Dermal Sensitization Threshold Research Articles

RIFM fragrance ingredient safety assessment, hexyl hexanoate, CAS Registry Number 6378-65-0

The existing information supports the use of this material as described in this safety assessment.Hexyl hexanoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hexyl isobutyrate (CAS # 2349-07-7) show that hexyl hexanoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to hexyl hexanoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; hexyl hexanoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hexyl hexanoate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, styryl acetate, CAS Registry Number 10521-96-7

Summary: The existing information supports the use of this material as described in this safety assessment. Styryl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that styryl acetate is not genotoxic. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material and the exposure to styryl acetate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; styryl acetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; styryl acetate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Ingredient (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]) are

RIFM fragrance ingredient safety assessment, tetrahydro-α-pentylfurfuryl acetate, CAS Registry Number 67634-08-6

The existing information supports the use of this material as described in this safety assessment.Tetrahydro-α-pentylfurfuryl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that tetrahydro-α-pentylfurfuryl acetate is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class III material, and the exposure to tetrahydro-α-pentylfurfuryl acetate is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; tetrahydro-α-pentylfurfuryl acetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; tetrahydro-α-pentylfurfuryl acetate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 2-acetylthiazole, CAS Registry Number 24295-03-2

The existing information supports the use of this material as described in this safety assessment. 2-Acetylthiazole was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-acetylthiazole is not genotoxic. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class II material, and the exposure to 2-acetylthiazole is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 2-acetylthiazole is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated, 2-acetylthiazole was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current Volume of Use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]) are <1.

RIFM fragrance ingredient safety assessment, ethyl (E)hex-3-enoate, CAS registry number 26553-46-8

The existing information supports the use of this material as described in this safety assessment.Ethyl (E)hex-3-enoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog methyl 3-hexenoate (CAS # 2396-78-3) show that ethyl (E)hex-3-enoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to ethyl (E)hex-3-enoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; ethyl (E)hex-3-enoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ethyl (E)hex-3-enoate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current Volume of Use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 2,2-dimethyl-3-methyl-3-butenyl propanoate, CAS Registry Number 104468-21-5

Summary: The existing information supports the use of this material as described in this safety assessment.2,2-Dimethyl-3-methyl-3-butenyl propanoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog rhodinyl formate (CAS # 141-09-3) show that 2,2-dimethyl-3-methyl-3-butenyl propanoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to 2,2-dimethyl-3-methyl-3-butenyl propanoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2,2-dimethyl-3-methyl-3-butenyl propanoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2,2-dimethyl-3-methyl-3-butenyl propanoate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 4-methylpentanoic acid, CAS Registry Number 646-07-1

The existing information supports the use of this material as described in this safety assessment. 4-Methylpentanoic acid was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 2-ethylbutyric acid (CAS # 88-09-5) show that 4-methylpentanoic acid is not expected to be genotoxic and provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 4-methylpentanoic acid is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to 4-methylpentanoic acid is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 4-methylpentanoic acid was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, ethyl 3-methylthiopropionate, CAS Registry Number 13327-56-5

The existing information supports the use of this material as described in this safety assessment. Ethyl 3-methylthiopropionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog methyl 3-methylthiopropionate (CAS # 13532-18-8) show that ethyl 3-methylthiopropionate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to ethyl 3-methylthiopropionate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; ethyl 3-methylthiopropionate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ethyl 3-methylthiopropionate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current Volume of Use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, butyl butyrate, CAS Registry Number 109-21-7

The existing information supports the use of this material as described in this safety assessment. Butyl lactate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl (L)-lactate (CAS # 687-47-8) show that butyl lactate is not expected to be genotoxic. Data on read-across materials butyl alcohol (CAS # 71-36-3) and lactic acid (CAS # 50-21-5) provide a calculated margin of exposure (MOE) > 100 for the repeated dose and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; butyl lactate is not expected to be phototoxic/photoallergenic. Data on butyl lactate provide a calculated MOE >100 for the local respiratory endpoint. The environmental endpoints were evaluated; butyl lactate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, p-α,α-trimethylbenzyl alcohol, CAS Registry Number 1197-01-9

The existing information supports the use of this material as described in this safety assessment. p-α,α-Trimethylbenzyl alcohol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that p-α,α-trimethylbenzyl alcohol is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to p-α,α-trimethylbenzyl alcohol is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; p-α,α- trimethylbenzyl alcohol is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; p-α,α-trimethylbenzyl alcohol was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, methyl 3-methylthiopropionate, CAS Registry Number 13532-18-8

The existing information supports the use of this material as described in this safety assessment. Ethyl 3-methylthiopropionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog methyl 3-methylthiopropionate (CAS # 13532-18-8) show that ethyl 3-methylthiopropionate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to ethyl 3-methylthiopropionate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; ethyl 3-methylthiopropionate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ethyl 3-methylthiopropionate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current Volume of Use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1. (Less)

RIFM fragrance ingredient safety assessment, 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one, CAS registry number 13215-88-8

The existing information supports the use of this material as described in this safety assessment.4-(2-Butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one is not genotoxic. Data on 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on data; 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-(2-butenylidene)-3,5,5-trimethylcyclohex-2-en-1-one was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Skin Sensitization Induction Risk Assessment of Common Ingredients in Commercially Available Cleansing Conditioners.

An essential step in ensuring the toxicological safety of cosmetic or personal care products is the evaluation of the skin sensitizing potential of product ingredients. We used a standardized protocol from cosmetic trade industry and consumer safety groups to evaluate the sensitization potential of ingredients in 3 commercially available cleansing conditioners. A total of 33 ingredients were evaluated. Each ingredient underwent (1) dermatological evaluation, (2) in silico analysis for irritation and sensitization potential, and (3) a literature evaluation to determine risk of sensitization. Consumer exposure level was compared with the weight-of-evidence no-expected sensitization induction level for the constituent. If a no-expected sensitization induction level for a specific ingredient was not available, the dermal sensitization threshold approach was used. A margin of safety was calculated for each constituent. The margins of safety for all evaluated ingredients in the cleansing conditioners were greater than 1. This analysis indicates that exposure to the individual ingredients present in these cleansing conditioners would not be expected to induce dermal sensitization in a consumer under the examined exposure scenario.

The dermal sensitization threshold (DST) approach for mixtures evaluated as negative in in vitro test methods; mixture DST.

Cosmetic ingredients often comprise complex mixtures, such as botanical extracts, which may contain skin sensitizing constituents. In our previous study for the sensitivity of the evaluations of skin sensitizing constituents in mixtures using the binary in vitro test battery with KeratinoSensTM and h-CLAT, some sensitizers showed higher detection limits in in vitro test methods than in murine local lymph node assays (LLNA). Thus, to minimize the uncertainty associated with decreased sensitivity for these sensitizers, a risk assessment strategy was developed for mixtures with negative results from the binary test battery. Assuming that the no expected sensitization induction level of mixtures (mixture NESIL) can be derived for mixtures with negative in vitro test results, we assessed 146 sensitizers with in vitro and LLNA data according to the assumption of indeterminate constituents in mixtures. Finally, we calculated 95th percentile probabilities of mixture NESILs and derived dermal sensitization thresholds for mixtures (mixture DST) with negative in vitro test results of 6010 μg/cm2. Feasibility studies indicated that this approach was practical for risk assessments of products in the cosmetic industry. This approach would be a novel risk assessment strategy for incorporating the DST approach and information from in vitro test methods.

RIFM fragrance ingredient safety assessment, benzyl isobutyrate, CAS Registry Number 103-28-6

The existing information supports the use of this material as described in this safety assessment. p-Tolyl isobutyrate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs ethyl p-tolyl carbonate (CAS # 22,719-81-9) and p-tolyl acetate (CAS # 140-39-6) show that p-tolyl isobutyrate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to p-tolyl isobutyrate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; p-tolyl isobutyrate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; p-tolyl isobutyrate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1. (Less)

The dermal sensitization threshold (DST) for chemicals classified as protein reactive

The dermal sensitization threshold (DST) for chemicals classified as protein reactive

Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data

In analogy to the Threshold of Toxicological Concern concept, a Threshold of Sensitization Concern (TSC) concept is proposed for chemicals with respect to their ability to induce an allergic contact dermatitis. Recently, the derivation of a dermal sensitization threshold was suggested based on an evaluation of animal data. In order to establish the concept with human data, we conducted a meta-analysis taking into account No Expected Sensitization Induction Levels for fragrance ingredients from the IFRA/RIFM dataset. Based on a statistical analysis by applying Sensitization Assessment Factors that account for interindividual variability and different exposure conditions, TSC values of 0.91 or 0.30 lg/cm2 can be derived in terms of amount per skin area. TSC values are compared with typical exposure levels of cosmetic products. A substance can be considered to be virtually safe if the quotient of exposure level and TSC is < 1. The findings derived from human data include several conservative assumptions and largely support the dermal sensitization thresholds previously derived from animal data. The TSC concept might in principle be used for any untested chemical and therefore help in some cases to waive animal testing.