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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
other: range-finding study
Type of information:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
31 August to 14 September, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
NTP Study, very reliable source
Justification for type of information:
Justification for Read Across is provided in Section 13 of IUCLID

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: range-finding study
Deviations:
not applicable
Principles of method if other than guideline:
2.5 mL/kg bw/day of test item in 1 % (v/v) corn oil was administered to groups of 5 male and 5 female Fischer 344 rats via oral gavage for 15 days at doses of 250, 500, 1000, 2000, 3000 mg/kg bw/day, alongside a vehicle control group. Animals were checked two times per day for signs of moribundity and mortality; moribund animals were killed. Initial (day 0) but not final body weights were taken. Necropsy was performed on all animals, except those autolyse/cannibalised.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 43 days
- Weight at study initiation: male 116-130 g, females 91-95 g
- Housing: 5 per cage, Polycarbonate cage with Ab-Sorb-Dri hardwood chips
- Diet: Purina Lab Chow, ad libitum
- Water: Acidified with HCl (pH 2.6) tap water; available ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
Not reported.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle: the vehicle was chosen because of the potential for chemical hydrolysis in water.
- Concentration in vehicle: 1% w/w
- Dose (vol): 2.5 mL/kg
- Highest rat dose undiluted: 3000 mg/kg.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses for the test item in corn oil were performed on every eighth dose mixture to confirm that the correct concentrations were administered to the test animals. The method of analysis involved a methanolic extraction as a purification step and a gas chromatographic assay as a quantitation step.
Duration of treatment / exposure:
15 days
Frequency of treatment:
15 consecutive days
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 per sex per doses
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were checked two times per day for signs of moribundity and mortality; moribund animals were killed. Initial (day 0) but not final body weights were taken.

Examinations

Sacrifice and pathology:
Necropsies were performed on all animals, except those excessively autolysed or cannibalised.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not examined
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
effects observed, treatment-related
Other effects:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All rats receiving 1000, 2000, or 3000 mg/kg/day, and 4/5 males and 2/5 females that received 500 mg/kg, died before the end of the study. Rats receiving 500 mg/kg/day or more were inactive after dosing. There were no dose-related findings at necropsy.

Applicant's summary and conclusion

Conclusions:
NOAEL (sub-acute, rat) = 250 mg/kg bw/day
LOAEL (sub-acute, rat) = 500 mg/kg bw/day (based on mortality)
Executive summary:

Sub-acute toxicity of the substance was evaluated in a dose range finding study. 2.5 mL/kg bw/day of test item in 1 % (v/v) corn oil was administered to groups of 5 male and 5 female Fischer 344 rats via oral gavage for 15 days at doses of 250, 500, 1000, 2000, 3000 mg/kg bw/day, alongside a vehicle control group. Animals were checked two times per day for signs of moribundity and mortality; moribund animals were killed. Initial (day 0) but not final body weights were taken. Necropsy was performed on all animals, except those autolyse/cannibalised.

All animals receiving either 1000, 2000 or 3000 mg/kg bw/day, plus and 4/5 males and 2/5 females receiving 500 mg/kg bw/day, died before the end of the study period. No mortality occurred in the low-dose group receiving 250 mg/kg bw/day. There were no dose-related findings at necropsy. Based on mortality, the NOAEL for sub-acute toxicity may be considered 250 mg/kg bw/day. The findings of this study were used to set the doses for a subsequent sub-chronic toxicity study.