

Diisostearyl malate.

Figure 2.

Map of the ester ingredients in this assessment and possible associated esterase metabolites.

All of these ingredients have at least 1 stereocenter denoted by d, l, dl, meso, or racemic (rac) in front of many of the names in the literature. Stereochemical forms for the ingredients are included if they were identified in the referenced studies.

Dialkyl esters

The dialkyl esters of malic acid can be manufactured from malic acid by traditional esterification techniques, with the appropriate alcohol, and with or without acid or metal catalyst (Fischer esterification).¹ For example, diethylhexyl malate can be manufactured from malic acid and ethylhexanol with a titanium catalyst.² It is likely that all of the diacid is consumed in the reaction and no malic acid is present in the final product.

Malic acid

Malic acid (monohydroxysuccinic acid), a white crystalline material, has one stereocenter, at the carbon bearing the hydroxyl group.³ The l-isomer is a natural constituent and common metabolite of plants (most commonly found in fruits) and animals.

dl-Malic acid is made by the catalytic oxidation of benzene to maleic acid, which is converted to malic acid by heating with steam under pressure.⁴ l-Malic acid is available through the microbiological fermentation of fumaric acid.⁵ The l-form of malic acid is the naturally occurring isomer and is found in unripe apples and other fruits.⁴

A mixture of maleic, fumaric, and rac-malic (or ±malic) acids heated with water in a closed space will cause the maleic acid to be consumed and the resulting solution to reach an equilibrium between fumaric acid and d-malic acid.⁶ Maleic and fumaric acids are by-products of malic acid.⁵ Malic acid is generally purified until the amounts of fumaric and maleic acids are 7.5 and <500 ppm, respectively.

In 2001, the Cosmetic Ingredient Review Expert Panel (Panel) reviewed and concluded that the dicaboxylic acid, malic acid, and its sodium salt (sodium malate) are safe for use as pH adjusters in cosmetic formulations.⁷ The Panel determined that the data are insufficient to determine the safety of these ingredients for any other functions. The data from the malic acid and sodium malate safety assessment are summarized in this report.

Chemical and Physical Properties

Chemical and physical property data are provided in Table 2. Diethylhexyl malate was reported to be 99% pure, with the impurities being unreacted raw materials.⁸ It is soluble in oil, ethanol, and silicone and insoluble in propylene glycol, water, and dimethicone.⁸

Table 2.

Physical and Chemical Properties of Alkyl Malates.

Property	Value	Reference
Diisostearyl malate
Physical form	Liquid	⁵⁵
Color	Clear colorless to slightly yellow	⁵⁵
Odor	Slight, typical	⁵⁵
Molecular weight g/mol	639.04	Calculated ⁵⁶
Molecular volume m³/kmol	0.6944 ± 3.0 × 10⁻⁴	Calculated ⁵⁶
Density/specific gravity at 20°C	0.920 ± 0.06 g/cm³	Calculated ⁵⁶
Vapor pressure, mm Hg at 25°C	3.4 E⁻²²	Calculated ⁵⁶
Boiling point, °C	676.3 ± 35.0°C	Calculated ⁵⁶
Water solubility	Insoluble	⁵⁷
Dibutyloctyl malate
Molecular weight, g/mol	470.73	Calculated ⁵⁶
Molecular volume, m³/kmol	0.4963 ± 3.0 × 10⁻⁴	Calculated ⁵⁶
Density/specific gravity at 20°C	0.948 ± 0.06	Calculated ⁵⁶
Vapor pressure, mm Hg at 25°C	2.84E⁻¹⁴	Calculated ⁵⁶
Boiling point, °C	547.6 ± 30.0	Calculated ⁵⁶
Water solubility, g/L at 25°C and pH 7	1.0⁻⁵	Calculated ⁵⁶
Di-C12-13 alkyl malate
Log Kow at 40°C	>6.4	⁵⁸
Diethylhexyl malate
Molecular weight, g/mol	358.51	Calculated ⁵⁶
Molecular volume, m³/kmol	364.2 ± 3.0 cm³	Calculated ⁵⁶
Density/specific gravity at 20°C	0.984 ± 0.06 g/cm³	Calculated ⁵⁶
Vapor pressure, mm Hg at 25°C	6.31 × 10⁻¹⁰	Calculated ⁵⁶
Boiling point, °C	448.4 ± 25.0	Calculated ⁵⁶
Diisoamyl malate
Molecular weight, g/mol	274.35	Calculated ⁵⁶
Molecular volume, m³/kmol	265.2 ± 3.0 cm³	Calculated ⁵⁶
Density/specific gravity at 20°C	1.006 g/cm³	Calculated ⁵⁹
Vapor pressure, mm Hg at 25°C	9.08E⁻⁰⁷	Calculated ⁵⁶
Boiling point, °C	152-157	Calculated ⁵⁹
Dioctyldodecyl malate
Molecular weight, g/mol	134.09	Calculated ⁵⁶
Density/specific gravity at 20°C	1.641 ± 0.06	Calculated ⁵⁶
Vapor pressure, mm Hg at 25°C	7.19E⁻⁰⁵	Calculated ⁵⁶
Boiling point, °C	306.4 ± 27.0	Calculated ⁵⁶

Use

Cosmetic

Data on ingredient usage are provided to the US Food and Drug Administration Voluntary Cosmetic Registration Program. A survey was conducted by the Personal Care Products Council regarding the maximum use concentrations for ingredients in this group (Table 3).^9,10

Table 3.

Frequency of Use and Concentration According to Duration and Exposure.^9,10

Use type	Uses	Concentration (%)	Uses	Concentration (%)	Uses	Concentration (%)
Use type	Diisostearyl malate		Di-C12-13 alkyl malate		Diethylhexyl malate
Total/range	694	0.001-82	27	1-36	12	0.4-2
Duration of use
Leave-on	690	0.2-82^a,b	24	1-36	11	0.4-2
Rinse-off	4	0.001-29	3	NR	1	2
Diluted for (bath) use	NR	NR	NR	NR
Exposure type
Eye area	87	0.2-36	1	NR	NR	NR
Incidental ingestion	345	5-82	NR	NR	NR	NR
Incidental inhalation-sprays	4	3-10	NR	1	NR	NR
Incidental inhalation-powders	28	0.4-12	NR	NR	NR	NR
Dermal	346	0.2-49^a,b	26	1-36	9	0.4-2
Deodorant (underarm)	NR	NR	NR	NR	NR	NR
Hair-noncoloring	3	0.001-15	1	3	3	2
Hair-coloring	NR	3	NR	NR	NR	NR
Nail	NR	0.4-49	NR	NR	NR	NR
Mucous Membrane	345	5-82	1	NR	NR	NR
Baby	NR	NR	NR	NR	NR	NR

Abbreviation: NR, none reported.

^a3% in a body oil listed under “other fragrance preparation”.

^b10% in a lip cream.

Diisostearyl malate was reported to be used in 690 leave-on products. Maximum concentration of use was reported to be up to 82% in leave-on products and 29% in rinse-off products. Di-C12-13 alkyl malate was reported to be used in 27 products and at a reported maximum use concentration of up to 36%. Diethylhexyl malate was reported to be used in 12 leave-on products at a maximum use concentration of up to 2% in leave-on and 2% in rinse-off products. There were no reported uses of dibutyloctyl malate, diisoamyl malate, and dioctyldodecyl malate.

Diisostearyl malate is reported to be used at concentrations of up to 10% in cosmetic products that may include sprays of which airborne particles could possibly be inhaled. The size distribution of 95% to 99% of the particles released from cosmetic sprays has had aerodynamic equivalent diameters >10 µm.^11

-14 Therefore, particles incidentally inhaled from cosmetic sprays would likely be deposited in the nasopharyngeal and bronchial regions and would not be respirable (ie, they would not enter the lungs) to any appreciable amount.^11,13

Noncosmetic

d-Malic acid is not generally recognized as safe (GRAS) for use in baby foods because babies cannot digest d-malic acid. When d- and l-malic acid meet the specifications indicated in the Food Chemicals Codex, they are GRAS as direct food additives for use as flavor enhancers, flavoring agents, adjuvants, and a pH control agent [21CFR184.1; 21CFR184.1069].¹⁵ Information on noncosmetic uses of dialkyl malates was not available.

Toxicokinetics

Absorption, Distribution, Metabolism, and Excretion

No absorption, distribution, metabolism, or excretion studies on the dialkyl malates in this report were found or submitted to Cosmetic Ingredient Review.

Oral and intraperitoneal

Malic Acid

Malic acid plays a part in carbohydrate metabolism and is a precursor of oxalacetic and pyruvic acids.¹⁶ Most of the radioactivity from 2.5 mg/kg U ¹⁴C-l-malic acid (specific activity 61 μCi/mmol) or 4-¹⁴C-dl-malic acid (sp. act. 93 μCi/mmol) administered orally or intraperitoneally (ip) to male albino Wistar Alderly Park SPF rats were excreted as carbon dioxide.¹⁷ Daily oral administration of 4 g/kg malic acid resulted in increased glucuronic acid excretion in the urine.¹⁸ When ¹⁴C-l-malic acid was administered ip and orally to male albino Wistar Alderly Park SPF rats, most of the radioactivity was excreted as carbon dioxide.¹⁷

Toxicological Studies

Acute Toxicity

Dermal

Di-C12-13 alkyl malate

The acute dermal median lethal dose (LD₅₀) of di-C12-13 alkyl malate for male and female Wistar rats (n = 5) was >2000 mg/kg (2 mL/kg; 100%).¹⁹ There were no clinical signs during the 7-day observation period and no pathology at necropsy.

Oral—nonhuman

Di-C12-13 alkyl malate

The acute oral LD₅₀ of di-C12-13 alkyl malate for Wistar rats (n = 5/sex) was >5000 mg/kg in sesame seed oil.²⁰ There were no mortalities. Intense fur erection and ante- and postmortem mycosis was observed in one foreleg.

Diethylhexyl malate

The reported LD₅₀ for diethylhexyl malate is >5g/kg for albino rats (strain not provided).²¹

Malic acid and sodium malate

Malic acid was administered as a 25% aqueous solution. Signs of toxicity included ataxia, prostration, convulsions, retraction of the abdomen, respiratory distress, cyanosis, and death. The oral LD₅₀s of malic acid for albino CD-1 outbred mice (n = 5/sex), albino Wistar rats (n = 5/sex), and Dutch-Belted rabbits (n = 5/sex) were approximately 2.66, 3.5, and 3 g/kg, respectively.^22

-25

The oral LD_LO of malic acid for rabbits was 5 g/kg.²⁶ The oral “lethal dose” of l-malic acid for rabbits was 5 g/kg and was 1 g/kg for sodium malate in dogs.²⁷

Dibutyl malate

The oral LD₅₀ of dibutyl malate was reported to be 3730 mg/kg for rats.²⁸

Other dose administration

Malic Acid

The acute LD₅₀ of malic acid administered intravenously (iv) was 2.4 g/kg for rabbits, and the ip LD₅₀ values for mice and rats were 50 to 100 and 100 to 200 mg/kg, respectively.²⁷

In a comparative study of the l - and d - stereocenters, the ip administration for rats (1 g/kg l-malic acid) was not lethal, but d-malic acid (same dose) killed rats within 20 to 25 minutes.²⁹ A mixture of 1 g/kg d-malic acid and 1 g/kg l-malic acid, administered according to the same protocol, was lethal with death occurring sooner with the mixture than it did with d -malic acid. No explanation was provided for the difference in toxicity between the 2 isomers.

The ip administration of 2 g/kg dl-malic acid was not lethal to rats.³⁰ The ip LD₅₀ of malic acid for mice and rats ranged from 50 to 100 and 100 to 200 mg/kg, respectively.

Repeated Dose Toxicity

Dermal

Di-C12-13 alkyl malate

Di-C12-13 alkyl malate (10 mL/kg; 1000 mg/kg/d) was dermally applied under occlusion daily to the shaved dorsal area of male and female New Zealand white rabbits (n = 5/sex) for 28 days.³¹ No clinical signs were observed during treatment and the 2-week observation period. Necropsies, hematology, and clinical chemistry (including liver function) were unremarkable.

Oral—nonhuman

Malic acid and sodium malate

In a chronic oral study of 3 extracts of malic acid (500, 5000, and 50 000ppm; 0.05%, 0.5%, and 5.0%), Charles River rats (n = 30/sex) had no compound-related lesions (types not provided) after feeding the test substance for 104 weeks.³² No significant changes or lesions were observed when dogs were fed malic acid (500, 5000, and 50 000 ppm) for 104 weeks.³³

Dibutyl malate

Dibutyl malate (300 mg/kg) produced renal tubular lesions and increased liver and kidney weights in a repeated oral dose and reproductive toxicity/developmental toxicity screening assay using rats. The no observed effects level (NOEL) was 95 mg/kg.²⁸

Reproductive and Developmental Toxicity

No reproductive or developmental studies were discovered for the ingredients in this safety assessment, however, data from developmental toxicity studies were available for malic acid and dibutyl malate.

Malic Acid

Malic acid did not cause developmental toxicity in albino CD-1 outbred mice (n = 25) up of to 266 mg/kg (days 6-15 of gestation), rats (n = 25-29) of up to 350 mg/kg (for 10 days during gestation), or Dutch-belted rabbits (n = 15-23) of up to 300 mg/kg (days 6-18 of gestation).^34
-36 In a multigenerational oral study of malic acid, there were no reproductive or developmental effects to albino rats for up to 10 000 ppm of feed for the P1, P2, F1, and F2 generations.³⁷

Malic acid (10.00 mg/egg in water) was injected into the air sac or yolk of white leghorn chicken eggs (n = 20) at the 0 or 96 hours of incubation.³⁸ There were no developmental effects observed when the chicks were examined after hatching.

Dibutyl Malate

In a repeated dose and reproductive toxicity/developmental toxicity screening assay for dibutyl malate (300 mg/kg), there were no adverse reproductive effects reported in rats.²⁸

Genotoxicity

Diisostearyl Malate

The potential of diisostearyl maleate to induce gene mutation was studied in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, using reverse mutation assay.³⁹ The assay was performed with and without metabolic activation at concentrations of 312.5, 625, 1250, 2500, and 5000 μg/plate. The test substance was not mutagenic under these test conditions. The results of the positive controls were as expected.

Di-C12-13 Alkyl Malate

In an Ames test, di-C12-13 alkyl malate (1, 10, 100, 1000, and 10 000 μg/plate) was not mutagenic to S typhimurium (strains TA98, TA100, TA1535, TA1537, and TA1538) with or without metabolic activation.⁴⁰ The results of the positive controls were as expected.

In a micronucleus assay using C57BL mice (n = 5/sex), di-C12-13 alkyl malate (250 mg/mL; 12 500 mg/kg in sesame seed oil) administered ip was not mutagentic.⁴¹ Erythrocytes harvested from bone marrow were examined at 24, 48, and 72 hours.

Carcinogenicity

There were no carcinogenicity studies discovered for the ingredients in this safety assessment.

Malic Acid

In a chronic oral study, feeding malic acid (500, 5000, and 50 000 ppm; 0.05%, 0.5%, and 5.0%) to Charles River rats (n = 30/sex) for 104 weeks resulted in no compound-related lesions (types not provided).³² No significant changes or lesions were observed when dogs were fed malic acid (500, 5000, and 50 000 ppm) for 104 weeks.³³

Irritation and Sensitization

Irritation

Dermal—nonhuman

Di-C12-13 alkyl malate

Di-C12-13 alkyl malate (10 mL/kg) was dermally applied under occlusion daily to the shaved dorsal area of male and female New Zealand white rabbits (n = 5) for 28 days.³¹ No erythema or edema was observed.

Di-C12-13 alkyl malate (500 mg in 0.5 mL sesame seed oil) was not a dermal irritant when administered to the shaved skin (20 cm²) of New Zealand white rabbits (n = 6) for 4 hours.⁴² No erythema or edema were observed at 1, 24, 48, and 72 hours.

Diethylhexyl malate

Diethylhexyl malate (100%; 0.5 mL) was applied to intact and abraded skin of New Zealand white rabbits (n = 6) under occlusion. The test sites were observed at 24 and 72 hours. The primary irritation index (PII) was 1.18; diethylhexyl malate was determined not to be a primary irritant to rabbits.⁴³

A primary dermal irritation test of diethylhexyl malate (100%) under occlusion for 24 hours was conducted using New Zealand white rabbits (n = 6).⁴⁴ The PII was 3.53. The authors concluded that diethylhexyl malate was not a dermal irritant to rabbits.

Malic acid

Malic acid (500 mg/24 hours) was moderately irritating to rabbit skin and was a strong irritant to guinea pigs.²⁵

Dermal—human

Di-C12-13 alkyl malate

In a human patch test (n = 38), di-C12-13 alkyl malate (100%; 0.5 mL) was not irritating when administered to a 1 cm² area under occlusion for 48 hours.⁴⁵ No erythema or edema was observed at 15 minutes and 24 hours.

Malic acid

In a test determining the subjective skin irritation potential (n = 10), the average irritation scores over a 15-minute period were 39.4, 37.1, and 23.1 for malic acid (1 mol/L in ethanol [SD40], ethoxydiglycol, and butylene glycol) at pH 3, 5, and 7, respectively.⁴⁶

In 2 human repeated insult patch tests (HRIPTs) of products containing malic acid (0.022725% and 0.00375%), these products were predicted to be non- to moderate irritants (Table 4).⁴⁷

Table 4.

Dermal Irritation, Sensitization, and Ocular Irritation Studies of Products Containing Malic Acid.⁴⁷

Test Material	Concentration of malic acid in product/actual concentration of malic acid tested/pH	n	Procedure	Results
Irritation
Hair styler	1%/0.022725%/3.6	101	Modified HRIPT. Induction 21 days, rest 10-24 days, challenge 4 days using semi-occlusive patch.	Predicted not to be a significant skin irritant. Standardized cumulative irritation = 1181.5, negative control (undosed patch) = 45.6, positive control (1% SLS) = 2052.8.
Hair shampoo	0.5%/0.000375%/3.0	98	Modified HRIPT. Induction 21 days, rest 10-24 days, challenge 4 days using occlusive patches.	Predicted to be a moderate skin irritant. Standardized cumulative irritation = 965.1, negative control (distilled water) = 33, positive control (0.1% SLS) = 1307.76.
Sensitization
Hair styler^a	1%/0.022725%/3.6	101	Modified HRIPT. Induction 21 days, rest 10-24 days, challenge 4 days using semi-occlusive patch.	Solution did not induce allergic contact dermatitis in any subject.
Hair shampoo^b	0.5%/0.000375%/3.0	98	Modified HRIPT. Induction 21 days, rest 10-24 days, challenge 4 days using occlusive patches.	Solution did not induce allergic contact dermatitis in any subject.
Test material	Concentration/pH	CMVA results (RC₅₀ (95% CI)	BCOP results (in vitro score/opacity score/permeability score)	Prediction
Ocular irritation
Hair styler	2.2757%/3.6	>50% (NA)	74.3/69.9/0.296	Severe ocular irritant
Hair shampoo	2.275%/3.0	1.6 (0.62-3.9)	9.09/5.4/0.246	Ocular irritant

Abbreviations: BCOP, bovine corneal opacity and permeability tests; CI, confidence interval; CMVA, chorioallantoic membrane vascular assay; HRIPT, human repeated insult patch test; NA, not applicable; RC₅₀, concentration at which 50% of the treated eggs show a positive response; SLS, sodium lauryl sulfate.

^aSame study as irritation study above.

^bSame study as irritation study above.

Ocular

Di-C12-13 alkyl malate

Di-C12-13 alkyl malate (100%; 0.1 mL) was not irritating to the eyes of New Zealand white rabbits (n = 6).⁴⁸ In a chorioallantoic membrane (CAM) assay, di-C12-13 alkyl malate (200 μL) was not predicted to be an ocular irritant.⁴⁹

Diethylhexyl malate

Diethylhexyl malate (100%; 0.1 mL) was administered into 1 eye of New Zealand white rabbits (n = 6).⁵⁰ The eyes were unwashed for 24 hours. At 24 and 72 hours and 4 and 7 days, the Draize score was 0. At 48 hours, the score was 0.3. The authors determined that diethylhexyl malate was not an ocular irritant to rabbits.

Diethylhexyl malate (100%; 0.1 mL) was administered into 1 eye of New Zealand white rabbits (unwashed, n = 6; washed after 4 seconds, n = 3).⁴⁴ At 24 hours, the Draize score for the unwashed eyes was 2.0 and 0.7 for the washed eyes. At 48 and 72 hours, the Draize score was 0. The authors determined that diethylhexyl malate was practically nonirritating to rabbits.

Malic acid

Malic acid caused severe ocular irritation in rabbit eyes.²⁵ In CAM vascular assay and bovine corneal opacity and permeability tests of products containing malic acid (2.2725%), these products were predicted to be ocular irritants (Table 4).⁴⁷

Sensitization

Dermal—nonhuman

Di-C12-13 alkyl malate

In a guinea pig sensitization assay (Buehler test) using female Hartley guinea pigs (n = 10), epicutaneous administration of di-C12-13 alkyl malate (100%) for three 6-hour exposures 7 days apart under occlusion was not sensitizing.⁵¹

Diethylhexyl malate

In a guinea pig sensitization test (Buehler test; n = 12) of diethylhexyl malate (100%), there was slight erythema on 2 sites after the sixth dose.²¹ There was no sensitization observed at challenge.

Dermal—human

Diisostearyl malate

An HRIPT (n = 51) of diisostearyl malate (100%; 0.2 mL, 0.2 g) was performed.⁵² No adverse effects were observed during induction or challenge.

Malic acid

In predictive testing using patients with atopic dermatitis, 18 of 34 patients reacted to a diet high in malic and citric acids and 6 reacted to a diet high in malic acid.⁵³ In an in vitro study assessing the effect of malic acid on cell renewal on human skin, an 18%, 10%, and 5% increase was observed at pH 3, 5, and 7, respectively. In 2 HRIPTs of products containing malic acid (0.022725% and 0.00375%), sensitization was not induced (Table 4).⁴⁷

Summary

Dialkyl malates are cosmetic ingredients that have a core of succinic acid (a 4-carbon, alkyl diacid) that is mono substituted. All of these ingredients have at least 1 stereocenter, and the stereoisomers are d - and l -forms and the racemic mixture, which is denoted d, l-. The INCI names are defined as ambiguous to these stereochemical details. While not a cosmetic ingredient, dibutyl malate is a dialkyl malate, and data regarding this chemical were considered relevant and were included.

Dialkyl malates function mostly as skin-conditioning agents—emollients. Malic acid can be produced by a process that uses maleic acid (a related but structurally different dicarboxylic acid), but the reaction products are generally purified until the amounts of fumaric and residual maleic acid are 7.5 and <500 ppm, respectively. It was considered likely that all of the diacid is consumed in the reaction, and no malic acid is present in the final product. Because these ingredients are diesters, however, esterases in the skin may metabolize them to the monoester or possibly to the free acid and corresponding alcohol.

The total number of reported uses of diisostearyl malate was 574 (572 uses in leave-on products) and was reported to be used at 0.001% to 82%. Di-C12-13 alkyl malate was reported to be used in 29 products and was reported to be used at 1% to 36% in leave-on products. Diethylhexyl malate was reported to be used in 10 products and was reported to be used at 0.4% to 2% in leave-on products and 2% in rinse-off products. There were no reported uses for dibutyloctyl malate, diisoamyl malate, and dioctyldodecyl malate.

d- and l-Malic acid, when meeting Food Chemicals Codex specifications, are GRAS as direct food additive for use as a flavor enhancers, flavoring agents, and adjuvants and as pH control agent but are not GRAS for use in baby foods.

Radiolabeled malic acid orally and ip administered to rats was excreted mostly as carbon dioxide.

The acute dermal LD₅₀ of di-C12-13 alkyl malate for rats was >2000 mg/kg. The acute oral LD₅₀ of di-C12-13 alkyl malate for rats was > 5000 mg/kg. The reported LD₅₀ for diethylhexyl malate was > 5g/kg for rats.

The oral LD₅₀ of malic acid for mice was 2.66 g/kg, 3.5 g/kg for rats, and 3 g/kg for rabbits. The oral lethal dose of malic acid was 5 g/kg in rabbits. The oral lethal dose of sodium malate was 1 g/kg in dogs. The iv LD₅₀ of malic acid was 2.4 g/kg for rabbits, and the ip LD₅₀ values for mice and rats were 50 to 100 and 100 to 200 mg/kg, respectively. The ip administration to rats of 1 g/kg l-malic acid was not lethal, but the same dose of d-malic acid killed rats within 20 to 25 minutes. The ip administration of 2 g/kg dl-malic acid was not lethal to rats.

There were no clinical signs observed during treatment and the 2-week observation period when 10 mL/kg di-C12-13 alkyl malate was dermally applied to rabbits for 28 days. In a chronic oral study, feeding malic acid up to 50 000 ppm to rats for 104 weeks resulted in some changes in body weight gains and feed consumption, but compound-related lesions were not observed. No significant changes or lesions were observed when dogs were fed malic acid in a chronic 104-week study.

Malic acid did not cause developmental toxicity in mice up to 266 mg/kg, rats up to 350 mg/kg, or rabbits up to 300 mg/kg. In a multigenerational oral study of malic acid, there were no reproductive or developmental effects in rats up to 10 000 ppm in the P1, P2, F1, and F2 generations. Malic acid at 10.00 mg in water/egg injected into the air sac or yolk of chicken eggs at the 0 or 96 hours of incubation caused no developmental effects in the chicks.

In a reverse mutation assay using S typhimurium, diisostearyl malate was not mutagenic with or without metabolic activation up to 5000 μg/plate. In an Ames test, di-C12-13 alkyl malate was not mutagenic to S typhimurium with or without metabolic activation up to 10 000 μg/plate.

In a micronucleus assay using C57BL mice (n = 5/sex), di-C12-13 alkyl malate (250 mg/mL; 12 500 mg/kg in sesame seed oil) administered ip was not mutagenic.

Di-C12-13 alkyl malate at 100% was not a dermal irritant in rabbits treated daily for 28 days. Malic acid (500 mg/24 h) was moderately irritating to rabbit skin and was a strong irritant to guinea pigs. In a test determining the subjective skin irritation potential, the average irritation scores over a 15-minute period were 39.4, 37.1, and 23.1 for malic acid at pH 3, 5, and 7, respectively.

In a human patch test, di-C12-13 alkyl malate was not irritating at 100%. Di-C12-13 alkyl malate was not irritating to the eyes of rabbits at 100%. In a CAM assay, di-C12-13 alkyl malate was not predicted to be an ocular irritant. Malic acid caused severe ocular irritation in rabbit eyes at 500 mg.

Di-C12-13 alkyl malate and diethylhexyl malate were not sensitizing to guinea pigs at 100%. No adverse effects were observed during induction or challenge in an HRIPT of diisostearyl malate at 100%.

In predictive testing using patients with atopic dermatitis, 18 of 34 patients reacted to a diet high in malic and citric acids, and 6 reacted to a diet high in malic acid. In assessing the effect of malic acid on cell renewal, an 18%, 10%, and 5% increase was observed at pH 3, 5, and 7, respectively. In 2 HRIPTs of products containing malic acid up to 0.022725%, sensitization was not induced.

Discussion

The similar chemical structures, physicochemical properties, functions, and concentrations in cosmetics allowed grouping these ingredients together and for extending the available toxicological data to support the safety of the entire group.

d-Malic acid was considered GRAS except for use in baby food, since babies cannot digest d-malic acid. It was considered likely that all of the malic acid reacted to alcohols to produce these dialkyl malates are consumed in the reaction and no malic acid is present in the final product. At most, malic acid may be a trace impurity in dialkyl malates. The Panel also considered the toxicity of maleic acid, a possible impurity of (and not to be confused with) malic acid. Because the amount of maleic acid in malic acid is low, it follows that use of dialkyl malates in cosmetics could not reach a level of toxicological concern for maleic acid. The Panel also noted that none of these ingredients are reported to be used in baby products.

The Panel noted that the previous conclusion of the malic acid/sodium malate safety assessment stated that there were insufficient data to reach a safety conclusion on the use of these ingredients as anything but pH adjusters, and there was a need for dermal sensitization studies. An HRIPT of diisostearyl malate at 100% did not result in irritation during induction or sensitization at challenge, and guinea pig sensitization tests of diethylhexyl malate and di-C12-13 alkyl malate, both at 100%, also did not produce sensitization in these animals. The Panel concluded that even though malic acid/sodium malate may be irritating, these results support the view that the dialkyl malates are not irritating or sensitizing.

There was concern expressed that the possible metabolite octyldodecanol is a penetration enhancer and dermal irritant. However, the potential concentration of the alcohol that would be generated in skin would be well below the level of concern.

The Panel discussed the issue of incidental inhalation exposure from cosmetic sprays and loose powders (ie, perfumes, face powders, body and hand sprays, and foot powders and sprays). These ingredients are reportedly used at concentrations up to 10% in cosmetic products that may be aerosolized. While there was a lack of inhalation toxicity data for the dialkyl malates in this safety assessment, the Panel noted that 95% to 99% of particles/droplets would not be respirable to any appreciable amount. Furthermore, these ingredients are not likely to cause any direct toxic effects in the upper respiratory tract, based on the properties of the dialkyl malates and on data that show that these ingredients are not irritants. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. The Panel considered other data available to characterize the potential for dialkyl malates to cause systemic toxicity, irritation, or sensitization. They noted the lack of systemic toxicity at high doses in acute and subchronic oral exposure studies, no irritation or sensitization in multiple tests of dermal and ocular exposure, and the absence of genotoxicity in 2 Ames assays and a micronucleus assay. A detailed discussion of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.

Conclusion

The Panel concluded that the following dialkyl malates are safe for use in cosmetics in the present practices of use and concentration in this safety assessment:

diisostearyl malate,

dibutyloctyl malate*,

di-C12-13 alkyl malate,

diethylhexyl malate,

diisoamyl malate*, and

dioctyldodecyl malate*

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

Footnotes

Appendix A: Possible Esterase Metabolite Summary Data Of Alcohols

Author Contributions

Becker contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Gill contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Bergfeld contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Belsito contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Hill contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Klaassen contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Liebler contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Marks contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Shank contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Slaga contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Snyder contributed to conception and design; contributed to analysis and interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Former CIR Director F. Alan Anderson contributed to conception and design, analysis, and interpretation and critically revised the manuscript.

Authors’ Note

Unpublished sources cited in this report are available from the Director, Cosmetic Ingredient Review, 1620L Street, NW, Suite 1200, Washington, DC 20036, USA.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The articles in this supplement were sponsored by the Cosmetic Ingredient Review. The Cosmetic Ingredient Review is financially supported by the Personal Care Products Council.

References

Kadesch

. Dibasic acids. J Am Oil Chem Soc. 1954;31(11):568–573.

Ikejiri

. Preparation of alkyl malates having low oligomer content. JP 2007-158498:(JP 2008-308451); 2008:1–9.

Kroschwitz

. Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. New York: John Wiley and Sons, Inc; 1999.

Lewis

Sr . Hazardous Chemicals Desk Reference. 2nd ed. New York: Van Nostrand Reinhold, 1993.

Miltenberger

. Ullmann’s Encyclopedia of Industry Chemistry. 5th ed. New York: VCH Publishing; 1989.

McKenzie

Plenderleith

Walker

. Optical activation of racemic acid by d-malic acid. J Chem Soc, Trans. 1923;123:2875–2880.

Andersen

. Final report on the safety assessment of malic acid and sodium malate. Int J Toxicol. 2001;20(suppl 1):47–55.

Personal Care Products Council. Information on diethylhexyl malate. Unpublished data submitted by Personal Care Products Council; 2011:31.

Personal Care Products Council. Dialkyl hydroxysuccinates: updated concentration of use information. Unpublished data submitted by the Personal Care Products Council; 2011:5.

10.

US Food and Drug Administration. FDA database. Cosmetic Production Fomulation and Frequency of Use Data Submitted to the Voluntary Cosmetic Registration Program (VCRP). Washington, DC: FDA; 2011. Data submitted in response to FOIA request.

11.

Bremmer

Prud’homme de Lodder

LCH

van Engelen

JGM

. Cosmetics Fact Sheet: to assess the risks for the consumer; Updated version for ConsExpo 4; 2006:1–77. Web site. http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf.

12.

Johnsen

. The influence of particle size. Spray Technol Mark. 2004;14(11):24–27.

13.

Rothe

. Special aspects of cosmetic spray safety evaluation; 2011. Unpublished information presented to the 26 September CIR Expert Panel. Washington DC.

14.

Rothe

. Special aspects of cosmetic spray safety evaluation; 2011. Unpublished information presented to the 26 September CIR Expert Panel. Washington DC.

15.

US Food and Drug Administration. Milk and Cream; 2011. Web site. http://frwebgate3.access.gpo.gov/cgi-bin/TEXTgate.cgi?WAISdocID=yBmmrz/9/1/0&WAISaction=retrieve.

16.

Anonamous. Malic and fumaric acids: british production opens up wider usage. Manuf Chem Aerosol News. 1964;35:56–59.

17.

Daniel

. The metabolism of l- and dl-malic acid by rats. Food Cosmetic Toxicol. 1969;7(2):103–106.

18.

Martin

Stenzel

. The influence of various chemicals and vitamin deficiencies on the excretion of glucuronic acid in the rat. Arch Biochem. 1944;3:325–331.

19.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) acute dermal toxicity in rats (limit dose). Unpublished data submitted by Personal Care Products Council; 1993:5.

20.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) acute oral toxicity in rats. Unpublished data submitted by Personal Care Products Council; 1992:5.

21.

Consumer Product Testing Co. Guinea pig sensitization (Buehler) diethylhexyl malate. experiment reference no 85222-5 addendum. Unpublished data submitted by Personal Care Products Council; 1985.

22.

Food and Drug Research Labs, Inc. FDRL. Oral LD₅₀ for mice of FDA 71-90 (Pomalus^R; Malic Acid). Report No. Laboratory No. 1762r; contract No. FDA 71-260. Study dated October 16; 1973:1-2. Submitted by FDA in response to an FOI request.

23.

Food and Drug Research Labs, Inc. FDRL. Oral LD₅₀ for rats of FDA 71-90 (Pomalus^R; Malic Acid). Report No. Laboratory No. 1763r; Contract No. FDA 71-260. Study dated October 16; 1973:1-2. Submitted by FDA in response to an FOI request.

24.

Food and Drug Research Labs, Inc. FDRL. Oral LD₅₀ for rabbits of FDA 71-90 (Pomalus^R; Malic Acid). Report No. Laboratory No. 1764r; Contract No. FDA 71-260. Study dated November 29; 1973:1-2. Submitted by FDA in response to an FOI request.

25.

Patty. Patty’s Industrial Hygiene and Toxicology. 3rd ed. New York: Wiley and Sons; 1981.

26.

Sax

. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Reinhold Company; 1979.

27.

Food and Agriculture Organization of the United Nations/World Health Organization. Toxicological evaluation of some antimicrobials, antioxidants, emulsifiers, stabilizers, flour-treatment agents, acids, and bases; 1967: 1–3. Submitted by FDA in response to an FOI request.

28.

Sullivan

Letter to Dr. Carol Eisenmann concerning diisostearyl malate, Schercemol™ DISM ester. Unpublished data submitted by Personal Care Products Council; 2012.

29.

Brookdale Dental Center of New York University. Letter from Dr. JR Stern to Dr. B La Du summarizing the results of testing acute testing with forms of malic acid. Unpublished data submitted by FDA in response to an FOI request; 1973:1.

30.

Stokinger

. Patty’s Industrial Hygiene and Toxicology. 3rd ed. New York: Wiley & Sons; 1981.

31.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) repeated dose dermal toxicity in rabbits (28 day). Unpublished data submitted by Personal Care Products Council; 1993: 5.

32.

TRW/Hazelton Laboratories. Final report: 24-month dietary administration to rats of compound X-5120. Project no. 165-126. Study dated Oct 19; 2011. Submitted by FDA in response to a FOI request.

33.

TRW/Hazelton Laboratories. Final report: 104-week dietary administration to dogs of compound X-5120. Project no. 165-129. Study dated Oct 15; 1971. Submitted by FDA in response to a FOI request.

34.

Food and Drug Research Laboratories. Teratologic evaluation of FDA 71-90 (Pomalus^®; Malic Acid) in mice. Laboratory no. 1765r. Contract no. FDA 71-260. Study dated Jan. 14; 1974. Submitted by FDA in response to FOI request.

35.

Food and Drug Research Laboratories. Teratologic evaluation of FDA 71-90 (Pomalus^®; Malic Acid) in rats. Laboratory no. 1766r. Contract no. FDA 71-260. Study dated Jan. 14; 1974. Submitted by FDA in response to FOI request.

36.

Food and Drug Research Laboratories. Teratologic evaluation of FDA 71-90 (Pomalus^®; Malic Acid) in rabbits. Laboratory no. 1767r. Contract no. FDA 71-260. Study dated May 17; 1974. Submitted by FDA in response to FOI request.

37.

Hazleton Laboratories Inc. Final report: Two generation reproduction study using rats of X-5120. Project no. 165-128. Study dated Nov 11; 1970. Submitted by FDA in response to a FOI request.

38.

Verrett

Scott

Reynaldo

Alterman

Thomas

. Toxicity and teratogenicity of food additive chemicals in the developing chicken embryo. Toxicol Appl Pharmacol. 1980;56(2):265–273.

39.

CIT Safety and Health Research Laboratories. Bacterial reverse mutation assay diisostearyl malate. Laboratory study number 27983 MMO. Unpublished data submitted by Personal Care Products Council; 2005: 24.

40.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) Salmonella typhimurium reverse mutation assay. Unpublished data submitted by Personal Care Products Council; 1992:5.

41.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) mutagenesis tests—micronucleus assay. Unpublished data submitted by Personal Care Products Council; 1994: 5.

42.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) primary skin irritation in rabbits. Unpublished data submitted by Personal Care Products Council; 1992: 5.

43.

Consumer Product Testing Co. Primary dermal irritation in rabbits diethylhexyl malate. Study No. 85290-1; 1982:1.

44.

Consumer Product Testing Co. Primary dermal irritation in rabbits. Primary ocular irritation in rabbits. Acute oral toxicity in rats diethylhexyl malate. Experiment Reference No. 85222-3. Unpublished data submitted by Personal Care Products Council; 1985.

45.

Biolab SGS SRL. Robust summary: human patch test bis (C12-13) alkyl-2-hydroxybutandioate (Di-C12-13 alkyl malate). Unpublished data submitted by Personal Care Products Council; 1992.

46.

Smith

. Comparative effectiveness of α-hydroxy acids on skin properties. Int J Cosmet Sci. 1996;18(2):75–83.

47.

Personal Care Products Council. Summaries of studies of products containing malic acid. Unpublished data submitted by the Personal Care Products Council; 2011: 3.

48.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) acute eye irritation in rabbits. Unpublished data submitted by Personal Care Products Council; 1992: 5.

49.

Pharmaco-LSR Ltd. The chorioallantonic membrane (CAM) test for predicting ocular irritancy bis (C12-13) alkyl-2-hydroxybutandioate (Di-C12-13 alkyl malate). Unpublished data submitted by the Personal Care Products Council; 1993.

50.

Consumer Product Testing Co. Primary ocular irritation in rabbits diethylhexyl malate. Study No. 82411. Unpublished data submitted by Personal Care Products Council; 1982: 1.

51.

Biolab SGS SRL. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) skin sensitization test in guinea pigs. Unpublished data submitted by Personal Care Products Council; 1992: 5.

52.

AMA Laboratories. 50 Human subject repeat insult patch test skin irritaiton/sensitization evaluation (occlusive patch) of PELMOL DISM (Diisostearyl Malate). AMA Ref. No.: MSO5.RIPT.K75540.50.PCI. (Ingredient tested neat (100% Diisostearyl Malate)). Unpublished data submitted by the Personal Care Products Council; 2005.

53.

Walsh

. Atopic dermatitis associated with citric and malic acid intolerance. Minn Med. 1979;62(9):637–639.

54.

Gottschalck

Breslawec

. International Cosmetic Ingredient Dictionary and Handbook. 14th ed. Washington, DC: Personal Care Products Council; 2012.

55.

Phoenix Chemical Inc. Specifications PELEMOL DISM (diisostearyl malate). Unpublished data submitted by the Personal Care Products Council; 2009.

56.

Advanced Chemistry Develoment (ACD/Labs) Software V11.02. Toronto, ON: ACD/Labs; 2010

57.

Phoenix Chemical Inc. Material safety data sheet PELEMOL DISM (diisostearyl malate). Unpublished data submitted by the Personal Care Products Council; 2009.

58.

Instituto Guido Donegani. Robust summary: Cosmacol EMI (Di-C12-13 alkyl malate) physical–chemical characterization: partition coefficient. Unpublished data submitted by Personal Care Products Council; 1993:2.

59.

Salit

. Cannot find the title in English or Russian. Zhurnal Obshchei Khimii. 1963;33(8):2746–2748.

60.

Wang

Bai

. Structure–activity relationships for rat and mouse LD50 of miscellaneous alcohols. Chemosphere. 1998;36(7):1475–1483.

61.

Barratt

. QSARS for the eye irritation potential of neutral organic chemicals. Toxicol In Vitro. 1997;11(1/2):1–8.

62.

Kreja

Seidel

. Evaluation of the genotoxic potential of some microbial volatile organic compounds (MVOC) with the comet assay, the micronucleus assay and the HPRT gene mutation assay. Mutat Res. 2002;513(1-2):143–150.

63.

Chen

Lian

Han

. Prediction of human skin permeability using artificial neural network (ANN) modeling. Acta Pharmacol Sin. 2007;28(4):591–600.

64.

Patel

ten Berge

Cronin

. Quantitative structure-activity relationships (QSARs) for the prediction of skin permeation of exogenous chemicals. Chemosphere. 2002;48(6):603–613.

65.

Santos-Filho Osvaldo

Hopfinger

AJZheng

Tao . Characterization of skin penetration processes of organic molecules using molecular similarity and QSAR analysis. Mol Pharm. 2004;1(6):466–476.

66.

Patlewicz

Dimitrov

Low

. TIMES-SS—A promising tool for the assessment of skin sensitization hazard. A characterization with respect to the OECD validation principles for (Q)SARs and an external evaluation for predictivity. Regul Toxicol Pharmacol. 2007;48(2):225–239.

67.

Elder

. Final report on the safety assessment of cetearyl alcohol, cetyl alcohol, isostearyl alcohol, myristyl alcohol, and behenyl alcohol. J Am Coll Toxicol. 1988;7(3):359–413.

68.

Kakubari

Sasaki

Takayasu

Yamauchi

Takayama

. Effects of ethylcellulose and 2-octyldodecanol additives on skin permeation and irritation with ethylene-vinyl acetate copolymer matrix patches containing formoterol fumarate. Biol Pharm Bull. 2006;29(8):1717–1722.

69.

Montenegro

Carbone

Puglisi

. Vehicle effects on in vitro release and skin permeation of octylmethoxycinnamate from microemulsions. Int J Pharm. 2011;405(1-2):162–168.

70.

Dawn

Forsyth

. Genital swelling caused by octyldodecanol contact dermatitis. Clin Exp Dermatol. 2003;28(2):228–229.

71.

Singh

Winhoven

Beck

. Contact sensitivity to octyldodecanol and trometamol in an anti-itch cream. Contact Dermatitis. 2007;56(5):289–290.

Safety Assessment of Dialkyl Malates as Used in Cosmetics

Abstract

Keywords

Introduction

Chemistry

Definition, Structure, and Manufacture

Dialkyl esters

Malic acid

Chemical and Physical Properties

Use

Cosmetic

Noncosmetic

Toxicokinetics

Absorption, Distribution, Metabolism, and Excretion

Oral and intraperitoneal

Malic Acid

Toxicological Studies

Acute Toxicity

Dermal

Di-C12-13 alkyl malate

Oral—nonhuman

Di-C12-13 alkyl malate

Diethylhexyl malate

Malic acid and sodium malate

Dibutyl malate

Other dose administration

Malic Acid

Repeated Dose Toxicity

Dermal

Di-C12-13 alkyl malate

Oral—nonhuman

Malic acid and sodium malate

Dibutyl malate

Reproductive and Developmental Toxicity

Malic Acid

Dibutyl Malate

Genotoxicity

Diisostearyl Malate

Di-C12-13 Alkyl Malate

Carcinogenicity

Malic Acid

Irritation and Sensitization

Irritation

Dermal—nonhuman

Di-C12-13 alkyl malate

Diethylhexyl malate

Malic acid

Dermal—human

Di-C12-13 alkyl malate

Malic acid

Ocular

Di-C12-13 alkyl malate

Diethylhexyl malate

Malic acid

Sensitization

Dermal—nonhuman

Di-C12-13 alkyl malate

Diethylhexyl malate

Dermal—human

Diisostearyl malate

Malic acid

Summary

Discussion

Conclusion

Footnotes

Appendix A: Possible Esterase Metabolite Summary Data Of Alcohols

Author Contributions

Authors’ Note

Declaration of Conflicting Interests

Funding

References