2-propylvaleric acid

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1976-1978

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short information available

Data source

Reference

Reference Type:

secondary source

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

GLP compliance:

no

Remarks:

stated in the report

Test material

Test material information

Constituent 1

Reference substance name:

Valproic acid

IUPAC Name:

Valproic acid

Details on test material:

- Name of test material (as cited in study report): Valproic acid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5 weeks
- Weight at study initiation: 80 to 150 g

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on exposure:

Treatment of controls: 2% v/w corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

107 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
90 and 180 mg/kg/day
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
81 and 161 mg/kg/day
Basis:
actual ingested
males

Doses / concentrations 3

Remarks:

Doses / Concentrations:
85 and 172 mg/kg/day
Basis:
actual ingested
females

No. of animals per sex per dose:

50 animals per sex per group for treatment
100 animals per sex for control

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not indicated

BODY WEIGHT: Yes
- Time schedule for examinations: not indicated

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

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

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Clinical signs: foot pad ulceration, ocular discharges and corneal opacity
Mortality: no significant mortality between the different groups
Survival in the various groups was comparable and ranged from 54-78% at the end of the treatment period.

BODY WEIGHT AND WEIGHT GAIN
Mean body weight: decrease of 7.8% and 10.9% in the high-dose male and female groups respectively
Mean body weight gain: decrease in the high-dose male and female groups of 9.4% and 14.9% respectively

HISTOPATHOLOGY: NON-NEOPLASTIC
A wide variety of incidental and spontaneous non-tumor lesions were observed and not considered to be drug-related

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Both benign and malignant spontaneous and incidental neoplasms (liver cell neoplasms, subcutaneous fibrosarcomas and fibromas, malignant mammary lesions, adrenal cortical adenomas, pheochromocytomas, thyroid C cell adenomas) were observed. None of the neoplasms were considered to be drug-related.

Relevance of carcinogenic effects / potential:

None of the neoplasms and non-tumor lesions were considered to be drug-related.

Effect levels

1

Dose descriptor:

dose level:

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: body weight gain: decrease of 9.4 % and 14.9 % in male and female groups respectively in comparison with controls during the last 6-12 months of treatment

Remarks on result:

other: Effect type: toxicity (migrated information)

2

Dose descriptor:

dose level:

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

other: body weight gain: decrease of 9.4 % and 14.9 % in male and female groups respectively in comparison with controls during the last 6-12 months of treatment

Remarks on result:

other: Effect type: toxicity (migrated information)

Applicant's summary and conclusion

Conclusions:

Valproic acid was not considered to be carcinogenic to male rats up to 161 mg/kg/day or to female rats up to 172 mg/kg/day when administered for 2 years.