Toxicology studies of trimethylolpropane triacrylate (technical grade) (CAS No. 15625-89-5) in F344/N rats, B6C3F1 mice, and genetically modified (FVB Tg.AC hemizygous) mice (dermal studies).

Abstract

Trimethylolpropane triacrylate is a multifunctional monomer with a wide range of industrial applications. It is used in the production of ultraviolet-curable inks, electron beam irradiation-curable coatings, and polymers and resins; as a component of photopolymer and flexographic printing plates and photoresists; and as an ingredient in acrylic glues and anaerobic sealants. The chemical is also used in paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Trimethylolpropane triacrylate was nominated by the National Cancer Institute for testing due to its high production volume and use, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were administered technical grade trimethylolpropane triacrylate (it is reactive and therefore not available as pure trimethylolpropane triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade trimethylolpropane triacrylate in acetone for 6 months. Genetic toxicology studies were conducted in B6C3F(1) and Tg.AC hemizygous mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Dosed rats had irritation at the site of application; this clinical finding was most commonly seen in rats administered 50 mg/kg or greater. Male and female rats had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, inflammation of the epidermis and dermis, ulceration, epidermal degeneration, and parakeratosis at the site of application. 2-WEEK STUDY IN B6C3F(1) MICE: Groups of five male and five female B6C3F(1) mice were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 16 days. All mice survived to the end of the study. The final mean body weight gain of 200 mg/kg males was less than that of the vehicle controls; 100 and 200 mg/kg females had significantly increased final mean body weights. Irritation at the site of application occurred in all dosed males, all 100 and 200 mg/kg females, and one 50 mg/kg female. Thymus weights of males administered 50 mg/kg or greater were significantly decreased. Dosed male and female mice had epidermal hyperplasia, hyperkeratosis, chronic active inflammation of the dermis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, and/or suppurative inflammation of the epidermis at the site of application. Atrophy of the thymus occurred in 100 and 200 mg/kg male mice. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Irritation at the site of application was noted in five males and all females administered 12 mg/kg. Hematology results indicated that trimethylolpropane triacrylate at the doses selected induced a neutrophil count increase at 12 mg/kg that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Thymus weights of 12 mg/kg males and 0.75 and 12 mg/kg females were decreased. Incidences of epidermal hyperplasia, degeneration, and necrosis (females only); chronic active inflammation of the dermis, hyperkeratosis, and sebaceous gland hyperplasia were generally increased at the site of application in 1.5 mg/kg or greater males and in 3 mg/kg or greater females. 3-MONTH STUDY IN B6C3F(1) MICE: Groups of 10 male and 10 female B6C3F(1) mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All animals survived to the end of the study; mean body weights of dosed groups were similar to those of the vehicle controls. Irritation at the site of application occurred in male and female mice administered 12 mg/kg. Hematology results indicated that trimethylolpropane triacrylate induced a neutrophil count increase at 12 mg/kg that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Increased incidences of several nonneoplastic lesions occurred at the site of application in 3 mg/kg and greater males and females, including hyperplasia of the epidermis, hyperkeratosis, epidermal degeneration (except 3 mg/kg females) and necrosis, chronic active inflammation of the dermis, and sebaceous gland hyperplasia. Epidermal suppurative inflammation and necrosis and dermal fibrosis occurred in 12 mg/kg males and females. 6-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 28 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 microg 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks; the dosing volume was held constant at 100 microL. Survival and mean body weights of dosed groups were similar to those of the vehicle controls throughout the study. Treatment-related clinical findings included papillomas at the site of application in 3 mg/kg and greater males and 6 and 12 mg/kg females. The heart weights of males and females administered 12 mg/kg and the kidney and lung weights of 12 mg/kg females were significantly increased. The lung weights of 6 and 12 mg/kg males and females were decreased. Squamous cell neoplasms at the site of application were associated with dermal application of trimethylolpropane triacrylate. At 6 months, the incidences of squamous cell papilloma were significantly increased in 6 and 12 mg/kg males and females. One female in each of the 1.5, 6, and 12 mg/kg groups also had squamous cell carcinoma. The incidence of squamous cell papilloma of the forestomach in 12 mg/kg females was significantly greater than that in the vehicle control group. Nonneoplastic skin lesions at the site of application in dosed mice included epidermal hyperplasia, hyperkeratosis, and chronic active inflammation. A hematopoietic disorder (myelodysplasia) also occurred in some 12 mg/kg males and females.

Genetic toxicology: No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from male or female B6C3F(1) mice treated with trimethlylolpropane triacrylate by skin painting for 3 months. Similarly, no increase in micronucleus frequency was seen in male or female Tg.AC hemizygous mice administered trimethylolpropane triacrylate by skin painting for 6 months.

Contact hypersensitivity studies: Studies were conducted with female BALB/c mice to evaluate the potential for trimethylolpropane triacrylate to induce contact hypersensitization. In an irritancy study in which the chemical, in acetone, was applied to the ear, the maximal nonirritating and minimal irritating doses were 0.1% and 0.25% trimethylolpropane triacrylate. No significant differences in the percentage of ear swelling occurred between trimethylolpropane triacrylate-sensitized and -challenged mice and background controls at 24 or 48 hours after dosing. The local lymph node assay indicated no significant increase in lymph node cell proliferation in mice administered trimethylolpropane triacrylate compared to that in the vehicle controls. Testing for sensitizing potential using the mouse ear swelling test and local lymph node assay failed to indicate trimethylolpropane triacrylate as a potential contact sensitizer.

Conclusions: Male and female Tg.AC hemizygous mice dosed with trimethylolpropane triacrylate for 6 months had significantly increased incidences and multiplicity of papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in dosed female mice. Increased incidences of forestomach squamous cell papilloma in female mice may have been related to chemical administration. Increased incidences of minimal to moderate (mostly mild) hyperplasia of the epidermis, hyperkeratosis, and chronic active inflammation also occurred at the site of application. A hematopoietic disorder (myelodysplasia) also occurred in exposed male and female mice.