Methyl carbamate

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to method equivalent or similar to OECD Guideline 451.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1987

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyl carbamate

EC Number:

209-939-2

EC Name:

Methyl carbamate

Cas Number:

598-55-0

Molecular formula:

C2H5NO2

IUPAC Name:

methyl carbamate

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Distilled water

Duration of treatment / exposure:

103 weeks

Frequency of treatment:

once a day (5 days per week)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100 and 200 mg/kg bw/day; additional group:0 and 400 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

50/sex for 0, 100 and 200 mg/kg bw/day
Additional group: 30/sex for 0 and 400 mg/kg bw/day.

Control animals:

yes, concurrent vehicle

Details on study design:

50 male and female rat were given test substance at dose level of 0, 100 and 200 mg/kg bw/day by oral gavage for 103 weeks (5 days per week). Additional groups of 30 rats of each sex were administered 0 or 1,000 mg/kg bw/day of test substance. 10 animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed.

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
Additional groups dosed 0 and 400 mg/kg bw/day
6 months: All vehicle control and dosed (400 mg/kg bw/day) rats survived.
12 months: All vehicle control male and female rats and dosed female rats survived. One of 10 dosed male rats died.
18 months: 1/10 dosed male and 8/10 dosed female and all vehicle control rats survived.
2 year study groups
Survival of dosed and vehicle control rats was similar (male: vehicle control, 19/60; low dose, 26/50; high dose, 29/50; female: 29/50; 36/50; 35/50).

BODY WEIGHT AND WEIGHT GAIN
2 year study groups:
Mean body weights of high dose (200 mg/kg bw/day) male rats were generally 5-9% lower than those of the vehicle controls after week 20. Mean body weights of high dose female rats were 5-8% lower than those of the vehicle controls after week 56.

GROSS PATHOLOGY
Additional groups dosed 0 and 400 mg/kg bw/day
6 months: Cytologic alterations and atypical proliferative changes were observed in the liver of all dosed male and female rats, and neoplastic nodules of the liver were onserved in 6/10 dosed male and 5/10 dosed female rats.
12 months: Neoplastic nodules of the liver were observed in 7/10 dosed male and 9/10 dosed female rats, and hepatocellular carcinomas were observed in 8/10 dosed male and 6/10 dosed female rats.
18 months: Hepatocellular carcinomas were observed in 9/10 dosed male and 8/10 dosed female rats
2 year study:
Chronic focal inflammation and cytologic alteration of the liver were observed at increased incidences in high dose rats of each sex. Hyperplasia of hepatocytes was observed at increased incidences in dosed male and high dose female rats. Neoplastic nodules or hepatocellular carcinomas (combined) in female rats occurred with a significant positive trend (0/50; 0/60; 6/49; P<0.01); the incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater (P < 0.03) than that in the vehicle controls. lncidences of liver neoplasms in dosed male rats were not significantly increased (4/50; 0/50; 7/49). lnflammation of the harderian gland was observed at increased incidences in dosed rats (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50). The lesions were considered to be chemically related. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male) and mammary gland (female).

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Neoplastic nodules, hepatocellular carcinomas and liver neoplasms were observed in 200 mg/kg bw/day dose level

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Incidence of inflammation of the harderian gland was increased at all dose levels (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50).

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Applicant's summary and conclusion

Conclusions:

There was clear evidence of carcinogenic activity for male and female F344/N rats given as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas.

Executive summary:

A study was conducted to study the carcinogenicity effects of test substance in male and female F344/N rats by method equivalent or similar to OECD Guideline 451. Animals were given test substance at dose levels of 0, 100 and 200 mg/kg bw/day by oral gavage for 103 weeks (5 days per week). Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg bw/day of test substance. 10 animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed. After 6 months, all animals survived. However, cytologic alterations and atypical proliferative changes were observed in the liver of all treated rats, and neoplastic nodules of the liver were observed in some treated rats. After 12 month studies, one of 10 dosed male rats died. Neoplastic nodules of the liver and hepatocellular carcinomas were observed in animals. After 18-months, 9 male and 2 female rats died in treated groups. Hepatocellular carcinomas were observed. In 2 years study, mean body weights of high dose rats (200 mg/kg bw /day) were lower than those of the vehicle controls. Chronic focal inflammation, cytologic alteration of the liver and hyperplasia of hepatocytes were observed in high dose rats. The incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater than that in the vehicle controls. However, it was not significantly increased in male rats. Test substance also induced inflammation of the harderian gland in male and female rats. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male) and mammary gland (female). Under the study conditions, there was clear evidence of carcinogenic activity for male and female F344/N rats given as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas (NTP, 1987).