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Benzyl acetate is used as a flavoring agent in foods, as a fragrance in soaps and perfumes, as a solvent for cellulose acetate and nitrate, and as a component of printing inks and varnish removers. The NTP previously studied the toxicology and carcinogenicity of this chemical in F344/N rats and B6C3F1 mice using the gavage route of administration and corn oil as a vehicle. Benzyl acetate increased the incidences of pancreatic acinar cell adenomas in male rats and the incidences of hepatocellular adenomas and forestomach neoplasms in male and female mice. Because of the confounding effect of corn oil on the incidences of pancreatic neoplasms and because of controversy over the use of the gavage route of administration, the NTP decided to restudy benzyl acetate using the dosed feed route of administration. In these repeat studies, male and female F344/N rats and B6C3F1 mice received benzyl acetate (at least 98% pure) in feed for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium nunnery, cultured Chinese hamster ovary cells, LS178Y mouse lymphoma cells, Drosophila melanogaster, and mouse bone marrow and peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 3,130, 6,250,12,500, 25,000, or 50,000 ppm (0, 230, 460, 900,1,750, or 3,900 mg/kg body weight for males and 0, 240, 480, 930,1,870, or 4,500 mg/kg for females) benzyl acetate for 13 weeks. Nine male and nine female rats receiving 50,000 ppm benzyl acetate died or were killed moribund between weeks 2 and 8 of the study. The mean body weight gain and the final mean body weight of 25,000 ppm males were significantly lower (P</=0.01) than those of the control group. Feed consumption by exposed rats, except the 25,000 and S0,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been due to toxicity or decreased palatability. Tremors and ataxia occurred only in the 50,000 ppm rats. These findings were first observed on day 15 in nine males and six females and continued until the end of the study. Cholesterol levels in 12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were lower than those in the controls. Chemical-related lesions occurred in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles occurred in most male and female 50,000 ppm rats. This effect was observed in the 1,000 mg/kg group in the previous gavage study (NTP, 1986). 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3, 130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 425, 1,000, 2,000, 3,700, or 7,900 mg/kg body weight for males and 0, 650, 1,280, 2,980, 4,300, or 9,400 mg/kg for females) benzyl acetate. One 50,000 ppm male mouse died and one 50,000 ppm female mouse was killed moribund before the end of the study. Mean body weight gains and final mean body weights of all exposed male and female mice were significantly lower than those of the controls and the mean body weight gains decreased with increased exposure level. Feed consumption by 3,130 ppm males and all exposed females was lower than that by the controls. Tremors occurred only in females and were first observed on day 16 in three females receiving 50,000 ppm, day 94 in one female receiving 25,000 ppm, and day 93 in one female receiving 12,500 ppm. The tremors continued until the end of the study. Necrosis of the brain involving the hippocampus occurred in four 50,000 ppm mice, one male and three females. Hepatocellular necrosis also occurred in the male with brain lesions. On reexamination of the previous 13-week gavage study (NTP, 1986), a similar lesion was seen in the brain of one 1,000 mg/kg female mouse; none were seen in 1,000 mg/kg male mi male mice. The lesion was less severe than that described in the present dosed feed study. The highest dose used in the gavage study was 1,000 mg/kg compared to an estimated high dose of 7,200 mg/kg for the feed study. 2-YEAR STUDY IN RATS: The doses selected for the 2-year feed study of benzyl acetate in F344/N rats were based on lower survival, mean body weights, and feed consumption, and on increased incidences of histopathologic brain lesions in 50,000 ppm male and female rats in the 13-week study. Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 3,000, 6,000, or 12,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of exposed rats was similar to that of the controls. The mean body weights of the 12,000 ppm males and exposed females were approximately 5&percnt; lower than those of the controls throughout most of the study. The feed consumption by 12,000 ppm males was slightly lower than that by the controls. Dietary levels of 3,000, 6,000, and 12,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 130, 260, and 510 mg/kg body weight (males) and 145, 290, and 575 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were found that could be attributed to benzyl acetate administration. Pathology Findings: No compound-related increased incidences of neoplasms or nonneoplastic lesions occurred in male or female F344/N rats receiving benzyl acetate for as long as 2 years. 2-YEAR STUDY IN MICE: The doses selected for the 2-year feed study of benzyl acetate in B6C3F1 mice were based primarily on lower body weight gains and lower final mean body weights of exposed mice in the 13-week study. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 330, 1,000, or 3,000 ppm benzyl acetate for 2 years. Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology: Survival of all exposed mice, except the 3,000 ppm females, was similar to that of the control groups. Survival of 3,000 ppm females was significantly higher than that of the control group. Throughout the 2-year study, the mean body weights of 1,000 and 3,000 ppm males and females were 2&percnt; to 14&percnt; lower than those of the control groups. Dietary levels of 330, 1,000, and 3,000 ppm benzyl acetate were estimated to result in average daily consumption levels of 35, 110, and 345 mg/kg (males) and 40, 130, and 375 mg/kg (females). No biologically significant changes in hematology or clinical chemistry parameters were observed in mice receiving 330,1,000, or 3,000 ppm benzyl acetate. Pathology Findings: No increase in neoplasm incidence in mice could be attributed to benzyl acetate administration in feed. This contrasts with the previous finding that administration of benzyl acetate in corn oil by gavage once daily 5 days a week for as long as 2 years was carcinogenic to mice, causing increased incidences of hepatocellular neoplasms and forestomach neoplasms. The contrast in results between the two studies may be due to differences in the dose levels used (highest dose: gavage, 1,000 mg/kg a day; feed, 360 mg/kg a day). Dose-related increased incidences or severities of nonneoplastic nasal lesions occurred in the most posterior portions of the nasal cavity in all exposed groups. The lesions occurred in the majority of the exposed mice and consisted of atrophy and degeneration, primarily of the olfactory epithelium, cystic hyperplasia of the nasal submucosal glands, pigmentation of the mucosal epithelium, and exudate accumulation. GENETIC TOXICOLOGY: Benzyl acetate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). However, a positive response was observed for benzyl acetate, with and without S9, in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells. No significant increases in the frequencies of sister chromatid exchanges or chromosomal aberrations occurred in cultured Chinese hamster ovary cells treated with benzyl acetate in vitro, with or without S9, and no increases in either sister chromatid exchanges or chromosomal aberrations occurred in bone marrow cells of male mice treated in vivo by intraperitoneal injection. No increase in sex-linked recessive lethal germ cell mutations occurred in male Drosophila melanogaster administered benzyl acetate in feed or by injection. Tests of benzyl acetate for induction of micronucleated erythrocytes in bone marrow and peripheral blood of mice were also negative. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of benzyl acetate in male or female F344/N rats receiving 3,000, 6,000, or 12,000 ppm; however, rats may have tolerated higher doses. There was no evidence of carcinogenic activity of benzyl acetate in male or female B6C3F1 mice receiving 330, 1,000, or 3,000 ppm. Nasal lesions associated with benzyl acetate exposure in male and female mice included nasal mucosa atrophy and degeneration (primarily of the olfactory epithelium), cystic hyperplasia of the nasal submucosal gland, and luminal exudate and pigmentation of the nasal mucosal epithelium. In previous 2-year gavage studies (TR-250), benzyl acetate increased the incidence of acinar cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenic activity in female F344/N rats receiving 250 or 500 mg/kg a day. There was some evidence of carcinogenic activity in male and female B6C3F1 mice, indicated by the increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. Synonyms: acetic acid benzyl ester, acetic acid phenyl methyl ester, (acetoxymethyl)benzene, acetoxytoluene, benzyl ethanoate, phenylmethyl acetate
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice Feed Studies). 1261

N-Methylolacrylamide is a cross-linking agent used in adhesives, binders for paper, crease-resistant textiles, resins, latex film, and sizing agents. Toxicology and carcinogenesis studies were conducted by administering N-methylolacrylamide (98% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells; an in vivo bone marrow micronucleus test was performed with B6C3F1 mice. Neurobehavioral assays were performed during the 13-week studies. Sixteen-Day Studies: The doses of N-methylolacrylamide used ranged from 25 to 400 mg/kg. All rats that received 400 mg/kg died within 4 days, and 3/5 male rats that received 200 mg/kg also died before the end of the studies. Compound-related clinical signs seen with 200 mg/kg included ataxia, muscle tremors, and hyperirritability. Ataxia after dosing was observed from day 7 to the end of the studies for rats that received 100 mg/kg. The final mean body weight of male rats that received 100 or 200 mg/kg was 10% or 27% lower than that of the vehicle controls. The final mean body weight of female rats that received 200 mg/kg was 20% lower than that of the vehicle controls. Compound-related lesions in rats included hyperplasia of the bronchiolar and tracheal epithelium, dysplasia of the nasal and tracheal epithelium, centrilobular hepatocellular necrosis, lymphoid depletion of the spleen, and myelin degeneration of the lumbar ventral spinal nerve. All 5 male and 4/5 female mice that received 400 mg/kg N-methylolacrylamide died on the second day of the 16-day studies. The surviving female mouse in the 400 mg/kg group and the male and female mice in the 200 mg/kg groups were ataxic after they were dosed, starting on day 2. Weight changes were inconsistent among dose groups. Bronchial epithelial hyperplasia (mild) appeared to be dose related in males and females. Sinusoidal congestion of the liver and vacuolar degeneration of myocardial fibers were seen in males and females given 400 mg/kg. Thirteen-Week Studies: The doses of N-methylolacrylamide used ranged from 12.5 to 200 mg/kg. All rats that received 100 or 200 mg/kg died before the end of the studies. Rats that received 100 or 200 mg/kg had hind limb ataxia, which progressed to hind limb paralysis. Rats that received 50 mg/kg had hind limb ataxia beginning at week 8, which progressed to hind limb paresis by week 11. The final mean body weight of rats that received 25 or 50 mg/kg was 8% or 16% lower than that of the vehicle controls for males and 6% or 10% lower for females. In neurobehavioral assessments, decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and at doses as low as 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly increased for male and female rats that received 50 mg/kg. Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses. Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders at gross examination. All mice that received 200 mg/kg N-methylolacrylamide died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. A decreased relative testis weight was observed for mice that received 12.5 mg/kg or more. The relative kidney weights for male mice receiving 50 or 100 mg/kg were greater than that for vehicle controls. Neurobehavioral studies indicated decreased forelimb grip strength in male and female mice at doses as low as 25 mg/kg. An exaggerated startle response was seen for female mice given 100 mg/kg. A reduction in rotarod performance was seen for male and female mice receiving 100 mg/kg and for male mice receiving 25 mg/kg. Hepatocellular necrosis anmale mice receiving 25 mg/kg. Hepatocellular necrosis and thymic lymphocytic necrosis were compound-related effects in mice given 200 mg/kg N-methylolacrylamide. Hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were present in 3/10 female mice given 200 mg/kg, and cytoplasmic vacuolization of the adrenal cortex was seen with lower doses. Based on the results of these short-term studies, 2-year studies were conducted by administering 0, 6, or 12 mg/kg N-methylolacrylamide in water by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. Groups of 50 mice of each sex were administered 0, 25, or 50 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were within 6&percnt; of those of vehicle controls throughout most of the studies. Mean body weights of dosed mice were as much as 25&percnt; greater than those of vehicle controls for females and as much as 13&percnt; greater for males. The survival of female rats given 25 mg/kg per day was lower than that of vehicle controls after day 550, but survival of female rats given 50 mg/kg per day was not different from that of vehicle controls (vehicle control, 35/50; low dose, 22/50; high dose, 33/50). No differences in survival were observed between any other groups of rats or mice of either sex (male rats: 28/50; 22/50; 27/50; male mice: 30/50; 20/50; 21/50; female mice: 41/50; 35/50; 33/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In rats, no biologically important nonneoplastic or neoplastic lesions were attributed to administration of N-methylolacrylamide. Higher doses might have increased the sensitivity of the studies to determine the presence or absence of a carcinogenic response. In mice, the incidences of adenomas of the Harderian gland were increased in males given either dose of N-methylolacrylamide and in females given the top dose (male: vehicle control, 1/48; low dose, 14/49; high dose, 29/50; female: 5/47; 8/45; 20/48). The incidences of carcinomas of the Harderian gland were not significantly increased by N-methylolacrylamide administration (male: 1/48; 0/49; 2/50; female: 0/47; 3/45; 2/48). The incidences of hepatocellular adenomas were increased in male and female mice given 50 mg/kg N-methylolacrylamide (male: 8/50; 4/50; 19/50; female: 3/50; 4/50; 17/49). The incidences of hepatocellular carcinomas were also marginally increased in dosed male mice (male: 6/50; 13/50; 12/50; female: 3/50; 3/50; 2/49). Hepatocellular adenomas and carcinomas (combined) occurred with positive trends, and the incidences in male and female mice receiving 50 mg/kg were increased compared with those in the vehicle controls (male: 12/50; 17/50; 26/50; female: 6/50; 7/50; 17/49). Chronic inflammation and alveolar epithelial hyperplasia of the lung were observed at increased incidences in mice given N-methylolacrylamide. Sentinel mice were seropositive for Sendai virus at 18 months. The incidences of alveolar/bronchiolar adenomas (3/49; 6/50; 11/50) and carcinomas (2/49; 4/50; 10/50) were increased in male mice given 50 mg/kg. Alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a positive trend in male mice (5/49; 10/50; 18/50). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was increased in female mice given the top dose of 50 mg/kg (6/50; 8/50; 13/49). Ovarian atrophy was observed at increased incidences in female mice receiving N-methylolacrylamide (3/50; 39/45; 38/47). The incidences of benign granulosa cell tumors were also increased in the dosed groups (0/50; 5/45; 5/47). The incidence of adenomas of the pars distalis in high dose female mice was significantly lower than that in vehicle controls (13/49; 5/14; 4/43). Genetic Toxicology: N-Methylolacrylamide was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without exogenous metabolic activation. N-Methylolacrylamide induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells with and without metabolic activation. No increase in micronucleated polychromatic erythrocytes (PCEs) was observed in the bone marrow of B6C3F1 mice after intraperitoneal injection of N-methylolacrylamide. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg per day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. In rats, because no biologically important toxic effects were attributed to N-methylolacrylamide administration, somewhat higher doses could have been used to increase the sensitivity of these studies for determining the presence or absence of a carcinogenic response. In female mice, ovarian atrophy was compound related. Synonyms: N-(hydroxymethyl)acrylamide; N-(hydroxymethyl)-2-propenamide; N-methanolacrylamide; monomethylolacrylamide
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PMID:NTP Toxicology and Carcinogenesis Studies of N-Methylolacrylamide (CAS No. 924-42-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1270 32