Interspecies assessment factors and skin sensitization risk assessment.

For many endpoints in toxicology, an interspecies safety factor remains a standard requirement. However, for skin sensitization, the hazard and potency predictions, notably from the local lymph node assay (LLNA) have been shown to correlate well with human data. Despite this, there are always exceptions, both over and under predictions. For this reason it has been suggested that an interspecies factor of 15 would accommodate potential "errors". An alternative approach is suggested in which an evidence-based strategy is taken: the large majority of the information indicates a human:LLNA ratio of 1, therefore a corrective factor would best be applied where our knowledge of the underlying chemistry of sensitization indicates that it is necessary.

Application of the expanded Creme RIFM consumer exposure model to fragrance ingredients in cosmetic, personal care and air care products.

As part of a joint project between the Research Institute for Fragrance Materials (RIFM) and Creme Global, a Monte Carlo model (here named the Creme RIFM model) has been developed to estimate consumer exposure to ingredients in personal care products. Details of the model produced in Phase 1 of the project have already been published. Further data on habits and practises have been collected which enable the model to estimate consumer exposure from dermal, oral and inhalation routes for 25 product types. . In addition, more accurate concentration data have been obtained which allow levels of fragrance ingredients in these product types to be modelled. Described is the use of this expanded model to estimate aggregate systemic exposure for eight fragrance ingredients. Results are shown for simulated systemic exposure (expressed as µg/kg bw/day) for each fragrance ingredient in each product type, along with simulated aggregate exposure. Highest fragrance exposure generally occurred from use of body lotions, body sprays and hydroalcoholic products. For the fragrances investigated, aggregate exposure calculated using this model was 11.5-25 fold lower than that calculated using deterministic methodology. The Creme RIFM model offers a very comprehensive and powerful tool for estimating aggregate exposure to fragrance ingredients.

Integrating habits and practices data for soaps, cosmetics and air care products into an existing aggregate exposure model.

In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products. The present study describes the development of Phase 2 Creme RIFM model by expanding the previously developed Phase 1 model to include an additional six product types. Using subject-matching algorithms, the subjects in the Phase 1 Creme RIFM database were paired with subjects in the SUPERB and BodyCare surveys based on age and gender. Consumption of the additional products was simulated to create a seven day diary allowing full data integration in a consistent format. The inhalation route was also included for air care and other products where a fraction of product used is inhaled, derived from the RIFM 2-box model. The expansion of the Phase 1 Creme RIFM model has resulted in a more extensive and refined model, which covers a broader range of product categories and now, includes all relevant routes of exposure. An evaluation of the performance of the model has been carried out in an accompanying publication to this one.

Novel database for exposure to fragrance ingredients in cosmetics and personal care products.

Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey. The frequency and combinations of products used at specific times during the day will allow the estimation of aggregate exposure for an individual consumer, and to the sample population. In the present study, habits and practices of personal care and cosmetic products have been obtained from market research data for 36,446 subjects across European countries and the United States in order to determine the exposure to fragrance ingredients. Each subject logged their product uses, time of day and body application sites in an online diary for seven consecutive days. The survey data did not contain information on the amount of product used per occasion or body measurements, such as weight and skin surface area. Nevertheless, this was found from the literature where the likely amount of product used per occasion or body measurement could be probabilistically chosen from distributions of data based on subject demographics. The daily aggregate applied consumer product exposure was estimated based on each subject's frequency of product use, and Monte Carlo simulations of their likely product amount per use and body measurements. Statistical analyses of the habits and practices and consumer product exposure are presented, which show the robustness of the data and the ability to estimate aggregate consumer product exposure. Consequently, the data and modelling methods presented show potential as a means of performing ingredient safety assessments for personal care and cosmetics products.

Use of an aggregate exposure model to estimate consumer exposure to fragrance ingredients in personal care and cosmetic products.

Ensuring the toxicological safety of fragrance ingredients used in personal care and cosmetic products is essential in product development and design, as well as in the regulatory compliance of the products. This requires an accurate estimation of consumer exposure which, in turn, requires an understanding of consumer habits and use of products. Where ingredients are used in multiple product types, it is important to take account of aggregate exposure in consumers using these products. This publication investigates the use of a newly developed probabilistic model, the Creme RIFM model, to estimate aggregate exposure to fragrance ingredients using the example of 2-phenylethanol (PEA). The output shown demonstrates the utility of the model in determining systemic and dermal exposure to fragrances from individual products, and aggregate exposure. The model provides valuable information not only for risk assessment, but also for risk management. It should be noted that data on the concentrations of PEA in products used in this article were obtained from limited sources and not the standard, industry wide surveys typically employed by the fragrance industry and are thus presented here to illustrate the output and utility of the newly developed model. They should not be considered an accurate representation of actual exposure to PEA.

Update to RIFM fragrance ingredient safety assessment, 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)-, CAS registry number 58461-27-1.

4-Hexen-1-ol, 5-methyl-2-(1-methylethenyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- 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 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from read-across analog 3-methylbut-3-en-1-ol (CAS # 763-32-6) show that there are no safety concerns for 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- is not expected to be photoirritating/photoallergenic. The environmental endpoints were evaluated; 4-hexen-1-ol, 5-methyl-2-(1-methylethenyl)- 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 (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany.

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed.

RIFM fragrance ingredient safety assessment, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)-, CAS Registry Number 499-44-5.

The existing information supports the use of this material as described in this safety assessment. This material has not been fully evaluated for photoallergenic potential. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- 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 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- 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. Based on data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- is a photoirritant but is not a concern under the current declared use levels. 2,4,6-Cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- was not evaluated for photoallergenicity. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 2,4,6-cycloheptatrien-1-one, 2-hydroxy-4-(1-methylethyl)- 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 (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

In vitro human skin absorption of linalool: Effects of vehicle composition, evaporation and occlusion on permeation and distribution.

In vitro human skin permeation and distribution of the fragrance material linalool (3,7-dimethyl-1,6-octadien-3-ol, CAS No. 78-70-6) following application in a range of single and mixed vehicles was determined, under unoccluded and occluded conditions, using human epidermal membranes. Vehicles were (70/30 v/v) ethanol[EtOH]/water, dipropyleneglycol [DPG], diethyl phthalate [DEP], (25/75 v/v) EtOH/DEP, (25/75 v/v) EtOH/DPG and petrolatum. Worst case absorbed dose values (% applied dose) for linalool under unoccluded conditions varied from 1.84% (DPG) to 4.08% (EtOH/water) and under occluded conditions from 5.9% (DEP) to 14.7% (EtOH/water). Occlusion always increased absorption but the magnitude of the effect varied with the vehicle from 2 to 6-fold. This study demonstrated that in vitro human skin permeation of linalool varied quite widely between test vehicles and that the magnitude of the effect of occlusion was also vehicle dependent. This was particularly significant in view of the reported variations in biological responses using different vehicles (Lalko et al., 2004; Politano et al., 2006).

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.

RIFM fragrance ingredient safety assessment, 3-phenylpropyl acetate, CAS Registry Number 122-72-5.

Therefore, the phenethyl formate MOE for the fertility endpoint can be calculated by dividing the phenethyl alcohol NOAEL in mg/kg/day by the total systemic exposure to phenethyl formate, 1000/0.00062 or 1612903.

RIFM fragrance ingredient safety assessment, (-)-(R)-α-phellandrene, CAS Registry Number 4221-98-1.

Therefore, the (-)-(R)-α-phellandrene MOE for the repeated dose toxicity endpoint can be calculated by dividing the (-)-(R)-α-phellandrene NOAEL in mg/kg/day by the total systemic exposure to (-)-(R)-α-phellandrene, 8.33/0.00040, or 20825.

RIFM fragrance ingredient safety assessment, 5-hydroxy-7-decenoic acid δ-lactone, CAS Registry Number 25524-95-2.

The existing information supports the use of this material as described in this safety assessment. 5-Hydroxy-7-decenoic acid δ-lactone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across material tetrahydro-6-(3-pentenyl)-2H-pyran-2-one (CAS # 32764-98-0) show that 5-hydroxy-7-decenoic acid δ-lactone 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 5-hydroxy-7-decenoic acid δ-lactone is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data show that there are no safety concerns for 5-hydroxy-7-decenoic acid δ-lactone for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 5-hydroxy-7-decenoic acid δ-lactone is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 5-Hydroxy-7-decenoic acid δ-lactone 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, octyl isobutyrate, CAS Registry Number 109-15-9.

The existing information supports the use of this material as described in this safety assessment. Octyl isobutyrate 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 octyl isobutyrate is not expected to be genotoxic. Data on analog propyl (2S)-2-(1,1-dimethylpropoxy)-propanoate (CAS # 319002-92-1) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose and reproductive toxicity endpoints. Data from analog hexyl 2-methylbutyrate (CAS # 10032-15-2) provided octyl isobutyrate a No Expected Sensitization Induction Level (NESIL) of 7000 µg/cm2 for the skin sensitization endpoint. Octyl isobutyrate is not expected to be phototoxic/photoallergenic based on ultraviolet/visible (UV/Vis) spectra. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure to is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; octyl 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.

RIFM fragrance ingredient safety assessment, 2,6-nonadienenitrile, CAS Registry Number 67019-89-0.

The existing information supports the use of this material as described in this safety assessment. 2,6-Nonadienenitrile was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2,6-nonadienenitrile is not genotoxic. Data on read-across analog E- and Z-2(+3),12-tridecadiennitrile (CAS # 124071-40-5) provided 2,6-nonadienenitrile 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 III material, and the exposure to 2,6-nonadienenitrile is below the TTC (0.0015 mg/kg/day and 0.47 mg/day, respectively). Data show that there are no safety concerns for 2,6-nonadienenitrile for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 2,6-nonadienenitrile is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2,6-nonadienenitrile 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-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal, CAS Registry Number 65405-84-7.

The existing information supports the use of this material as described in this safety assessment. 4-(2,6,6-Trimethyl-2-cyclohexen)-2-methylbutanal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal 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 4-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data provided 4-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal a No Expected Sensitization Induction Level (NESIL) of 1100 µg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; 4-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-(2,6,6-trimethyl-2-cyclohexen)-2-methylbutanal 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.

Update to RIFM fragrance ingredient safety assessment, α-irone, CAS registry number 79-69-6.

In addition, the total systemic exposure to α-irone (1.1 µg/kg/day) is below the TTC (30 µg/kg/day; Kroes et al., 2007) for the repeated dose toxicity endpoint of a Cramer Class I material at the current level of use.

RIFM fragrance ingredient safety assessment, l-carvone, CAS Registry Number 6485-40-1.

l-Carvone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that l-carvone is not genotoxic and provided a No Expected Sensitization Induction Level (NESIL) of 2600 µg/cm2 for the skin sensitization endpoint. Data on l-carvone provided a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on data and ultraviolet/visible (UV/Vis) spectra; l-carvone is not phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material (0.47 mg/day); the exposure to l-carvone is below the TTC. The environmental endpoints were evaluated; l-carvone 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, ß-caryophyllene, CAS Registry Number 87-44-5.

The existing information supports the use of this material as described in this safety assessment. ß-Caryophyllene was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that ß-caryophyllene is not genotoxic. Data on ß-caryophyllene provided a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity and fertility endpoints. The developmental and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to ß-caryophyllene is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively. Data show that there are no safety concerns for ß-caryophyllene for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on data and ultraviolet/visible (UV/Vis) spectra; ß-caryophyllene is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ß-caryophyllene 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.