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Description of key information

In a combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline male and female rats received following doses of test substance: 0 (vehicle), 8, 40, 200 mg/kg/day. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term 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: a study according to OECD TG 422 and GLP
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males, 45 days
Females, from 14 days before mating to day 3 of lactation
Frequency of treatment:
no data
Remarks:
Doses / Concentrations:
0 (Vehicle), 8, 40, 200 mg/kg/day
Basis:
other: vehicle: corn oil
No. of animals per sex per dose:
Males: 12; Females: 12/group
Control animals:
yes
Details on study design:
Males should be dosed during 2 weeks before matingto detect the majority of effects on male fertilty.
Females should be dosed for 2 weeks in order to elicit any adverse effects on oestrus.
the animals are then mated.
the test substance is administered to both sexes throughout the mating period and pregnancy and up to day 4 of lactationwhen all animals including offspring were killed
Positive control:
no
Observations and examinations performed and frequency:
clinical signs and mortality
hematology, clinical chemistry
Sacrifice and pathology:
gross necropsy including dead and killed pups, organ weight determinations
histopathological examination
Statistics:
yes, applied methods not specified
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
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
Histopathological findings: neoplastic:
effects observed, treatment-related
Dose descriptor:
NOEL
Effect level:
< 8 mg/kg bw/day (nominal)
Sex:
male/female
Critical effects observed:
not specified

--There were no abnormal clinical signs attributable to the administration of the test substance, although, one female rat given 200 mg/kg died during delivery.

--The body weight gain of females given 200 mg/kg was lower than that of the controls during the gestation period.

--Hematological examination revealed decreases in red blood cells in males given 8 mg/kg or more, decreases in hematocrit and hemoglobin, increases in reticulocytes, and slight anemia in males given 40 and 200 mg/kg.

--Blood clinical examination revealed increases in total protein, albumin and gamma-GTP and decreases in creatinine in males given 40 and 200 mg/kg. Total bilirubin and the A/G ratio were increased in males given 200 mg/kg.

--Absolute and relative liver and kidney weights showed increase or a tendency for increase in both sexes given 200 mg/kg.

--Necropsy revealed enlargement of the liver in both sexes given 200 mg/kg, and enlargement of kidneys in males given 200 mg/kg. Other treatment-related gross findings included atrophy of the thymus and enlargement of the adrenal glands in treated females.

--Histopathological examination revealed swelling and single cell necrosis of liver cells in both sexes given 200 mg/kg. Moreover, mitosis of liver cells were observed in males given 200 mg/kg.

The slight increase in the incidence of hyaline droplets of the renal tubules in males and basophilic change of the renal tubules in females, both given 200 mg/kg, were also noted in a few females given 8 mg/kg or more, and necrosis of the renal tubules was observed in a few females given 40 and 200 mg/kg.

A variety of lesions including a moderate degree of pigment deposit in the spleen, atrophy of the thymus, swelling of the liver cells, ulcer action in the stomach, duodenum and large intestine, single liver cell necrosis and fibrosis of the renal tubular epithelium, were observed in females that delivered all stillborn pups and in females where all pups died, in the group given 200 mg/kg.

--Counting of numbers of spermatogenic cells at stage VIII in the testes from control males and males given 200 mg/kg revealed no treatment-related effects.

Executive summary:

The test substance was studied for oral toxicity in an OECD combined repeat dose and reproductive/developmental toxicity screening test (OECD TG 422 and GLP) at doses of 0, 8, 40 and 200 mg/kg/day. With regard to repeat dose toxicity, one female rat given 200 mg/kg died during delivery. Body weight gain of females given 200 mg/kg was lower than that of controls during the gestation period. Hematological examination showed decreases of red blood cells in males given 8 mg/kg or more, as well as decreases of hematocrit and hemoglobin, increases of reticulocytes, and slight anemia in males given 40 and 200 mg/kg. Blood chemical examination revealed increases in total protein, albumin and y-GTP and decreases in creatinine in males given 40 and 200 mg/kg. Increases in total bilirubin and A/G ratio were also observed in males given 200 mg/kg. Absolute and relative weights of the liver and kidneys showed increases or a tendency for increase in both sexes given 200 mg/kg and mg/kg. As gross findings, enlargement of the liver was observed in both sexes given 200 mg/kg and enlargement of the kidneys in males given 200 mg/kg. Histopathologial examination revealed swelling and single cell necrosis of liver cells in both sexes given 200 mg/kg. Moreover, mitosis of liver cells were observed in the liver of males given 200 mg/kg. The slight increase in the incidence of hyaline droplets of renal tubules in males and basophilic change of the renal tubules in females, both given 200 mg/kg, were also noted in a few females given 8 mg/kg or more, and necrosis of the renal tubules was observed in a few females given 40 and 200 mg/kg.

The author declared 8 mg/kg as LOEL, because slight effects on red blood cells in male rats (red blood counts: control 7.98 mg/kg; 8 mg/kg= 7.79 mg/kg) and histopathology were observed, but the effects on red blood cells were isolated effects and no other effects were observed.

Basophile changes (control group= 1 rat; 8 mg/kg= 2 rats; 40 mg/kg= 1 rat; 200 mg/kg 5 rats) The results were not dose related and no significant effect was seen in the 8 mg/kg group of female rats

Because the effects were not seen as adverse the LOEL = NOAEL of 8 mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
guideline stuy under GLP conditions

Additional information

In a combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline male and female rats received following doses of test substance: 0 (vehicle), 8, 40, 200 mg/kg/day. 12 male rats were treated for 45 days and 12 females /group were treated from 14 days before mating to day 3 of lactation. In terms of reproductive/developmental toxicity, one female given 200 mg/kg died during delivery. All pups were stillborn in two females and all pups died during the lactation period in three females of the treated group given 200 mg/kg. In the same group the number of live pups born was decreased and the live birth index, viability index of the pups at Day 4 after birth and delivery demonstrated tendencies for index decrease. NOELs for reproductive performance of males and females, and pup development are considered to be 200 mg/kg/day for males and 40 mg/kg/day for females (Chemicals Investigation Promoting Council, 1996).

With regard to repeat dose toxicity, one female rat given 200 mg/kg died during delivery. Body weight gain of females given 200 mg/kg was lower than that of controls during the gestation period. hematological examination showed decreases of red blood cells in males given 8 mg/kg or more, as well as decreases of hematocrit and hemoglobin, increases of reticulocytes, and slight anemia in males given 40 and 200 mg/kg. Blood chemical examination revealed increases in total protein, albumin and y-GTP and decreases in creatinine in males given 40 and 200 mg/kg. Increases in total bilirubin and A/G ratio were also observed in males given 200 mg/kg. Absolute and relative weights of the liver and kidneys showed increases or a tendency for increase in both sexes given 200 mg/kg bw/day. As gross findings, enlargement of the liver was observed in both sexes given 200 mg/kg and enlargement of the kidneys in males given 200 mg/kg. Histopathologial examination revealed swelling and single cell necrosis of liver cells in both sexes given 200 mg/kg. Moreover, mitosis of liver cells were observed in the liver of males given 200 mg/kg. The slight increase in the incidence of hyaline droplets of renal tubules in males and basophilic change of the renal tubules in females, both given 200 mg/kg, were also noted in a few females given 8 mg/kg or more, and necrosis of the renal tubules was observed in a few females given 40 and 200 mg/kg.

NOELs for repeat dose toxicity are considered to be less than 8 mg/kg/day for both sexes (Chemical Investigation Promoting Council, 1996).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The only available study performed according to OECD TG 422 under GLP conditions and evaluated with Klimisch score 1

Justification for classification or non-classification

No classification/labelling is required

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