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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comprehensive developmental study according to scientifficall accepted methods and conducted according to GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
25 mated females per dose group were dosed by gavage with 0, 20, 120, and 300 mg/kg from gestation day 6 through gestation day 15. All females were euthanized on gestation day 20 and subjected to cesean section. Fetuses were individually weighted, sexed and examined for external, visceral and skeletal abnormalities.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Flectol pastilles; no data on purity

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Females determined to be suitable test subjects, based on age, healthy appearance and body weight were cohabited with resident SD male rats.
Duration of treatment / exposure:
From gestation days 6 to 15.
Frequency of treatment:
Daily
Duration of test:
All females were eutanized on gestation day 20 and subjected to cesian section.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 120, 300 mg/kg
Basis:
no data
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
120 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: but only in maternal toxic doses

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Homogeneiety and stability of the test material was analysed and considered to be appropriate.

No effect on maternal survival and pregnancy status

Clinical signs: 120 mg/kg: slight increase in the incidence of dark material aroundd the nose and post-dose salvation; 300 mg/kg: increased incidence of reddish vaginal discharge, soft stool, fecal stain, urine stain, dark material around the nose and/or eye(s) and post-dose observation of salvation, rubbing of chin on cage floor and dried red material around mouth.

Body weight gain: 300 mg/kg: statistically reduced during gestation days 6 -9.

Food consumption: 120 mg/kg: statistically decreased during gestation days 9 -12; 300 mg/kg: statistically decreased during days 6 -9, 9 -12, 6 -12 and 12 -16.

Maternal necropsy observations were generally unremarcably.

Maternal liver weight: dose related statistically significant increase in the 120 and 300 mg/kg groups

Cesarean section: no effect on any parameter

Fetal morphologicalobservations: low incidence of various external and skeletal malformations known to occur spontaneously in this rat strain was observed in control 20 and 120 mg/kg groups; the developmental variations observed were in addition generally similar between the three groups. At 300 mg/kg the number of litter with malformations was statistically increased with increased number of litter with kinked tail, rib anomalies and vertebral abnormalities with or without associated rib anomalies. Statistical increase in the 300 mg/kg group in the number of litter with variaous developmental variations were noted (malalingned sternegra(e), 14th rudimentary rib, 7th cervical rib and 27 presacral vertebrae. Additional statistically not significant in the 300 mg/kg were: discendent ureter(s), renal papilla(e) not developed and 14th full rib.

Applicant's summary and conclusion

Executive summary:

A dose of 20 mg/kg was considered a NOEL for maternal toxicity and a dose of 120 was considered a NOEL for develiopmental toxicity.