Toxicity and carcinogenicity of riddelliine in rats and mice.

These investigations of riddelliine analyzed potential carcinogenesis and the utility of the female-rat/male-mouse design in bioassays and dose-response. Groups of 50 Fischer rats and B6C3F1 mice were gavage-administered riddelliine 5 days per week for 105 weeks. The dose levels for male rats were 0 or 1.0 mg/kg body weight; female rats 0, 0.01, 0.033, 0.1, 0.33, or 1.0 mg/kg; male mice 0, 0.1, 0.3, or 1.0, 3.0 mg/kg; and female mice 0 or 3.0 mg/kg. The dose groups were purposely designed to evaluate the dose-response relationship only in female rats and male mice. In rats, liver hemangiosarcoma, hepatocellular adenoma, and mononuclear cell leukemia were significantly increased in the 1.0 mg/kg male and female dose groups. Non-neoplastic lesions occurred in the liver and kidney of male and female rats. In mice, hemangiosarcomas increased significantly in the liver of males in the 3.0 mg/kg dose group. Alveolar/bronchiolar neoplasms in the 3.0 mg/kg dose group of female mice were significantly increased. Hepatocellular neoplasms were significantly decreased in the 1.0 mg/kg dose group of male and 3.0 mg/kg dose groups of male and female mice. Non-neoplastic lesions occurred in the liver and kidney of male and female, and lung and arteries of female mice. These studies demonstrate toxicity and carcinogenicity of riddelliine in rats and mice, and a dose-response relationship in female rats and male mice under the experimental conditions employed.

Carcinogenic activity of the flame retardant, 2,2-bis(bromomethyl)-1,3-propanediol in rodents, and comparison with the carcinogenicity of other NTP brominated chemicals.

Several brominated chemicals have been shown to be multisite-multispecies carcinogens in laboratory animals, and in this paper we report that the flame retardant, 2,2-bis(bromomethyl)-1,3-propanediol (BMP) is also a multisite carcinogen in both sexes of Fischer 344 rats and B6C3F1 mice. BMP was administered continuously in the diet for up to 2 yr to rats at doses of 0, 2,500, 5,000, or 10,000 ppm and to mice at doses of 0, 312, 625, or 1,250 ppm. Interim groups of rats were examined at 15 mo. An additional recovery group of male rats received the chemical for 3 mo at 20,000 ppm in the feed, and then the control diet for the remainder of the study. Chemical exposure caused neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small intestine, large intestine, mesothelium, kidney, urinary bladder, lung, thyroid gland, seminal vesicle, hematopoietic system, and pancreas in the male rat; mammary gland, oral cavity, esophagus, and thyroid gland in the female rat; lung, kidney, and Harderian gland in male mice; and subcutaneous tissue, lung, and Harderian gland in the female mouse. The recovery group of male rats presented with the same spectrum of treatment-related neoplasms as in the core study. In this recovery group, BMP (at 20,000 ppm) caused irreversible effects at numerous sites after 90 days of exposure that was not detectable by histologic examination, but without further exposure resulted in carcinogenic responses at 2 yr. BMP is mutagenic in the salmonella test, but it was not determined if the BMP-induced effects that eventually lead to development of neoplasms at multiple sites are the same in both species and in all organ systems affected.

Tumors of the bladder, kidney, and intestine of F344 rats and liver of B6C3F1 mice administered o-nitroanisole in feed.

o-Nitroanisole, a mutagenic intermediate used in the manufacture of azo dyes, was administered in feed for 2 years at concentrations of 0, 222, 666, or 2000 ppm to groups of 60 male and 60 female F344 rats. No significant increase in neoplasms occurred in these groups of rats. Additional (stop exposure) groups of 60 male and 60 female F344 rats received diets containing 0, 6000, or 18,000 ppm for 27 weeks followed by maintenance on control diets for up to an additional 77 weeks. Survival of the stop exposure groups was reduced because of the development of chemical related neoplasms of the urinary bladder. After 13, 28, 40, and 65 weeks on study, 10 rats per group were necropsied and evaluated for the presence of chemical associated lesions. Hyperplasia of the epithelium of the urinary bladder was significantly increased at all interim evaluations. A transitional cell carcinoma was observed at the 13-week evaluation in one male rat that received 18,000 ppm and thereafter transitional cell neoplasms of the bladder were present in male and female rats at each interim evaluation. Adenomatous polyps of the large intestine were significantly increased in groups that received 6000 or 18,000 ppm. In addition carcinomas of the large intestine were present in four males and two females that received 18,000 ppm. Hyperplasia of the transitional epithelium of the renal pelvis was significantly increased in groups of rats that received 6000 or 18,000 ppm and transitional cell papillomas were observed in three males and one female that received 18,000 ppm. Transitional cell carcinomas of the kidney occurred in one male that received 6000 ppm and six males and one female that received 18,000. Groups of 60 male and 60 female B6C3F1 mice received dietary concentrations of 0, 666, 2000, or 6000 ppm o-nitroanisole for 2 years. No stop exposure study was conducted with mice. The only neoplastic response observed in mice was in the liver of males; hepatocellular adenomas or carcinomas were increased in groups of male mice that received 2000 or 6000 ppm. No increase in neoplasms associated with chemical exposure occurred in female mice.

Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice.

The bioavailability and pharmacokinetics of zidovudine (3'-azido-3'-deoxythymidine) (AZT) were determined in female B6C3F1 mice after administration of 15, 30, and 60 mg/kg doses via oral gavage or intravenous injection. Three animals in each administration group were sacrificed, and blood samples were collected at each of the following times: 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 min after drug administration. Plasma zidovudine concentrations were determined by HPLC. After oral administration, mean maximum plasma concentrations (Cmax) of 9.1, 18.9, and 40.3 mg/liter were observed at 18.3, 21.7, and 15.0 min (tmax) for the 15, 30, and 60 mg/kg doses, respectively. Following intravenous administration, mean Cmax values of 15.9, 41.8, and 76.0 mg/liter were observed for the 15, 30, and 60 mg/kg doses, respectively. Nonlinear least squares regression of all data sets, using a 1/y weight, indicated that zidovudine disposition was best described by a one-compartment open model with first-order absorption, where appropriate, and first-order elimination. The mean elimination half-life values ranged from 17.3 to 19.9 min for the three intravenous doses and from 16.5 to 21.9 min for the three oral doses. The mean values for the apparent volume of distribution (Vd) ranged from 0.8 to 1.0 liter/kg following oral and intravenous administration. There were no significant differences in Vd between the oral and intravenous groups. The mean total body clearance values ranged from 28.9 to 34.3 ml/min/kg following intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic toxicity studies of t-butyl alcohol in rats and mice.

The purpose of this study was to evaluate the toxicity of t-butyl alcohol, an important commodity chemical, an additive to unleaded gasoline, and a contaminant of drinking water. Ninety-day toxicity studies were conducted in B6C3F1 mice and Fischer 344 (F344) rats of both sexes using dosed water. Dose levels of t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality was observed at the 4% level of both sexes and species. Weight-gain depression was present in all dose levels of male rats; 4% female rats; 1, 2, and 4% male mice; and 2 and 4% female mice. Water consumption was increased at lower dose levels in male rats and decreased in the higher dose levels of both sexes of rats and female mice. Clinical signs in rats were ataxia in both sexes and hypoactivity in males. Clinical signs in mice were ataxia, abnormal posture, and hypoactivity. In rats, urine volumes were reduced, in association with crystalluria. Gross lesions at necropsy were urinary tract calculi, renal pelvic and ureteral dilatation, and thickening of the urinary bladder mucosa. Microscopic lesions were hyperplasia of transitional epithelia and inflammation of the urinary bladder. In male rats treated with t-butyl alcohol, microscopic renal changes were suggestive of alpha-2 mu-globulin nephropathy. No-effect levels for the urinary tract lesions were 1% in male rats and mice (803.7 mg/kg/day for the male rats and 1565.8 mg/kg/day for the male mice) and 2% in female rats and mice (1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day for the female mice). The results indicate that in rodents the urinary tract is the target organ for t-butyl alcohol toxicity, and males are more sensitive to t-butyl alcohol toxicity than females.

Hematologic toxicity of AZT and ddC administered as single agents and in combination to rats and mice.

Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) were conducted in F344/N rats and B6C3F1 mice. The drugs were administered as single agents and in combination. In all studies, animals were treated by oral gavage twice a day, 7 days a week. In studies of the individual compounds, each was administered for 13 weeks at the following concentrations: AZT in rats, 0, 125, 250, 500, 1000 mg/kg and in mice, 0, 25, 50, 100, 400, 1000 mg/kg; ddC in rats and mice, 0, 250, 1000, 2000 mg/kg. Additional male rats and female mice that were treated with 0, 250, 1000, or 2000 mg/kg ddC and male and female mice treated with 0, 50, 400, 1000 mg/kg AZT were maintained for 30 days after treatment was stopped (at 94 days) to evaluate the reversibility of toxic effects. Hematologic variables were measured on Days 5, 23, and 94 (last day of dosing), and on Day 123 (after a 30-day period without treatment). AZT and ddC produced dose-related, poorly regenerative, macrocytic anemias as evidenced by decreases in erythrocyte counts, hematocrits, and hemoglobin concentrations and increases in mean corpuscular hemoglobin and mean corpuscular volume. Bone marrow samples in rats treated with AZT were hyperplastic whereas those in mice treated with AZT and rats and mice treated with ddC were hypoplastic. The hematologic toxicity of AZT was more severe than that of ddC. Generally, toxic effects of either chemical were greater in mice than in rats and more pronounced in female than in male animals. After 30 days without dosing, hematologic effects either resolved or dramatically improved. In studies in which ddC and AZT were administered in combination for 4 weeks at concentrations of 0/0, 0/500, 500/0, 10/500, 100/500, 500/500, and 500/1000 mg/kg ddC/AZT, there was macrocytic anemia in animals in the lower doses and marked microcytic anemia in surviving male mice in higher dose groups. Most female mice died in the 500/500 and 500/1000 mg/kg ddC/AZT dose groups. At lower concentrations (100/500, 500/1000 mg/kg ddC/AZT), effects of the two drugs were similar to those in the single drug studies. At higher concentrations (500/500 and 500/1000 mg/kg ddC/AZT), the combination treatment produced enhanced hematopoietic toxicity. These studies demonstrated the early and progressive time course of toxicity of AZT and ddC, species differences in sensitivities and responses, and reversibility of effects after termination of treatment. Based on these findings, a chronic toxicity study is being conducted with AZT in mice.

Carcinogenesis studies of dichlorvos in Fischer rats and B6C3F1 mice.

Dichlorvos (dichlorovinyl dimethyl phosphoric acid ester) is a cholinesterase inhibitor used widely as a contact and stomach insecticide for control of internal and external parasites. Carcinogenesis studies were conducted by administering dichlorvos in corn oil by gavage 5 times a week for 103 weeks to groups of 50 male and 50 female Fischer rats at 0, 4, or 8 mg/kg body weight, to groups of 50 male B6C3F1 mice at 0, 10, or 20 mg/kg, and to groups of 50 female B6C3F1 mice at 0, 20, or 40 mg/kg. During the course of the studies, body weights and survival rates of the male and female rats and mice were not different from those of their respective controls; females of both species appeared to gain more weight than controls. Neoplasms induced by dichlorvos included adenomas of the exocrine pancreas (male rats), mononuclear cell leukemia (male rats), and squamous cell papilloma of the forestomach (male and female mice; two other female mice had squamous cell carcinomas). Lesions observed in female rats that may have been due to dichlorvos administration included adenomas of the exocrine pancreas and fibroadenomas of the mammary gland. The results demonstrated that dichlorvos is carcinogenic for Fischer rats and B6C3F1 mice.

Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection.

Adverse effects stemming from the therapeutic use of dideoxynucleoside derivatives continue to occur in patients with AIDS or AIDS-related complex. For example, the continued use of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didoxycytidine (ddC), both of which confer clinical benefits in AIDS patients, may be complicated by anemia, neutropenia and thrombocytopenia and ddC also causes peripheral neuropathy. Subsequently, the National Toxicology Program (NTP) has undertaken efforts to define and characterize the toxicities associated with currently employed and potential AIDS therapeutics in experimental animals, with particular emphasis on the hematopoietic and immune systems. In addition to AZT and ddC, 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydrodideoxythymidine (d4T) have been examined. The present studies describe: (1) the development of a poorly regenerative macrocytic anemia in mice exposed to AZT or ddC. This anemia demonstrates a rapid and progressive time course of toxicity and reversibility after cessation of treatment; (2) the selective suppression of erythroid progenitor cells in mice exposed to d4T without concomitant effects on myeloid stem cells. Myelotoxicity appears to show metabolism-dependent strain-specificity and is more evident following in vitro exposure than in vivo exposure; and (3) the immunosuppressive effects following subchronic (30-day) exposure. Of the nucleoside derivatives studied, only ddA and ddI altered immune function and these changes were confined to suppression of antibody responses. It can be concluded that the overall similarities in the hematopoietic and immune system effects between rodents and humans indicate that such animal toxicology studies provide important information relevant to the toxicity of these drugs.

14-day and 90-day toxicity studies of C.I. Pigment Red 3 in Fischer 344 rats and B6C3F1 mice.

Treatment of F344 rats and B6C3F1 mice with C.I. Pigment Red 3 in the diet (10, 5.0, 2.5, 1.25, 0.6 or 0.3%) for 14 and 90 days resulted in haematological alterations consistent with haemolytic anaemia. Rats appeared to be more sensitive than mice to the haematological effects. Histological lesions were observed in rats and mice after exposure for 90 days. Target organs in the rat were the spleen, bone marrow, liver and kidney. Lesions in the spleen consisted of a haematopoietic cell proliferation, iron-positive pigment and congestion of the red pulp, and inflammation of the splenic capsule. Changes in the livers of rats consisted of haematopoietic cell proliferation and iron-positive pigment in Kupffer cells. Haematopoietic cell proliferation also occurred in the bone marrow of treated rats. The presence of iron-positive pigment and a slightly increased incidence of protein casts were seen in the kidney. Target organs in mice were the spleen, liver and kidney. Histological lesions in mice after exposure for 90 days included increased haematopoietic cell proliferation in the liver and spleen, and iron-positive pigment in the spleen. Mild cytomegaly of the renal tubular epithelia was also observed in exposed mice.

Toxic responses in F344 rats and B6C3F1 mice given roxarsone in their diets for up to 13 weeks.

Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.

Studies on the short-term toxicity of theophylline in rats and mice.

The purpose of these studies was to evaluate the short-term toxicity of theophylline, a compound present in tea and used in a variety of clinical applications. Fourteen-day repeated-dose toxicity studies were conducted in B6C3F1 mice and F344 rats of both sexes. Theophylline was administered in feed (0, 500, 1000, 2000, 4000, and 8000 ppm) or by gavage in corn oil (12.5-twice daily, 25, 50, 50-twice daily, 100, 200, 200-twice daily, and 400 mg/kg). Dosed-feed exposure to theophylline at concentrations up to 8000 ppm induced no significant toxicity except for dose-related uterine hypoplasia in rats. Palatability problems at that level precluded administration of higher concentrations. In the gavage study, 400 mg/kg was acutely toxic for both species, but mice and rats differed in that this same daily dose administered as two separate doses of 200 mg/kg was acutely toxic in rats but not in mice. No dose-related weight gain depression was evident in mice; weight gain was depressed in the majority of dose levels in rats and was pronounced at the higher levels. Clinical signs in mice were squinting and distended testes in males, and in rats, rapid respiration (all doses), squinting, and hunching. Gross necropsies, organ weights, clinical pathology, and pathology identified no target organs in mice, while histopathologic observations in rats suggested heart and stomach as possible target organs. Histopathologic effects in a number of other tissues, including lung, thymus, bone marrow, spleen, and uterus, were considered to reflect agonal changes in treated rats, possibly related to inanition. The results suggest that both species and sex differences exist with respect to sensitivity to theophylline toxicity, with F344 rats being more sensitive than B6C3F1 mice and male rats being more sensitive than female rats.

Comparative toxicity and carcinogenicity of two chlorinated paraffins in F344/N rats and B6C3F1 mice.

The toxicity and carcinogenicity of chlorinated paraffins containing C12 with 60% Cl, and C23 with 43% Cl, were assessed in prechronic and 2-year gavage studies using F344/N rats and B6C3F1 mice of both sexes. Single administrations of chlorinated paraffins were nonlethal in rats and mice, but repeated-dose and 2-year studies demonstrated toxic responses that differed with the paraffins. The C23,Cl43% paraffin produced a granulomatous inflammation in the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studies and marked liver enlargement in 13-week studies. In 2-year studies, the C23,Cl43% paraffin caused hepatic and lymphatic granulomatous inflammation and hyperplasia in both sexes of rats, and was associated with marginal increases in adrenal medullary pheochromocytomas in female rats and hepatocellular neoplasms in female mice and with clear increases in malignant lymphomas in male mice. The C12,Cl60% paraffin caused marked liver enlargement in rats and increased the severity of nephropathy in male rats and the incidence of nephropathy in female rats. C12,Cl60% also caused hepatocellular neoplasms in both sexes of rats and mice: kidney tubular cell adenomas and adenocarcinomas in male rats, thyroid follicular cell neoplasms in female rats and female mice, and a marginal increase in mononuclear cell leukemia in male rats. Thus, the short-chain, heavily chlorinated paraffin appears to have a greater potential for chronic toxicity and carcinogenicity than the longer-chain, lightly chlorinated paraffin. Both paraffins have been reported to be nonmutagenic in bacteria. (National Toxicology Program (1986) Technical Report, NIH Publications 86-2561 and 86-2564).

Benzyl acetate carcinogenicity, metabolism, and disposition in Fischer 344 rats and B6C3F1 mice.

Carcinogenesis studies of benzyl acetate (a fragrance and flavoring agent) were conducted in F344 rats and B6C3F1 mice. The chemical was given in corn oil by gavage once daily, 5 days/week for 103 weeks, to groups of 50 animals of each sex and species. For rats the doses were 0, 250, and 500 mg/kg body weight and for mice the doses were 0, 500, and 1000 mg/kg. Mean body weights of control and dosed rats and mice were not affected adversely by benzyl acetate. The survival of control and low dose female mice was lower than that of the high dose group. A genital tract infection may have contributed to the reduced survival. No other significant difference in survival was observed for dosed rats or mice. Benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90% of the administered dose recovered as various metabolites in the urine within 24 h. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Under the conditions of these studies, benzyl acetate administration was associated with an increased incidence of acinar cell adenoma of the exocrine pancreas in male F344/N rats. No evidence of carcinogenicity was found for female F344/N rats. For male and female B6C3F1 mice there was evidence of carcinogenicity, in that benzyl acetate caused an increased incidence of hepatocellular neoplasms (particularly adenomas) and squamous cell neoplasms of the forestomach.

Toxicity of hexachlorocyclopentadiene: subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice.

A 13-week subchronic study was conducted by administering hexachlorocyclopentadiene ( HCCP ) in corn oil by gavage to groups of ten male and ten female F344 rats at doses of 150, 75, 38, 19, 10 or 0 mg kg-1, and to groups of ten male and ten female B6C3F1 mice at doses of 300, 150, 75, 38, 19 or 0 mg kg-1. The doses were administered once a day, five days per week for 13 weeks. Chemically induced deaths occurred at 150 and 300 mg kg-1 in rats and at 300 mg kg-1 in mice. A significant (P less than 0.05) depression in mean body-weight change relative to controls was observed in male and female rats receiving greater than or equal to 38 and greater than or equal to 75 mg kg-1, respectively, and in male and female mice receiving 150 and 300 mg kg-1, respectively. There was a significant (P less than 0.05) increase in liver and kidney weight: brain weight ratios in the high-dose female rats (75 and 150 mg kg-1) and female mice at all doses (19-300 mg kg-1). HCCP caused proliferative and inflammatory changes of the epithelia in the forestomach of male rats, and male and female mice receiving greater than or equal to 38 mg kg-1 and in female rats receiving greater than or equal to 19 mg kg dose level. Nephrosis characterized by proximal tubular dilation, cytoplasmic vacuolization, cytomegaly, karyomegaly and anisokaryosis occurred in male and female rats and female mice receiving greater than or equal to 38 mg kg-1.

Absence of carcinogenic response in F344 rats and B6C3F1 mice given D-mannitol in the diet for two years.

Diets containing 2.5 or 5% D-mannitol were fed to groups of 50 F344 rats and 50 B6C3F1 mice of each sex for 103 wk. Similar groups served as controls. There were no significant differences in survival between treated and control rats or between treated and control mice. Mean body weights were similar in treated and control male rats and in treated and control female mice. Throughout the study, the mean body weights of female rats on the 5% diet were slightly (less than 10%) lower than those of the controls, and by the end of the study the mean body weights of treated male mice were slightly (c. 10%) higher than those of the controls. Feed consumption by treated and control animals was approximately the same in rats and mice of either sex. The incidence of dilation of the gastric fundal gland was higher (46%) in treated female rats than in the controls (12%). A mild nephrosis, characterized by focal vacuolization of the renal tubular epithelium, showed an increased incidence in treated mice of both sexes and was considered to be related to the administration of D-mannitol. There were no statistically significant increases in tumour incidence in any of the treated groups when compared with the corresponding controls. Under the conditions of this bioassay, D-mannitol was not shown to be carcinogenic for F344 rats or B6C3F1 mice of either sex.

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde.

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.