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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP condition

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: NTP Protocol
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): γ-Butyrolactone
- Physical state: liquid
- Analytical purity: 97.92%
- Impurities (identity and concentrations): 11 impurities were identified by GC method, there is no data on chemical identity of these impuries.
- Stability under test conditions: stable
- Storage condition of test material: stored at 5°C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female F344/N rats, obtained from Charles River Breeding Laboratories (Kingston, NY). The average age of rats was 51 days old at the beginning of the study. Animals were observed for 19 days before the study started. Rats were housed five to a solid-bottom polycarbonate cage and the light cycle was 12-hour light and dark. Temperature was maintained between 22-24 deg C with RH of 35-62%.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 56, 112, 225, 450, or 900 mg/kg bw
Basis:
other: by gavage in 5 mL corn oil
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Animals were observed twice a day and clinical observations were recorded once a week. Animals were weighed at the start of the study and weekly thereafter.
Sacrifice and pathology:
Surviving animals were killed at the end of the 13-week studies. Necropsies were performed on all study animals. The brain, heart, right kidney, liver, lungs, and thymus of survivors were weighed at necropsy. Complete histopathology was performed on all animals killed or dying during the study, all control animals, rats receiving 900 mg/kg, male rats receiving 450 mg/kg. The liver and nose (nasal cavity and turbinates) were examined from rats in the 56, 112, and 225 mg/kg dose groups and from female rats in the 450 mg/kg dose groups. Tissues routinely examined include: adrenal gland, bone and marrow (femur), brain, clitoral gland, esophagus, epididymis, heart, kidney, large intestine, liver, lung with mainstem bronchi, lymph nodes (mesenteric, mandibular), mammary gland, nasal cavity and turbinates, ovary, pancreas, parathyroid gland, pituitary gland, prostate gland, salivary gland, seminal vesicle, skeletal muscle (thigh), skin, small intestine, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, uterus, and gross lesions and tissue masses (with regional lymph nodes).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
males and females at 900 mg/kg became recumbent several minutes after dosing but were normal at next observation.
Mortality:
mortality observed, treatment-related
Description (incidence):
males and females at 900 mg/kg became recumbent several minutes after dosing but were normal at next observation.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
males given 450 mg/kg had decreased mean body weights and body weight gains.
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:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

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Dose descriptor:
NOAEL
Effect level:
225 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on body weights. No specific target organs were identified.
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on 1 death in the 900 mg/kg group. No specific target organs were identified.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All high-dose males and one high-dose female died. Males receiving 450 mg/kg gained less body weight. There was no body-weight effect in females at any dose level. Other than inflammation of the nasal mucosa in all groups of dosed rats, there were no specific organ effects. The nasal mucosa irritation was considered to be a non-specific effect of gavage with a volatile agent. NTP reports that similar lesions have been observed in other NTP gavage studies with a variety of chemicals and that the lack of any histologically evident degenerative lesions may be attributed in part to the rapid absorption and metabolism of the chemical.

Rats at the higher dose levels (225 mg/kg and above) showed signs of sedation after dosing during the first 2-3 weeks of study that diminished in intensity with continued dosing, and rats showed no visible signs of sedation after three weeks of dosing. While this effect is clearly attributable to the test substance, it is not considered relevant to establishing a chronic NOAEL for workers or consumers except in cases of accidental poisoning.

Applicant's summary and conclusion