Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
other: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Rats were treated daily orally by gavage with the test item in water from day 6 to day 15 p.c.. The fetuses were delivered by cesarian section on the 20th day of gestation.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
from day 6 to day 15 p.c.
Frequency of treatment:
daily
No. of animals per sex per dose:
27 female rats

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Details on embryotoxic / teratogenic effects:
The following parameters of maternal toxicity were impaired:
 
the body weight gain in the 60 and 360 mg/kg group dams and the feed intake in the 360 mg/kg group (60 mg/kg marginally) were reduced during the treatment period. Decreased water consumption and reduced faeces excretion were observed in some dams of the 360 mg/kg group.
 
The following parameters on intrauterine development were affected:
 
In the 360 mg/kg group increased numbers of placentas with necrotic border and slightly reduced placental weights were observed. In the 360 mg/kg group increased numbers of fetuses with skeletal variations and retardations were observed. St the dosed of 360 mg/kg b.w. increased incidences of vertebral and multiple malformations that may occur spontaneously were evident, while the overall incidence of malformations was comparable between control and 360 mg/kg group. A treatment related effect for this slightly different distribution cannot be excluded.
 
However, primary developmental toxicity was not evident, since all embryotoxic findings observed at the dose of 360 mg/kg appeared in a maternally toxic dose range.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
skeletal malformations
other: increased numbers of placentas with necrotic border and slightly reduced placental weights.
Remarks on result:
other: Primary developmental toxicity was not evident, since all embryotoxic findings observed at the dose of 360 mg/kg appeared in a maternally toxic dose range.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL maternal toxicity: 10 mg/kg bw
NOAEL developmental toxicity: 60 mg/kg bw
Executive summary:

The developmental toxicity potential of the substance to rats was evaluated. Wistar rats were exposed to the substance, via the oral route, daily from day 6 to day 15 p.c. The following parameters of maternal toxicity were impaired:

the body weight gain in the 60 and 360 mg/kg group dams and the feed intake in the 360 mg/kg group (60 mg/kg marginally) were reduced during the treatment period. Decreased water consumption and reduced faeces excretion were observed in some dams of the 360 mg/kg group.  

The following parameters on intrauterine development were affected:

In the 360 mg/kg group increased numbers of placentas with necrotic border and slightly reduced placental weights were observed. In the 360 mg/kg group increased numbers of fetuses with skeletal variations and retardations were observed. St the dosed of 360 mg/kg b.w. increased incidences of vertebral and multiple malformations that may occur spontaneously were evident, while the overall incidence of malformations was comparable between control and 360 mg/kg group. A treatment related effect for this slightly different distribution cannot be excluded.

However, primary developmental toxicity was not evident, since all embryotoxic findings observed at the dose of 360 mg/kg appeared in a maternally toxic dose range.

NOAEL maternal toxicity: 10 mg/kg bw day

NOAEL developmental toxicity: 60 mg/kg bw day