2-Hydroxy-4-methoxybenzophenone (2H4MBP) is approved by the U.S. Food and Drug Administration for use in sunscreens and other personal products in concentrations of up to 6% either alone or in combination formulations and as an indirect food additive in acrylic and modified acrylic plastics that come into contact with food. 2H4MBP was nominated to the National Toxicology Program by the National Cancer Institute due to widespread exposure via sunscreen use and lack of carcinogenicity data. 2H4MBP was also nominated by a private individual to ascertain genotoxic potential. Male and female Sprague Dawley (Hsd:Sprague Dawley SD) rats (after weaning) and B6C3F1/N mice were exposed to 2H4MBP (greater than 99% pure) in feed for 2 years. Perinatal studies and 14-week interim evaluations were also conducted in rats. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli.
Two-year Study in Rats
Beginning on gestation day (GD) 6, groups of 42, 35, 35, and 43 F0 time-mated female rats were fed diets containing 0, 1,000, 3,000, and 10,000 ppm 2H4MBP, respectively, for 39 days. Groups of 50 (1,000 and 3,000 ppm) or 60 (0 and 10,000 ppm) F1 rats per sex continued on study after weaning and were fed diets containing the same exposure concentrations for 105 weeks; 10 F1 rats per sex from the 0 and 10,000 ppm groups were evaluated at 14 weeks. Dietary concentrations of 1,000, 3,000, and 10,000 ppm resulted in average daily doses of approximately 58, 168, and 585 mg 2H4MBP/kg body weight for males and 60, 180, and 632 mg/kg for females.
Survival of all exposed groups of F1 male and female rats was not significantly different from that of the control groups. Over the course of the study, mean body weights of F1 males and females in the 10,000 ppm exposure groups were 10–25% lower than those of the control groups. After week 77, F1 female mean body weights in the 3,000 ppm exposure group were 10% lower than those of the control group. Feed consumption by exposed groups of F1 males and females was generally similar to that by the control group throughout the study.
In the brain, the occurrence of malignant meningiomas in males at the end of the 2-year study was 0/50, 1/50, 3/50, and 0/50. One male in the 3,000 ppm group had a malignant meningioma in the spinal cord.
In the thyroid gland, the incidence of C-cell adenoma in 3,000 ppm females was significantly greater than that in the control group at the end of the 2-year study.
In the uterus, the incidence of stromal polyp in 3,000 ppm females was significantly increased. A significantly increased incidence of atypical endometrium hyperplasia of the uterus also occurred at 3,000 ppm; however, the incidence of adenocarcinoma was significantly decreased in this group.
In the adrenal cortex, the incidences of focal hypertrophy were significantly increased in 1,000 and 3,000 ppm females at the end of the 2-year study.
In the testes, the incidence of interstitial cell hyperplasia occurred with a positive trend at the end of the 2-year study.
Two-year Study in Mice
Groups of 50 male and 50 female mice were fed diets containing 0, 1,000, 3,000, or 10,000 ppm 2H4MBP (equivalent to average daily doses of approximately 113, 339, and 1,207 mg 2H4MBP/kg body weight for males and 109, 320, and 1,278 mg/kg for females) for 104 (females) or 105 (males) weeks. Survival of all exposed groups of male and female mice was not significantly different from that of the control groups. Mean body weights of 1,000 and 3,000 ppm males and females were within 10% of those of the control groups throughout the study. Mean body weights of 10,000 ppm males and females were at least 10% lower than those of the control groups generally after weeks 17 and 12, respectively. Feed consumption by exposed groups of males and females was not significantly different from that by the control groups.
The incidences of pigment in the bone marrow were significantly increased in 10,000 ppm males and females. The incidences of pigment in the spleen were significantly increased in 10,000 ppm males and 3,000 and 10,000 ppm females.
In the liver, the incidence of hepatocyte syncytial alteration was significantly increased in all exposed groups of males.
In the kidney, the incidence of renal tubule cytoplasmic alteration was significantly increased in 10,000 ppm males. The incidence of osseous metaplasia was significantly increased in 10,000 ppm females compared to the control group.
Results of bacterial mutagenicity tests conducted using standard testing approaches with the same lot of 2H4MBP tested in the 2-year studies were negative in TA98 and TA100, as well as in Escherichia coli strain WP2 uvrA pKM101, with and without rat liver S9.
Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenic activity of 2H4MBP exposure in male Hsd:Sprague Dawley SD rats based on the occurrence of malignant meningiomas in the brain. There was equivocal evidence of carcinogenic activity in female Hsd:Sprague Dawley SD rats based on the increased incidence of thyroid C-cell adenomas and the increased incidence of uterine stromal polyps. There was no evidence of carcinogenic activity in male or female B6C3F1/N mice at exposure concentrations of 1,000, 3,000, and 10,000 ppm.
Increases in the incidences of nonneoplastic lesions of the testis in male rats and of the uterus and adrenal cortex in female rats occurred with exposure to 2H4MBP. Increases in the incidences of nonneoplastic lesions of the bone marrow (males and females), spleen (males and females), kidney (males and females), and liver (males) in mice occurred with exposure to 2H4MBP.
National Toxicology Program (NTP). 2020. NTP technical report on the toxicology and carcinogenesis studies of 2-hydroxy-4-methoxybenzophenone (CASRN 131-57-7) administered in feed to Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice. Research Triangle Park, NC: National Toxicology Program. Technical Report 597. https://doi.org/10.22427/NTP-TR-597