Update to RIFM fragrance ingredient safety assessment, 2,4-dimethylbenzyl acetate, CAS Registry Number 62346-96-7.

The MOE is greater than 100. Without adjustment for specific uncertainty factors related to inter-species and intra-species variation, the material exposure by inhalation at 0.0040 mg/day is deemed to be safe under the most conservative consumer exposure scenario.

The RIFM approach to evaluating Natural Complex Substances (NCS).

The Research Institute for Fragrance Materials, Inc. (RIFM) has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS; 2) verify whether the Threshold of Toxicological Concern (TTC) can be applied; 3) verify whether the NCS risk assessment can be achieved on a component basis; and 4) determine whether data must be generated. Using in silico tools, RIFM examined NCS similarities based on the plant part, processing, and composition of materials across 81 plant families to address data gaps. Data generated from the Creme RIFM Aggregate Exposure Model for over 900 fragrance NCS demonstrate that dermal exposure is the primary route of human exposure for NCS fragrance uses. Over a third of materials are below the most conservative TTC limits. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

RIFM fragrance ingredient safety assessment, methyl 2-nonenoate, CAS Registry Number 111-79-5.

The existing information supports the use of this material as described in this safety assessment. Methyl 2-nonenoate 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 trans-2,cis-4-decadienoate (CAS # 3025-30-7) show that methyl 2-nonenoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to methyl 2-nonenoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from the target and read-across analog isobutyl-2-butenoate (CAS # 589-66-2) do not indicate the material is a sensitizer. The phototoxicity/photoallergenicity endpoints were evaluated based on data and UV spectra; methyl 2-nonenoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-nonenoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, isobutyl propionate, CAS Registry Number 540-42-1.

The existing information supports the use of this material as described in this safety assessment. Isobutyl propionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog isobutyl acetate (CAS # 110-19-0) show that isobutyl propionate is not expected to be genotoxic. Data from read-across analog isoamyl acetate (CAS # 123-92-2) show that there are no safety concerns for isobutyl propionate for skin sensitization under the current declared levels of use. The repeated dose and reproductive endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to isobutyl propionate is below the TTC (0.03 mg/kg/day and 0.03 mg/kg/day, respectively). For the local respiratory endpoint, a calculated MOE >100 was provided by read-across analog butyl acetate (CAS # 123-86-4). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; isobutyl propionate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; isobutyl propionate is not PBT as per the IFRA Environmental Standards. For the risk assessment, isobutyl propionate was not able to be risk screened as there were no reported volumes of use for North America or Europe in the 2015 IFRA Survey.

RIFM fragrance ingredient safety assessment, propanal diethyl acetal, CAS registry number 4744-08-5.

There are insufficient toxicity data on the target material propanal diethyl acetal (CAS # 4744-08-5). Hence, in silico evaluation was conducted to determine read-across analogs for this material. Based on structural similarity, reactivity, metabolism data, physical-chemical properties, and expert judgment, analogs acetal (CAS # 105-57-7) and butane, 1,1'-[methylenebis(oxy)]bis- (CAS # 2568-90-3) were identified as read-across materials with sufficient data for toxicological evaluation of genotoxicity.

Opinion of the Scientific Committee on consumer safety (SCCS) - Final opinion on the safety of fragrance ingredient Acetylated Vetiver Oil (AVO) - (Vetiveria zizanioides root extract acetylated) - Submission III.

On the basis of the safety assessment carried out using a conservative approach, the SCCS considers the use of Acetylated Vetiver Oil (AVO) with 1% alpha-tocopherol as a fragrance ingredient in cosmetic leave-on and rinse-off type products safe at the concentrations proposed by IFRA. Acetylated Vetiver Oil (AVO) contains some constituents that belong to the chemical group of aldehydes and ketones that are known to be reactive towards biological entities, such as DNA and proteins. However, the overall health risk of such components is likely to be negligible at the concentrations intended to be used in cosmetics products. The SCCS has noted that Acetylated Vetiver Oil (AVO) is a moderate skin sensitiser in test animals. Considering the results of the HRIPT study and the fact that AVO has been used for years in cosmetics without evidence of sensitising potential, it is unlikely that AVO would be causing contact allergy in humans. Inhalation toxicity of Acetylated Vetiver Oil (AVO) was not assessed in this Opinion because no data were provided. Assessment of the inhalation risk would be needed if Acetylated Vetiver Oil (AVO) was intended to be used in sprayable products.

RIFM fragrance ingredient safety assessment, ethylene brassylate, CAS Registry Number 105-95-3.

: The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The local respiratory toxicity endpoint was completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (1.4 mg/day). The repeated dose toxicity endpoint was completed using ethylene dodecanedioate (CAS # 54982-83-1) as a suitable read across analog, which provided a MOE > 100. The developmental and reproductive toxicity endpoint was completed using oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2) as a suitable read across analog, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra along with data on the target material. The environmental endpoint was completed as described in the RIFM Framework along with data on the suitable read across analog oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2).

RIFM fragrance ingredient safety assessment, linalyl benzoate, CAS Registry Number 126-64-7.

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic. Data from the suitable read across analog linalyl phenylacetate (CAS # 7143-69-3) show that this material does not have skin sensitization potential. The repeated dose toxicity endpoint was completed using linalyl cinnamate (CAS # 78-37-5) as a suitable read across analog, which provided a MOE > 100. The developmental and reproductive toxicity endpoint was completed using linalool (CAS # 78-70-6), dehydrolinalool (CAS # 29171-20-8), benzoic acid (CAS # 65-85-0) and sodium benzoate (CAS # 532-32-1) as suitable read across analogs, which provided a MOE > 100. The local respiratory toxicity endpoint was completed using linalool (CAS # 78-70-6) and benzoic acid (CAS # 65-85-0) as suitable read across analogs, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework along with data from the suitable read across analog linalyl cinnamate (CAS # 78-375).

RIFM fragrance ingredient safety assessment, 2-ethyl-1-butanol, CAS Registry Number 97-95-0.

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analog 2-ethylhexanol (CAS # 104-76-7) show that this material is not genotoxic. Data from the suitable read across analog isopropyl alcohol (CAS # 67-63-0) show that this material does not have skin sensitization potential. The local respiratory toxicity endpoint was completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (1.4 mg/day). The repeated dose toxicity endpoint was completed using 2-ethylhexanol (CAS # 104-76-7) and 1-heptanol, 2-propyl (CAS # 10042-59-8) as suitable read across analogs, which provided a MOE > 100. The developmental and reproductive toxicity endpoint was completed using 2-ethyl-hexanol (CAS # 104-76-7) and isobutyl alcohol (CAS # 78-83-1) as suitable read across analogs, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, 3,7-dimethyl-1,6-nonadien-3-ol, CAS Registry Number 10339-55-6.

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analog linalool (CAS # 78-70-6) show that this material is not genotoxic nor does it have skin sensitization potential and also provided a MOE > 100 for the local respiratory endpoint. The repeated dose, developmental and reproductive toxicity endpoints were completed using nerolidol (isomer unspecified, CAS # 7212-44-4) as a suitable read across analog, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, 2-ethyl-1-hexanol, CAS registry number 104-76-7.

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic. Data from the suitable read across analog 2-butyloctan-1-ol (CAS # 3913-02-8) show that this material does not have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The developmental and repeat dose toxicity endpoints were completed data on the target material which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, linalyl cinnamate, CAS Registry Number 78-37-5.

The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The developmental toxicity endpoint was completed using linalool (CAS # 78-70-6), dehydrolinalool (CAS # 29171-20-8) and cinnamic acid (CAS # 621-82-9) as suitable read across analogs, which provided a MOE > 100. The repeated dose toxicity endpoint was completed using data on the target material which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, 2-methylundecanol, CAS Registry Number 10522-26-6.

This material was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analogs 2-butyloctan-1-ol (CAS # 3913-02-8) and 2-ethyl-1-hexanol (CAS # 104-76-7) show that this material is not genotoxic nor does it have skin sensitization potential. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03 and 1.4 mg/day, respectively). The repeated dose toxicity endpoint was completed using 2-ethyl-1-hexanol (CAS # 104-76-7) and 1-heptanol, 2-propyl (CAS # 10042-59-8) as suitable read across analogs, which provided a MOE > 100. The developmental toxicity endpoint was completed using 2-ethyl-1-hexanol (CAS # 104-76-7) as a suitable read across analog, which provided a MOE > 100 The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, 1-(1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthyl)propan-1-one, CAS Registry Number 74499-60-8.

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the target material and the suitable read across analog 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (CAS # 21145-77-7) show that this material is not genotoxic. Data from the suitable read across analog 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (CAS # 21145-77-7) provided a MOE > 100 for the repeat dose and developmental toxicity endpoints. The reproductive and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class II material (0.009 mg/kg/day and 0.47 mg/day, respectively). Data on the target material showed that this material is below the non-reactive DST for skin sensitization and did not have the potential for phototoxicity or photoallergenicity. The environmental endpoint was completed as described in the RIFM Framework.

RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7.

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analog benzyl acetate (CAS # 140-11-4) show that this material is not genotoxic nor does it have skin sensitization potential and also provided a MOE > 100 for the repeated dose, developmental and reproductive, and local respiratory toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework.