ABSTRACT
The alkyl cyclic ketone (ACK) fragrance ingredients are a diverse group of structures with similar metabolic and toxicity profiles. ACK fragrance materials demonstrate low acute toxicity. Upon repeat dose testing, some adverse effects in biochemical and hematological parameters, and slightly increased liver and kidney weights were reported, primarily at high doses, resulting from adaptive effects. Developmental effects occurred only in the presence of maternal toxicity. Assays in bacteria and mammalian cell systems and the mouse micronucleus assay did not demonstrate genotoxicity. ACK fragrance ingredients are considered non-irritating to the skin of humans; results showed few reactions, most of which were equivocal or involved doses greater than those in consumer products. Mild to moderate eye irritation in animal tests was observed with most compounds; however, full recovery was usually observed. Human sensitization studies indicate that ACK fragrance ingredients have a low sensitization potential. Diagnostic patch-tests indicated low sensitizing potential in humans; except for fragrance materials which caused reactions at 1% or 5%. Phototoxicity and photosensitization were not demonstrated in humans, and, with the possible exception of acetyl cedrene, would not be expected. It is concluded that ACK materials do not present a safety concern at current levels of use as fragrance ingredients.
Subject(s)
Perfume/chemistry , Perfume/toxicity , Animals , Consumer Product Safety , Humans , Irritants , Ketones/pharmacokinetics , Ketones/toxicity , Mice , Patch Tests , Risk Assessment , Toxicity Tests/methodsABSTRACT
The cyclopentanone and cyclopentenone group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.002% to 15.16% in hydroalcoholic products; systemic exposures vary from 0.0003 to 0.7122 mg/kg/day. The cyclopentanones and cyclopentenones had a low order of acute toxicity and no significant toxicity in repeat dose studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Developmental toxicity was not observed. Minimal evidence of skin irritation in humans is associated with current levels of use. Eleven materials were tested undiluted for eye irritation; three were considered irritants. No phototoxic and photosensitization reactions were seen with nine materials tested. At concentrations higher than current reported use, 14 materials were non-sensitizing in HRIPT or maximization tests. 2-Hexylidene cyclopentanone, 2-heptylidenecyclopentan-1-one and 3-methyl-2-(pentyloxy)-2-cyclopenten-1-one are weak sensitizers and have IFRA Standards. Risk of sensitization to the cyclopentanones and cyclopentenones is generally small under current levels of use. The Panel is of the opinion that there are no safety concerns for the cyclopentanones and cyclopentenones at reported levels of use and exposure as fragrance ingredients.
Subject(s)
Cyclopentanes/toxicity , Perfume , Skin/drug effects , Animals , Cyclopentanes/pharmacokinetics , Humans , Toxicity TestsABSTRACT
The aryl alkyl alcohol simple acid ester derivatives (AAASAE) group of fragrance ingredients was critically evaluated for safety following a complete literature search of the pertinent data. For high end users, calculated maximum skin exposures vary widely from 0.01% to 4.17%. AAASAE exhibit a common route of primary metabolism by carboxylesterases resulting in the formation of the simple acid and an aryl alkyl alcohol. They have low acute toxicity. No significant toxicity was observed in repeat-dose toxicity tests. There was no evidence of carcinogenicity of benzyl alcohol when it was administered in the feed; gavage studies resulted in pancreatic carcinogenesis due to the corn oil vehicle. The AAASAE are not mutagenic in bacterial systems or in vitro in mammalian cells, and have little to no in vivo genotoxicity. Reproductive and developmental toxicity data show no indication of adverse effects on reproductive function and NOELs for maternal and developmental toxicity are far in excess of current exposure levels. The AAASAE are generally not irritating or sensitizing at the current levels of exposure. The Panel is of the opinion that there are no safety concerns regarding the AAASAE at the current levels of use and exposure.
Subject(s)
Alcohols/toxicity , Perfume , Skin/drug effects , Alcohols/chemistry , Alcohols/pharmacokinetics , Animals , Esters , Humans , Mice , Rabbits , Rats , Toxicity TestsABSTRACT
The aryl alkyl alcohol (AAA) fragrance ingredients are a diverse group of chemical structures with similar metabolic and toxicity profiles. The AAA fragrances demonstrate low acute and subchronic dermal and oral toxicity. No carcinogenicity in rats or mice was observed in 2-year chronic testing of benzyl alcohol or α-methylbenzyl alcohol; the latter did induce species and gender-specific renal adenomas in male rats at the high dose. There was no to little genotoxicity, mutagenicity, or clastogenicity in the mutagenic in vitro bacterial assays, and in vitro mammalian cell assays. All in vivo micronucleus assays were negative. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels. At concentrations likely to be encountered by consumers, AAA fragrance ingredients are non-irritating to the skin. The potential for eye irritation is minimal. With the exception of benzyl alcohol and to a lesser extent phenethyl and 2-phenoxyethyl AAA alcohols, human sensitization studies, diagnostic patch tests and human induction studies, indicate that AAA fragrance ingredients generally have no or low sensitization potential. Available data indicate that the potential for photosensitization is low. It is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.
Subject(s)
Alcohols/toxicity , Perfume , Skin/drug effects , Alcohols/pharmacokinetics , Animals , Guinea Pigs , Humans , Rats , Toxicity TestsABSTRACT
The macrocyclic ketone (MK) group of fragrance ingredients was evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.13% to 1.10%; systemic exposures vary from 0.0005 to 0.0441 mg/kg/day. The MKs had low acute toxicity and no significant repeat dose toxicity. Liver weight and blood biochemistry effects were reversible after 2 weeks. No genotoxicity in bacteria and mammalian cell lines was observed. Reproductive toxicity was not observed for 3-methylcyclopentadecenone in an OECD compliant study. In humans, MKs are generally not irritating after one application. Animal studies showed irritation for some materials at concentrations higher than current consumer exposure. At rates consistent with current human exposure, phototoxicity and photosensitization were not observed. In animals, some MKs are sensitizers only at concentrations of 20%, 30%, or 100%, which are higher than current consumer exposure. No evidence of sensitization was observed in human tests. In patients with fragrance allergy, reactions were seen with cyclopentadecanone (3/178). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MKs at reported levels of use and exposure as fragrance ingredients.
Subject(s)
Irritants/toxicity , Ketones/chemistry , Ketones/toxicity , Perfume/chemistry , Perfume/toxicity , Toxicity Tests/methods , Animals , Consumer Product Safety , Humans , Irritants/chemistry , Risk AssessmentABSTRACT
The cinnamyl phenylpropyl fragrance ingredients are a diverse group of chemical structures that have similar metabolic and toxicity profiles. A toxicological and dermatological review of these fragrance ingredients is presented. The common characteristic structural element of cinnamyl phenylpropyl materials is an aryl substituted primary alcohol/aldehyde/ester. For high end users, calculated maximum dermal exposures vary from 0.14% to 0.72%; systemic exposures vary from 0.0002 to 0.0280 mg/kg/day. Human dermatological studies show that these materials are not generally irritants or sensitizers at lower exposures from consumer products. Reactions (0.9%) in fragrance sensitive patients were observed with 3-phenyl-1-propanol at 5% in petrolatum. The cinnamyl phenylpropyl materials had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. The cinnamyl phenylpropyl alcohol materials participate in the same beta oxidation pathways as their parent cinnamic acid derivatives, including common routes of absorption, distribution, and metabolic detoxification, and exhibit similar toxicological endpoints. Based on the review of available data, it is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.
Subject(s)
Consumer Product Safety , Irritants/chemistry , Irritants/toxicity , Perfume/chemistry , Perfume/toxicity , Animals , Cinnamates/chemistry , Cinnamates/toxicity , Humans , Mucous Membrane/drug effects , Mucous Membrane/pathology , Propanols/chemistry , Propanols/toxicity , Risk Assessment , Skin/drug effects , Skin/pathology , Toxicity Tests/methodsABSTRACT
The Macrocyclic Lactone and Lactide derivative (ML) group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.47% to 11.15%; systemic exposures vary from 0.0008 to 0.25mg/kg/day. The MLs had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. Effects on blood biochemistry were reversible after 2 weeks of no treatment. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Reproductive and developmental toxicity was not observed. Human dermatological studies show MLs are generally not irritating after one application. Minor irritation was observed in a few individuals following multiple applications. At rates consistent with reported levels for current human exposure, no phototoxicity or photosensitization was observed. In animal studies, the MLs are not sensitizers at lower exposures from consumer products. Eleven ML materials were evaluated for human sensitization. Of these, only ethylene brassylate showed evidence of sensitization in 2/27 studies (sensitization frequency 4/2059 total). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MLs at reported levels of use and exposure as fragrance ingredients.
Subject(s)
Consumer Product Safety , Irritants/toxicity , Lactones/chemistry , Lactones/toxicity , Perfume/chemistry , Perfume/toxicity , Animals , DNA Damage/drug effects , Dioxanes/chemistry , Dioxanes/toxicity , Humans , Irritants/chemistry , Odorants , Risk Assessment , Skin/drug effects , Skin/pathology , Skin Diseases/chemically induced , Skin Diseases/pathology , Toxicity Tests/methodsABSTRACT
A systematic classification of substances (or mixtures of substances) with regard to various toxicological endpoints is a prerequisite for the implementation of occupational safety strategies. As its principal task the "Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area" of the "Deutsche Forschungsgemeinschaft" (DFG-MAK Commission) derives and recommends maximum workplace concentrations and biological tolerance values (MAK and BAT values) based exclusively on scientific arguments. Several endpoints are evaluated separately in detail, e.g. carcinogenicity, risks during pregnancy, germ cell mutagenicity or contribution to systemic toxicity after cutaneous absorption. Skin- and airway sensitization is also considered; the present paper focuses on these two endpoints.
Subject(s)
Dermatitis, Contact/etiology , European Union , Hazardous Substances/classification , Hazardous Substances/toxicity , Occupational Exposure/classification , Occupational Exposure/legislation & jurisprudence , Respiratory System/drug effects , Skin/drug effects , Dermatitis, Contact/pathology , Dermatitis, Contact/physiopathology , Female , Germany , Guidelines as Topic , Humans , Internationality , Male , Occupational Exposure/adverse effects , Occupational Exposure/standards , Pregnancy , Toxicity Tests , WorkplaceABSTRACT
The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In humans, no evidence of skin irritation was found at concentrations of 2-10%. Undiluted, 11 materials evaluated caused moderate to severe eye irritation. As current end product use levels are between 0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to elicit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that 2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no safety concerns regarding BCSA under the present levels of use and exposure.
Subject(s)
Alcohols/chemistry , Alcohols/toxicity , Perfume/chemistry , Perfume/toxicity , Animals , Dermatitis, Allergic Contact , Dermatitis, Phototoxic , Eye Injuries/chemically induced , HumansABSTRACT
An evaluation and review of a structurally related group of fragrance materials.
Subject(s)
Acetates/chemistry , Acetates/toxicity , Perfume/chemistry , Perfume/toxicity , Acetates/pharmacokinetics , Animals , Humans , Hydrocarbons, Cyclic/chemistry , Hydrocarbons, Cyclic/pharmacokinetics , Hydrocarbons, Cyclic/toxicity , Perfume/pharmacokineticsABSTRACT
An evaluation and review of a structurally related group of fragrance materials.
Subject(s)
Cinnamates/toxicity , Perfume/toxicity , Propanols/toxicity , Skin/drug effects , Administration, Cutaneous , Allergens/classification , Allergens/pharmacokinetics , Allergens/toxicity , Animals , Cinnamates/classification , Cinnamates/pharmacokinetics , Consumer Product Safety , Esters , Humans , Noxae/classification , Noxae/pharmacokinetics , Noxae/toxicity , Perfume/classification , Perfume/pharmacokinetics , Propanols/classification , Propanols/pharmacokinetics , Risk Assessment , Skin/metabolism , Skin Absorption , Skin Irritancy Tests , Skin Tests , Toxicity TestsABSTRACT
An evaluation and review of a structurally related group of fragrance materials.
Subject(s)
Norisoprenoids/toxicity , Perfume/toxicity , Skin/drug effects , Administration, Cutaneous , Administration, Oral , Allergens/classification , Allergens/pharmacokinetics , Allergens/toxicity , Animals , Consumer Product Safety , Dose-Response Relationship, Drug , Expert Testimony , Female , Humans , Male , Norisoprenoids/chemistry , Norisoprenoids/pharmacokinetics , Noxae/classification , Noxae/pharmacokinetics , Noxae/toxicity , Perfume/classification , Perfume/pharmacokinetics , Risk Assessment , Skin/metabolism , Skin/pathology , Skin Absorption , Skin Irritancy Tests , Toxicity TestsABSTRACT
An evaluation and review of a structurally related group of fragrance materials.
Subject(s)
Cyclooxygenase Inhibitors/toxicity , Noxae/toxicity , Perfume/toxicity , Salicylates/toxicity , Skin/drug effects , Allergens/classification , Allergens/pharmacokinetics , Allergens/toxicity , Animals , Consumer Product Safety , Cyclooxygenase Inhibitors/classification , Cyclooxygenase Inhibitors/pharmacokinetics , Dose-Response Relationship, Drug , Expert Testimony , Humans , Noxae/classification , Noxae/pharmacokinetics , Perfume/pharmacokinetics , Risk Assessment , Salicylates/classification , Salicylates/pharmacokinetics , Skin/metabolism , Skin Absorption , Skin Irritancy Tests , Skin Tests , Toxicity TestsABSTRACT
MON 863, a genetically engineered corn variety that contains the gene for modified Bacillus thuringiensis Cry3Bb1 protein to protect against corn rootworm, was tested in a 90-day toxicity study as part of the process to gain regulatory approval. This study was reanalyzed by Séralini et al. who contended that the study showed possible hepatorenal effects of MON 863. An Expert Panel was convened to assess the original study results as analyzed by the Monsanto Company and the reanalysis conducted by Séralini et al. The Expert Panel concludes that the Séralini et al. reanalysis provided no evidence to indicate that MON 863 was associated with adverse effects in the 90-day rat study. In each case, statistical findings reported by both Monsanto and Séralini et al. were considered to be unrelated to treatment or of no biological or clinical importance because they failed to demonstrate a dose-response relationship, reproducibility over time, association with other relevant changes (e.g., histopathology), occurrence in both sexes, difference outside the normal range of variation, or biological plausibility with respect to cause-and-effect. The Séralini et al. reanalysis does not advance any new scientific data to indicate that MON 863 caused adverse effects in the 90-day rat study.
Subject(s)
Endotoxins/adverse effects , Endotoxins/genetics , Food Industry/standards , Food, Genetically Modified/standards , Zea mays/genetics , Animals , Food, Genetically Modified/adverse effects , Reproducibility of Results , Time FactorsABSTRACT
The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.
