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.

Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local lymph node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining lymph node cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.

Reliable exposure information for cosmetic and other personal care products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of product applied, and the frequency of use. To obtain current data, a study to assess consumer use practices was undertaken. Three widely used types of cosmetic products - facial cleanser, hair conditioner, and eye shadow - were included in the study. Three hundred and sixty women, ages 18-69 years, who regularly use the products of interest, were recruited nationwide within the US. Subjects were provided with a new container of the brand of product they normally use and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analyses of the data were conducted to derive summary distributions of use patterns. The mean and median usage per application, respectively, for the three product types were: facial cleanser, 2.57 g and 2.11 g; hair conditioner, 13.13 g and 10.21 g; and eye shadow, 0.03 g and 0.009 g. The mean and median usage per day for the three product types was: facial cleanser, 4.06 g and 3.25 g; hair conditioner, 13.77 g and 10.62 g; and eye shadow, 0.04 g and 0.010 g. The mean number of applications per day for facial cleanser, hair conditioner, and eye shadow was 1.6, 1.1, and 1.2, respectively. This study provides an estimate of current exposure information for commonly used products which will be useful for risk assessment purposes.

Accurate exposure information for cosmetic products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of cosmetic product applied, and the frequency of use. To obtain current data, a study to assess consumer use practices was undertaken. The study included three widely used cosmetic product types: lipstick, body lotion, and face cream. Three hundred and sixty women, ages 19–65 years, who regularly use the products of interest, were recruited at ten different geographical locations within the US. The number of recruits was chosen to ensure a minimum of 300 completes per product type. Subjects were provided with prototype test products, and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analysis of the data was conducted to derive summary distribution of use patterns. The mean and median usage per application, respectively, for the three products was: face cream, 1.22g and 0.84g; lipstick, 10mg and 5mg; and body lotion, 4.42g and 3.45g. The mean and median usage per day for the three products was: face cream, 2.05g and 1.53g; lipstick, 24mg and 13mg; and body lotion, 8.70g and 7.63g. The mean number of applications per day for face cream and lipstick was 1.77 and 2.35, respectively. For body lotion, the mean number of applications per day was dependent on body area, and was 2.12, 1.52, 1.11, 0.95, 0.43, 0.26, and 0.40 for hands, arms, legs, feet, neck and throat, back, and other body areas, respectively. The effect of product preference on use practices was also investigated. This study provides current cosmetic exposure information for commonly used products which will be useful for risk assessment purposes.

The Research Institute for Fragrance Materials Inc. (RIFM) has approached sensitization studies with fragrance materials as primary prevention of sensitization in the healthy, normal population. Secondary prevention, or avoidance of elicitation, most often suggested by dermatologists for patients presenting with dermatitis, has not been part of its program effort. Historically, RIFM evaluated the sensitization potential of fragrance materials using the human maximization test method; no animal models were used. In general, petrolatum was used as the vehicle. This is a harsh procedure whose main use may provide a measure of the uppermost limits of sensitization. Treating skin with sodium lauryl sulfate may be problematic and finding a laboratory to conduct the study may also be difficult. In addition, using a human predictive test method for both hazard and safety assessments is not ideal. The current practice involves a hazard assessment using an animal model, followed by a safety assessment in a human repeated-insult patch test (HRIPT). The animal test method is used to identify the sensitization potential and a no-effect level. Following a review of the no-effect level and the maximum skin level, a safety assessment in humans can be conducted. RIFM also modified the original vehicle used in sensitization testing, since petrolatum presents two major difficulties: solubility and inconsistent effects on skin penetration. Since the greatest exposure to fragrance materials is considered to be from a cologne-type product, ethanol was chosen as a more realistic vehicle. Further modification resulted in combinations of ethanol and diethyl phthalate, due to diethyl phthalate’s use in many perfume formulations as a solvent and fluidizer. Human testing should not be conducted as a hazard assessment. If conducted as a safety study, induction of sensitization should be a rare occurrence. Thus, follow-up studies are not meaningful since the number of sensitized volunteers would be low. However, following a series of the RIPTs with various concentrations of hydroxycitronellal, RIFM identified a group of 41 individuals who became sensitized. An extensive 3-phase use study, with 3 diagnostic patch tests and 4 whole-body dermatological examinations showed that most subjects were able to use a bar soap, a moisurizing lotion and cologne-type products with up to 1% hydroxycitronellal. In subjects where sensitization was induced by predictive testing, no serious recurring adverse dermatological conditions developed.

7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexa-methylcyclopenta-gamma-2-be nzopyran (HHCB) are two large volume fragrance ingredients widely used in consumer products. As part of the risk evaluation, the systemic exposures to these materials was determined in rats under occlusion and in humans under simulated conditions of exposure. Ring 14C-labeled AHTN or HHCB were applied dermally in alcoholic solutions to rats at doses of 4.5 mg/kg and occluded for 6 h. Urine, feces and air were collected for up to 120 h and analyzed for radioactivity. Pairs of rats were sacrificed periodically for analysis of tissues and organs. The total amount absorbed was approximately 19% for AHTN and 14% for HHCB. In both cases, significant amounts diffused into the skin, most of which was further absorbed but a significant amount of which was lost to surface dressing by reverse diffusion and/or desquamation. Ring 14C-labeled AHTN or HHCB were applied in alcoholic solutions without occlusion to three male volunteers at concentrations approximating that which might be encountered in a typical cologne type product. After a 6-h period, all material was removed from the surface of the skin. Blood, feces and urine were collected over a 5-day period. For both materials, levels in blood and plasma were below limits of detection at all times. Based on excretion, primarily in the urine, the total absorbed dose was approximately 1 and 0.1% for AHTN and HHCB, respectively. However, over the 5-day period, 14.5% of AHTN and 19.5% of HHCB was recovered from the skin in dressings over the site of application indicating that a 'reservoir' had formed in the skin but the material in the reservoir was lost, by desquamation and/or by reverse absorption, and not available systemically. A mean of 24% (AHTN) and 22% (HHCB) was shown to evaporate under the conditions of exposure.

Musk ketone, musk xylene, musk tibetene and moskene, synthetic musks used in fragrances, were applied dermally to rats in daily doses of 240 (musk ketone and musk xylene only), 75, 24 or 7.5 mg/kg body weight for 90 days. The chemically related musk ambrette, a known neurotoxin in rats, was used as a positive control. While musk ambrette was clearly neurotoxic and caused testicular atrophy, as had been previously reported, the other compounds tested caused neither effect. The only effects of application of these materials were some organ weight changes at the higher doses, but these were not associated with histopathological changes in any of the tissues. The no-effect levels were: musk ketone, 75 mg/kg for males and females; musk xylene, 75 mg/kg for males and 24 mg/kg for females; moskene, 24 mg/kg for males and 75 mg/kg (highest dose administered) for females; and musk tibetene, 75 mg/kg (highest dose) for males and females.

Contact DermatitisVolume 23, Issue 4 p. 249-249 An investigation of the potential for allergic contact sensitization of several oakmoss preparations R. A. Ford, R. A. Ford Research Institute for Fragrance Materials, 375 Sylvan Avenue, Englewood Cliffs, NJ 07632, USASearch for more papers by this authorA. M. Api, A. M. Api Research Institute for Fragrance Materials, 375 Sylvan Avenue, Englewood Cliffs, NJ 07632, USASearch for more papers by this author R. A. Ford, R. A. Ford Research Institute for Fragrance Materials, 375 Sylvan Avenue, Englewood Cliffs, NJ 07632, USASearch for more papers by this authorA. M. Api, A. M. Api Research Institute for Fragrance Materials, 375 Sylvan Avenue, Englewood Cliffs, NJ 07632, USASearch for more papers by this author First published: October 1990 https://doi.org/10.1111/j.1600-0536.1990.tb05041.xCitations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue4October 1990Pages 249-249 RelatedInformation

Hydroxycitronellal, an important ingredient in fragrances, was studied for its sensitizing potential in human skin. Fifteen human maximization tests were conducted with hydroxycitronellal obtained from four different sources at induction concentrations from 5 to 12%. No reactions were induced at 5% in two separate panels while 10% sensitized 2/25 panelists in one test but none in a second. Induction at 12% produced sensitization in 8 of 11 tests. Impurities do not appear to be a sensitizing factor. There is some evidence that the l-stereoisomer is a less potent sensitizer than the d-stereoisomer. In an initial modified human repeat-insult patch-test two positive reactions to challenge were observed among 197 panelists, one at a concentration of 5% and the other at 7.5%. When 100 of the non-reacting panelists were re-exposed in the same way, allergic sensitization reactions appeared during the induction period with concentrations as low as 2.5%. When 28 sensitized panelists were exposed to 1% concentrations in a simulated use test, there were three reactors. A no-effect level for sensitization has not been determined although the lowest concentrations tested were in the product usage range.

Vetiveryl acetate is a fragrance material prepared by the acetylation of vetiver oil. Three possible production processes yield complex mixtures that vary in composition based on the geographic and botanic origins of the starting material. These production processes result in four distinct commercial qualities of vetiveryl acetate that are used in perfumery. A sample of each commercial quality was tested in the Local Lymph Node Assay (LLNA) to characterize its sensitization potential and to compare the potency of each. The LLNAs were conducted according to the methods described in OECD Guideline 429. Groups of five CBA/J female mice were utilized throughout the study. Each material was tested at five dose levels ranging from 1% to 25% w/v in 1:3 ethanol:diethyl phthalate. The Stimulation Index (SI) values were calculated for each dose level based on pooled lymph nodes, and an SI of 3 or more was considered a positive response. Linear interpolation of the dose response data from each LLNA was used to derive an estimated concentration (EC3) required to elicit an SI value of 3. The EC3 value was then taken as a measure of relative potency and used to compare the sensitization potential between each quality. All four samples of vetiveryl acetate can be regarded as potential sensitizers because the tests resulted in SI values greater than 3. EC3 values ranged from 9.3% to 13.3% (2317 μg/cm 2 to 3325 μg/cm 2 ). The study demonstrated that there was little difference in the sensitization potential between each quality, and the materials are considered weak dermal sensitizers. The data from this study will be useful in guiding the direction of future human studies to confirm a No Expected Sensitization Induction Level (NESIL) and provide information to a Quantitative Risk Assessment (QRA) for these materials.

The in vitro human skin penetration of linalool (CAS# 78-70-6) was assessed in three vehicles relevant to fragrance exposure