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Cosmetic regulations prohibit animal testing for the purpose of safety assessment and recent registration, evaluation and authorization of chemicals guidance states that the local lymph node assay (LLNA) in mice shall only be conducted if in vitro data cannot give sufficient information for classification and labeling. However, Quantitative Risk Assessment for fragrance ingredients requires an NESIL (no expected sensitization induction level), a dose not expected to cause induction of skin sensitization in humans. In absence of human data, this is derived from the LLNA and it remains a key challenge for risk assessors to derive this value from nonanimal data. Here we present a workflow using structural information, reactivity data and KeratinoSens results to predict an LLNA result as a point of departure. Specific additional tests (metabolic activation, complementary reactivity tests) are applied in selected cases depending on the chemical domain of a molecule. Finally, in vitro and in vivo data on close analogues are used to estimate uncertainty of the prediction in the specific chemical domain. This approach was applied to three molecules which were subsequently tested in the LLNA and 22 molecules with available and sometimes discordant human and LLNA data. Four additional case studies illustrate how this approach is being applied to recently developed molecules in the absence of animal data. Estimation of uncertainty and how this can be applied to determine a final NESIL for risk assessment is discussed. We conclude that, in the data-rich domain of fragrance ingredients, sensitization risk assessment without animal testing is possible in most cases by this integrated approach.

Several aromatic aldehydes such as 3-(4-tert-butylphenyl)-2-methylpropanal were shown to adversely affect the reproductive system in male rats following oral gavage dose of ≥ 25 mg/kg bw/d. It was hypothesized that these aldehydes are metabolized to benzoic acids such as p-tert-butylbenzoic acid as key toxic principle and that Coenzyme A (CoA) conjugates may be formed from such acids. Here we performed a detailed structure activity relationship study on the formation of benzoic acids from p-alkyl-phenylpropanals and related chemicals in rat hepatocytes in suspension. Formation of CoA conjugates from either p-alkyl-phenylpropanals directly or from their benzoic acid metabolites was further assessed in plated rat hepatocytes using high resolution LC-MS. All of the test chemicals causing reproductive adverse effects in male rats formed p-alkyl-benzoic acids in rat hepatocytes in suspension. Compounds metabolized to p-alkyl-benzoic acids led to accumulation of p-alkyl-benzoyl-CoA conjugates at high and steady levels in plated rat hepatocytes, whereas CoA conjugates of most other xenobiotic acids were only transiently detected in this in vitro system. The correlation between this metabolic fate and the toxic outcome may indicate that accumulation of the alkyl-benzoyl-CoA conjugates in testicular cells could impair male reproduction by adversely affecting CoA-dependent processes required for spermatogenesis. This hypothesis prompted a search for new p-alkyl-phenylpropanal derivatives which do not form benzoic acid metabolites and the corresponding CoA conjugates. It was found that such metabolism did not occur with a derivative containing an o-methyl substituent, ie, 3-(4-isobutyl-2-methylphenyl)propanal. This congener preserved the fragrance quality but lacked the male reproductive toxicity in a 28-day rat study, as predicted from its in vitro metabolism., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The oxidized forms of the fragrance terpenes limonene and linalool are known to cause allergic contact dermatitis. Significant rates of contact allergy to these fragrances have been reported in European studies and in a recent worldwide study. Patch testing to oxidized terpenes is not routinely carried out either in the U.K. or in other centres internationally., Objectives: To investigate the prevalence of contact allergy to oxidized limonene and linalool in the U.K., Methods: Between 1 August 2011 and 31 December 2012, 4731 consecutive patients in 13 U.K. dermatology departments were tested for hydroperoxides of limonene 0·3% pet., hydroperoxides of linalool 1·0% pet., stabilized limonene 10·0% pet. and stabilized linalool 10·0% pet. Doubtful (?+) and equivocal (±) reactions were grouped together as irritant reactions., Results: Two hundred and thirty-seven patients (5·0%) had a positive patch test reaction to hydroperoxides of limonene 0·3% pet. and 281 (5·9%) to hydroperoxides of linalool 1·0% pet. Irritant reactions to one or both oxidized terpenes were found in 242 patients (7·3%). Eleven patients (0·2%) had a positive patch test reaction to the stabilized terpenes alone., Conclusions: This large, multicentre U.K. audit shows a significant rate of allergy to the hydroperoxides of limonene and linalool plus a high rate of irritant reactions. Testing to the oxidized forms alone captures the majority (97·0%; 411 of 422) of positive reactions; testing to nonoxidized terpenes appears to be less useful. We recommend that the hydroperoxides of limonene and linalool be added to an extended baseline patch test series., (© 2014 British Association of Dermatologists.)

Background: Work-associated respiratory symptoms may be caused by disorders of both the lower and upper respiratory tract. We propose that occupational exposures may initiate and/or trigger recurrent hyperkinetic laryngeal symptoms, predominantly episodic dyspnoea, dysphonia, cough and sensation of tension in the throat-work-associated irritable larynx syndrome (WILS)., Aims: To examine characteristics of individual and work-related factors that are associated with WILS, occupational asthma (OA) and work-exacerbated asthma (WEA)., Methods: Subjects with WILS, OA and WEA were identified from an occupational lung disease clinic. A review of 448 charts of patients attending the clinic between 2002 and 2006 was undertaken, with information entered onto a standardized abstraction form., Results: Fifty subjects were identified with OA, 40 with WEA and 30 with WILS. Subjects with the diagnosis of WILS were more likely to be female and more frequently reported symptoms of gastro-oesophageal reflux. The most common triggers of workplace symptoms in the WILS group were odours, fumes, perfumes and cleaning agents. Fourteen patients with WILS identified a specific precipitating event at the workplace at the time of the onset of their symptoms and five of these subjects presented to an emergency department within 24 h of the event., Conclusions: Dysfunction of the upper airway is an important cause of work-associated respiratory symptoms. The identification and management of WILS requires a multidisciplinary approach with a focus on modifying work-related and intrinsic factors that may perpetuate symptoms.

In this study, the nature of non-immune immediate contact reactions (NIICR) produced by cinnamic aldehyde, benzoic acid and sorbic acid were investigated, with particular interest in the 'quenching' ability of eugenol. Three groups of human subjects were studied, and the guinea-pig ear was also used as a model of NIICR. Cinnamic aldehyde, benzoic acid and sorbic acid were all able to produce NIICR in the majority of subjects studied. There was a strong correlation between the susceptibility of each subject to each urticant, but no correlation between the susceptibility to NIICR and age, atopic status or tanning ability. Eugenol caused a reduction in NIICR induced by all three urticants. This 'quenching' effect was apparent even when the eugenol was applied up to 60 min prior to application of cinnamic aldehyde, and its effect was not eliminated by washing. In the guinea-pig-ear model, ear thickening was induced by all three urticants, and this response was inhibited by eugenol.