https://www.scialliconsulting.com/publications/08%20Laufersweiler%20TTC.pdf

Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern

The objective of this study was to determine the frequency of reactivity to a series of commonly fragrances in dermatological patients. A total of 48 fragrances (FF) were chosen, based on the publication of Fenn in 1989 in which the lop 25 constituents of 3 types (1. perfumes, 2. household products, 3. soaps) of 400 commercial products on the US market had been determined. In a pilot study on a total of 1069 patients in 11 centres, the appropriate test concentration and vehicle were examined. For most fragrances, 1% and 5% were chosen, and petrolatum proved to be the best vehicle in comparison to isopropyl myristate and diethyl phthalate. In the main study, a set of 5 to 10 fragrances at 2 concentrations was patch tested in each centre on a minimum of 100 consecutive patients seen in the patch test clinic. These patients were also patch tested to a standard series with the 8% fragrance mix (FM) and its 8 constituents. In patients with a positive reaction to any of the 48 FF, a careful history with regard to past or present reactions to perfumed products was taken. A total of 1323 patients were tested in 11 centres. The 8% FM was positive in 89 patients (8.3% of 1072 patients). Allergic reactions to the constituents were most frequent to oak moss (24), isoeugenol (20), eugenol (13), cinnamic aldehyde (10) and geraniol (8). Reactions read as allergic on day 3/4 were observed only 10 × to 7 materials of the new series (Iso L: Super® (2), Lyral® (3), Cyclacet® (1), DMBCA (1), Vertofix® (1), citronellol (1) and amyl salicylate (1)). The remaining 41 fragrances were negative. 28 irritant or doubtful reactions on day 3/4 were observed to a total of 19 FF materials (more than 1 reaction: 5% citronellol (2), 1%amyl salicylate (2), 1%isononyl acetate (3), 0.1% musk xylol (2). 1%citral (2), and 1% ionone beta (2)). Clinical relevance of positive reactions to any of the FF series was not proved in a single case. This included the 4 reactions in patients who were negative to the 8% FM. In conclusion, the top 25 fragrances commonly found in various products caused few reactions in dermatological patients and these few appeared to be clinically irrelevant, with the possible exeption of Lyral®. However, this data should be interpreted in the light of the relatively small number of patients tested (only 100 in most centres).

Patch testing with fragrances: results of a multicenter study of the European Environmental and Contact Dermatitis Research Group with 48 frequently used constituents of perfumes.

Toxicology review and risk assessment of resorcinol: thyroid effects.

Gestational risk factors for Wilms' tumor were investigated in a pair-matched case-control study. Cases who were under 15 years of age at diagnosis during 1970-1983 were identified through the registries of the three main hospitals treating childhood cancer in the greater Philadelphia area. Controls were selected by random digit dialing and were matched to cases on race, birth date, and telephone area code and exchange. Because of a low participation rate among nonwhites, results are reported only for the 88 white matched pairs whose parents were interviewed by telephone. Of the hypothesized risk factors, maternal use of hair-coloring products in the year prior to the index child's birth (odds ratio, 3.6; P = 0.003) and hypertension or fluid retention during pregnancy (odds ratio, 5.0, P = 0.01) were significantly associated with increased risk of Wilms' tumor. Use of hair-coloring products was strongly associated with cases in which Wilms' tumor was diagnosed before 2 years of age (odds ratio, 15; P = 0.001). For two other gestational factors, tea drinking and vaginal infection, the odds ratios were significantly elevated for all cases and the effects were concentrated among the nongenetic cases. Bilateral cases had a significantly higher mean birth weight than did their controls. Older maternal age was significantly associated with the genetic form of Wilms' tumor. Adjustment for possible confounders and consideration of the time interval between the index pregnancy and the interview did not substantially alter the findings.

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Gestational Risk Factors for Wilms' Tumor: Results of a Case-Control Study

Aromatic amines are organic compounds that contain at least one amino group attached directly to an aryl moiety. Aromatic amines represent one of the most important classes of industrial and environmental chemicals. Many aromatic amines have been shown to be potent carcinogens, mutagens, skin sensitizers, and/or hematotoxicants capable of inducing methemoglobinemia. Since the introduction of substituted anilines and naphthylamines as intermediates for the manufacture of azo dyes in the mid-1800s, aromatic amines have found numerous uses in various industries. Substantial worker exposure to aromatic amines with subsequent induction of bladder cancer occurred before preventive measures were instituted. Beyond occupational exposure, humans may also be exposed to aromatic amines through environmental sources. At least three carcinogenic aromatic amines (4-aminobiphenyl, 2-naphthylamine, and o-toluidine) have been detected in cigarette smoke. Many commonly used pharmaceuticals contain or are aromatic amines. Owing to their hazard potential, aromatic amines have been the subject of many biomonitoring studies, making them model compounds in molecular dosimetry and epidemiology studies. Since extensive information is available on the metabolic pathways and, to a lesser extent, the mechanism(s) of action, aromatic amines have also become targets for genetic polymorphism studies with ultimate goals of identifying susceptible subpopulations and designing of strategies for cancer prevention and intervention. The multifaceted interest in aromatic amines has continued to attract a tremendous amount of scientific studies and attention. Since the publication of the previous edition of Patty's on aromatic amines, many reviews and important research articles on aromatic amines and halogenated nitroaromatics have been published. In addition, a number of heterocyclic aromatic amines have attracted increasing attention as carcinogens of environmental significance. In this chapter, we present an overview of the aromatic amine class as a whole with emphasis on recent studies, followed by an updated description on individual chemicals grouped into eight subgroups of structurally related compounds.


Keywords:

Aromatic amino compounds;
carcinogenicity;
halogenated derivatives;
hemoglobin binding;
mechanism of action;
methemoglobinemia;
mutagenicity;
nitro–amino compounds;
skin sensitization;
teratogenicity

Aromatic Amino and Nitro–Amino Compounds and Their Halogenated Derivatives

Teratological assessment of five oxidative hair dyes in the rat.

The oxidative dye N-phenyl-para-phenylenediamine was evaluated for teratogenic potential. The dye was administered by gavage to pregnant Sprague-Dawley rats at dose levels of 50, 100, and 200 mg/kg on gestation days six through fifteen. No signs of toxicity were observed during the treatment period. A significant reduction in mean maternal weight gain was noted during treatment at the high dose level of 200 mg/kg. The test material did not produce embryotoxic nor fetal toxic effects at dose levels utilized. Evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye treated and control groups. Oral exposure of dams to the positive control, Vitamin A, resulted in a significant increase in the number of litters with fetuses having external, visceral, and skeletal anomalies.

Evaluation of the teratogenic potential of the oxidative dye N-phenyl-para-phenylenediamine.

A quantitative in vitro assay for the evaluation of phototoxic potential of topically applied materials. II. Modification and assessment of low level activity

The oxidative dye 4-methyl-N-ethylamino phenol sulfate was evaluated for teratogenic potential. The dye was administered by gavage to pregnant Sprague-Dawley rats at dose levels of 300, 600, and 1200 mg/kg on gestation days six through fifteen. No signs of toxicity were observed during the treatment period. A significant reduction in mean maternal weight gain was noted during treatment at the high dose level of 1200 mg/kg. The test material did not produce embryotoxic nor fetal toxic effects at dose levels utilized. Evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye treated and control groups. Oral exposure of dams to the positive control, Vitamin A, resulted in a significant increase in the number of litters with abnormal fetuses.

R. W. Schnetzinger

Papers

Teratological assessment of five oxidative hair dyes in the rat.

Evaluation of the teratogenic potential of the oxidative dye N-phenyl-para-phenylenediamine.

A quantitative in vitro assay for the evaluation of phototoxic potential of topically applied materials. II. Modification and assessment of low level activity

Teratological Assessment of the Oxidative Dye 4-Methyl-N-Ethylamino Phenol Sulfate