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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
Study period:
26 November 2003 to 8 August 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
21 September 1998
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Specific details on test material used for the study:
The substance is the Source of the read-across.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Forty males and forty females were accepted into the study. The mailes wighed 188 to 250 g, females 152 to 198 g, and were ca. 5 to 8 weeks old. The animals were allowed free access to food and water.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 d.
Frequency of treatment:
Daily.
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 male and 10 female.
Control animals:
yes, concurrent vehicle
Details on study design:
The test material was administered daily for ninety consecutive days by gavage using a stainless steel cannula attached to a disposable plactic syringe. Control animals were treated in an identical manner with 4 ml/kg/day of dried arachis oil BP.
The volume of test and control material administered to each animal was based on the most recent bodywight and was adjusted at weekly intervals.

Examinations

Observations and examinations performed and frequency:
All animals were examined for overt signs of toxicity, ill-health, or behavioural change immediately before dosing, and one and five hours after dosing during the working week. Animals were observed immediately before dosing, and one hour after dosing at weekends and public holidays.
Sacrifice and pathology:
All animals were subjected to a gross necropsy examination and comprehensive histopathological evaluation of selected tissues.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Incidental findings detected at 1000 and 250 mg/kg/day were attributed to the unpalatable or slightly irritant nature of the test material formulation and were not indicative of systemic toxicity.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Trachea: ephithelial decilation in animals of either sex at 1000 mg/kg/day, and for males treated with 250 mg/kg/day.
Stomach: Agllomeration of secretion observed in the gastric mucosa of animals of either sex treated with 1000 mg/kg/day. Acanthosis and hyperkeratosis of the epithelium of the forestomach were also observed.
Neuropathological findings:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
water consumption and compound intake
ophthalmological examination
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
Key result
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Treatment related changes observed at 250 and 1000 mg/kg/day, with no such effects at 50 mg/kg/d. The NOEL therefore considered to be 50 mg/kg/day.
The microscopic gastric and tracheal changes seen at 250 and 1000 mg/kg/day, together with associated clinical findings, were considered to be due to the irritant nature of the test material and not to represent a true systemic effect of treatment. Exclusion of the findings associated with irritancy give a NOAEL of 1000 mg/kg/day.