Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of the ESSCA network, 2015-2018.

BACKGROUND: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. OBJECTIVES: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. MATERIALS AND METHODS: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. RESULTS: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. CONCLUSIONS: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.

Derivation of cancer no significant risk levels and screening safety assessment for 2-nitropropane in spray products.

Two proposition 65 no-significant-risk level (NSRL)-type values were derived for 2-nitropropane (2-NP), in the absence of a Californian published NSRL. In addition, a safety assessment was performed based on estimated typical consumer inhalation and dermal exposure to 2-NP during indoor application of paint from a spray can containing the solvent 1-nitropropane. For the NSRL derivation, benchmark dose (BMD) modeling was performed using hepatocellular carcinoma incidence data from 2-NP single exposure inhalation studies in Sprague-Dawley rats. Several BMD models provided an acceptable fit for the male rat hepatocellular carcinoma incidence data (gamma, log-probit, log-logistic and multistage); therefore, the mean of the BMD lower limits from each model were used as the point of departure to derive the inhalation cancer potency. The oral human cancer potency was derived from the inhalation human cancer potency based on the ratio of the uptake factors for inhalation vs. oral routes. The derived inhalation and oral NSRLs are 67 µg/day and 32 µg/day, respectively. For the inhalation and dermal exposure assessment, three key factors were analyzed: the 2-NP residual concentration in the spray paint product, the mass of spray paint used and the frequency of use. Based on the screening exposure assessment, potential consumer inhalation and dermal exposure to 2-NP from indoor application of paint from a spray can does not exceed our proposed NSRLs, and a warning label is therefore not required for spray can products containing the solvent 1-nitropropane where 2-NP is a minor contaminant.

Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 2. Patch test relationship to formaldehyde contact allergy, experimental provocation tests, amount of formaldehyde released, and assessment of risk to consumers allergic to formaldehyde.

This is the second part of an article on formaldehyde-releasers in cosmetics. The patch test relationship between the releasers in cosmetics to formaldehyde contact allergy is reviewed and it is assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals with contact allergy to formaldehyde. There is a clear relationship between positive patch test reactions to formaldehyde-releasers and formaldehyde contact allergy: 15% of all reactions to 2-bromo-2-nitropropane-1,3-diol and 40-60% of the reactions to the other releasers are caused by a reaction to the formaldehyde in the test material. There is only fragmented data on the amount of free formaldehyde in cosmetics preserved with formaldehyde donors. However, all releasers (with the exception of 2-bromo-2-nitropropane-1,3-diol, for which adequate data are lacking) can, in the right circumstances of concentration and product composition, release >200 p.p.m. formaldehyde, which may result in allergic contact dermatitis. Whether this is actually the case in any particular product cannot be determined from the ingredient labelling. Therefore, we recommend advising patients allergic to formaldehyde to avoid leave-on cosmetics preserved with quaternium-15, diazolidinyl urea, DMDM hydantoin, or imidazolidinyl urea, acknowledging that many would tolerate some products.

Evaluation of carcinogenic responses in the Eker rat following short-term exposure to selected nephrotoxins and carcinogens.

This study examined the response of the Eker rat to nephrotoxic compounds and to genotoxic nonrenal carcinogens. Groups of male Eker rats received either no treatment; a vehicle treatment; treatment with a noncarcinogenic nephrotoxin (aluminum nitrilotriacetate, 2 mg/kg/day of aluminum, intraperitoneally, 3 days per week or cyclosporine A, 30 mg/kg/day, orally by gavage, 7 days/week); or treatment with a genotoxic nonrenal carcinogen (furan, 8 mg/kg/day, orally by gavage, 5 days/week or 2,4-diaminotoluene, 6.5 mg/kg/day, orally by gavage, 7 days/week or 2-nitropropane, 89 mg/kg/day, orally by gavage, 3 days/week). Duration of treatment was 4 and/or 6 months. Tissues from the Eker rats were evaluated microscopically and numbers of proliferative renal lesions were counted. Administration of nephrotoxic compounds (Al-NTA and cyclosporine) significantly increased the number of preneoplastic and neoplastic renal lesions in the Eker rat compared to concurrent vehicle controls. The genotoxic nonrenal carcinogens had no consistent effect on numbers of preneoplastic or neoplastic renal lesions and did not produce neoplasms in the expected target organ (liver).

Chronic inhalation exposure of rats to nitromethane.

Male and female Long-Evans rats were housed in inhalation chambers and exposed to vapors of nitromethane (NM) at either 100 or 200 ppm. The animals were exposed 7 hr per day, 5 days per week for 2 years. Control groups of rats were also housed in a similar inhalation chamber, but NM was not introduced into the chamber. The animals were observed daily for signs of pharmacologic or toxicologic effect and body weights were recorded periodically. At the 2-year termination of the exposure period, clinical laboratory examinations (serum chemistry and hematology) were performed on selected animals and all surviving animals were sacrificed. All animals were necropsied and subjected to a thorough histopathologic examination. During the study there were no pharmacologic effects from exposure to NM at either 100 or 200 ppm. There was no effect on mortality on either sex at either exposure level. Body weights of male rats exposed to NM were not significantly different from those of control rats, but the body weights of female rats of both exposure groups were slightly less than their controls. There was no effect of exposure of rats of either sex to either level of NM on hematology. There were no clinically significant effects on serum chemistry. There were no effects of exposure to NM on organ weights. There were no significant differences in the nonneoplastic or neoplastic pathology related to exposure to NM.

Dose-dependent emergence of preneoplastic foci in rat livers after exposure to 2-nitropropane.

Male and female Sprague-Dawley rats, 4-6 days old were exposed for 3 weeks (6 h/day, 5 days/week) to 2-nitropropane vapours of 0, 25, 40, 50, 80 and 125 ppm. One week later polychlorinated biphenyls (Clophen A50, 10 mg/kg body weight) were administered for promotion twice a week for 8 weeks. Thirteen weeks after starting the experiments the logarithms of the numbers of preneoplastic liver foci deficient in adenosine-5'-triphosphatase were found to be linearly related to the exposure concentrations of 2-nitropropane. Male rats exhibited an approximately four times lower foci incidence than females.

Comparison of acute toxic effects of intraperitoneally injected nitromethane and nitroethane in rats.

Male 3-month-old Wistar rats dosed i.p. with 200 mg/kg of nitromethane or -ethane showed increased acid proteinase activity in the brain 4 h after the injection. The change was accompanied by a marginal increase in the cerebral glutathione concentration. Nitroethane caused enhanced epoxide hydrolase and UDP-glucuronosyltransferase activity in the hepatic microsomal fraction up to 48 h while 7-ethoxycoumarin o-deethylase decreased. These biochemical changes were accompanied by proliferation of smooth endoplasmic reticulum and degranulation and disorganization of the rough endoplasmic reticulum of the nitroethane-exposed liver cells. The hepatic effects of nitromethane were restricted to decreased cytochrome c reductase activity with proliferation of smooth endoplasmic reticulum. The results point at limited peroxidative damage possibly involving reduction of the nitrogroup.