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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study design according to OECD Guideline 421. Study in Japanese without complete English translation.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Lot/batch No.: PAK5633
Purity: 98.3 %

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: 50-52 days
females: from 14 days before mating to day 3 of lactation (38 to 54 days according to mating lenght)

terminal kill:
males: days 51-53
females: day 4 of lactation
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 6, 30, 150 or 750 mg/kg bw/day
Basis:

No. of animals per sex per dose:
12 m / 12 f
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 1 day

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see attached file)
HISTOPATHOLOGY: Yes (see attached file)
Statistics:
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):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
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:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
In males, exophthalmos was noted in 2 animals at 750 mg/kg bw. Transiently lowered food consumption was also noted at 750 mg/kg bw. No changes caused by the substance were noted in terms of body weight, necropsy findings, organ weights, or sperm examination. On histopathological examination, vacuolization of lens fibers and hyperplasia of epithelium lentis were noted in 2 and 1 animal, respectively, at 750 mg/kg bw.
In females, mydriasis was noted at 750 mg/kg bw. Transiently lowered body weight were evident at 750 mg/kg bw during the pregnancy period and transiently reduced food consumption was noted before mating. No changes caused by the substance were noted with regard to necropsy, organ weights, or histopathological examination.

The individual results are summarised in the attached file Tables and Figures.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Limited effects and reversible
Dose descriptor:
LOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: exophtalmos in males; mydriasis in females

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
From this study a NOAEL of 150 mg/kg bw for male and female rats was derived.
Executive summary:

In this study performed according to OECD Guideline 421, male and female Crj :CD (SD) rats were dosed orally via gavage with 0, 6, 30, 150 or 750 mg/kg bw over 50-52 days (m) and from 14 days before mating to day 3 of lactation. Terminal kill in males was on days 51-53 and in females on day 4 of lactation.

In males, exophtalmos was noted in 2 animals at 750 mg/kg bw. Transiently lowered food consumption was also noted at 750 mg/kg bw. No changes caused by the substance were noted in terms of body weight, necropsy findings, organ weights, or sperm examination. On histopathological examination, vacuolization of lens fibers and hyperplasia of epithelium lentis were noted in 2 and 1 animal, respectively, at 750 mg/kg bw.

In females, mydriasis was noted at 750 mg/kg bw. Transiently lowered body weight were evident at 750 mg/kg bw during the pregnancy period and transiently reduced food consumption was noted before mating. No changes caused by the substance were noted with regard to necropsy, organ weights, or histopathological examination.

From this study a NOAEL of 150 mg/kg bw for male and female rats was derived.