Registration Dossier

Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between 21 June 1999 and 05 December 1999
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Commission Directive 92/69/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Arachis oil BP
Details on oral exposure:
Method of administration:
Gavage
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes, concurrent no treatment
Positive control:
No

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
With the exception of the 1000 mg/kg/day male interim decedent, clinical signs at this dose level were confined to increased salivation around the time of dosing from day 6
onwards among animals of either sex and an isolated incident of noisy and gasping respiration in one female on Day 27. The adversely affected male developed noisy and gasping
respiration on day 21, and by day 24 the animal additionally showed abdominal distension, diuresis, dehydration and laboured respiration. By the following morning, this
individual had shown a further decline in condition including hunched posture, ptosis and tiptoe gait; the animal was subsequently killed in extremis without further treatment.

No clinically observable signs of toxicity were detected in animals of either sex treated with 150 or 15 mg/kg/day.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male treated with 1000 mg/kg/day was killed in extremis at the start of Day 25 following a severe deterioration in condition.
There were no further deaths during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse effect on bodyweight development was detected during the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effect on food consumption was detected during the study.
Food efficiency:
not examined
Description (incidence and severity):
Not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No adverse effect on water intake was detected.
Ophthalmological findings:
not examined
Description (incidence and severity):
Not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related haematological changes were detected.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Females treated with 1000 mg/kg/day showed a statistically significant increase in plasma inorganic phosphorous concentration when compared with controls. There was no
reciprocal change in plasma calcium level or any histopathological evidence of renal dysfunction; therefore this intergroup difference was considered to be of no
toxicological significance. It may also be noted there was a tendency towards a dose-dependent increase in plasma inorganic phosphorous concentration in male animals. This
did not reach statistical significance.
Urinalysis findings:
not examined
Description (incidence and severity):
Not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Detailed open-field observations confirmed the noisy respiration noted clinically in one female treated with 1000 mg/kg/day; the transient nature of this finding was consistent with the accidental introduction of the test material formulation into the upper respiratory tract.

No behavioural changes were detected at the 150 or 15 mg/kg/day dose levels.
Immunological findings:
not examined
Description (incidence and severity):
Not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treament-related oragn weight changes were detected.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Surviving 1000 mg/kg/day males showed dark liver at terminal kill. The male interim decedent from this dose level showed macroscopic findings including small spleen, gaseous distension of the intestines and stomach and thinning/sloughing of the non-glandular gastric epithelium.

Females treated with 1000 mg/kg/day and animals of either sex from the 150 or 15 mg/kg/day treatment group showed no treatment-related macroscopic abnormalities at terminal
kill.
Neuropathological findings:
not examined
Description (incidence and severity):
Not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic examination of tissues revealed an increased incidence and severity of agglomeration of secretion and goblet cell hyperplasia in the stomach of animals of either
sex treated with 1000 mg/kg/day but not amongst rats from any other exposure level.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No effects observed
Other effects:
no effects observed
Description (incidence and severity):
No other effects mentioned
Details on results:
As described above

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Classified as: Not classified