Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
batch number is not presented for the vehicle (purified water) in the study report; autolysed foetuses were not sexed at the time of hysterectomy and head sections were archived in the same way as brain sections.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
batch number is not presented for the vehicle (purified water) in the study report; autolysed foetuses were not sexed at the time of hysterectomy and head sections were archived in the same way as brain sections.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
This is formulation of 49.2% of the test substance in water.

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
oral: gavage
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Day 6 to 28 post coitum
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
vehicle alone
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
10 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
No. of animals per sex per dose:
22 mated females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: GD 6-28

Examinations

Maternal examinations:
- Food consumption and body weight were recorded at designated intervals. 
- Clinical signs were checked each day.
Ovaries and uterine content:
- On Day 29 post-coitum, all the surviving dams were sacrificed and subjected to a macroscopic post-mortem examination. A gross examination of placentas was also performed. The fetuses were removed by hysterectomy and the uterus weighed. The net body weight gain was calculated. The litter parameters, namely, the number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were recorded. The fetuses were weighed and submitted to external examination.
Fetal examinations:
- The live fetuses were killed and then subjected to a fresh dissection and detailed examination of soft tissue, including body, head and brain. The sex was determined. The carcasses were then fixed and the skeletons (including cartilage) stained and examined.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 30 mg/kg bw/day:
- the relevant clinical signs concerned the deceased females and two prematurely sacrificed females. No other clinical signs were noted in females from this group.
At 10 mg/kg bw/day:
- there were no relevant clinical signs except for two females with blood in the bedding on Days 22 and 23 post-coitum or absence of feces from Day 26 post-coitum
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
At 30 mg/kg bw/day:
- three females died and two females were prematurely sacrificed for ethical reasons or abortion.
At 10 mg/kg bw/day:
- there were no deaths.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 30 mg/kg bw/day:
- body weight gain was transiently reduced (GD 9-12, -70% below the control, p<0.05) but returned to normal values thereafter.
At 10 mg/kg bw/day:
- reduction of maternal body weight gain did not reach statistical significance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
At 10 mg/kg bw/day:
- reduction of food consumption did not reach statistical significance.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
At 30 mg/kg bw/day:
- the necropsies revealed in 8/22 females: accentuated lobular pattern in the liver, pale liver, whitish areas and/or blackish deposits and/or edema in the stomach mucosa, reddish or brownish foci on the lungs, blackish contents in the intestines, dilated intestines and dilated gall bladder.
At 10 mg/kg bw/day:
- the necropsies revealed in 5/22 females: dilated gall bladder, accentuated lobular pattern.
- pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The fluctuations recorded for the mean number of resorptions (early or late) and the mean number of dead foetuses and consequently for the percentages of post-implantation loss were also not considered to be treatment-related, as they were minimal and not dose-related.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
The fluctuations recorded for the mean number of resorptions (early or late) and the mean number of dead foetuses and consequently for the percentages of post-implantation loss were also not considered to be treatment-related, as they were minimal and not dose-related.
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
The fluctuations recorded for the mean number of resorptions (early or late) and the mean number of dead foetuses and consequently for the percentages of post-implantation loss were also not considered to be treatment-related, as they were minimal and not dose-related.
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
The fluctuations noted in the mean number of corpora lutea and implantation sites were slight and not dose-related, they were consequently considered not to be treatment-related.
Details on maternal toxic effects:
At 3 mg/kg bw/day:
- no signs of maternal toxicity

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
3 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
gross pathology
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
30 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no reproductive toxicity observed

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: general toxicity, no effects observed on reproductive organs

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The occurrence of some external malformations throughout all treated groups, including the controls, did not suggest any substance-related origin because of their low incidence, absence of dose-relationship and/or statistical significance.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No relevant malformations was noted but the presence of a full supernumerary 13th pair of ribs (as a foetal variation), was markedly increased at 10 and 30 mg/kg bw/day. These differences in foetal or litter incidence, which were within background data, were most probably due to a low control value. The incidence of one other skeletal variation (unossified 5th sternebra) was significantly greater but in the low dose-group only.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The occurrence of some soft tissue malformations throughout all treated groups, including the controls, did not suggest any substance-related origin because of their low incidence, absence of dose-relationship and/or statistical significance.
Details on embryotoxic / teratogenic effects:
Conclusion: 
There were no treatment-related effects on litter data parameters and no treatment-related findings upon external, visceral or skeletal observation in any of the dose groups. The test substance was not teratogenic in rabbits.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
general and developmental toxicity
Effect level:
30 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No treatment related developmental effect up to the highest dose

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Result

The test substance was not teratogenic in rabbits.

- LO(A)EL maternal toxic effects:
10 mg/kg bw/d, based on necropsy findings in 5/22 animals. Incidence was increased to 8/22 at 30 mg/kg bw/day (dilated gallbladder 3/22, accentuated lobular pattern liver 3/22).
Foci (reddish/brownish) in the lung was also observed in 2 females, but also in view of findings in range finding study and parallel study with comparable compound, this can be caused by inadvertent presence of substance into the airways and not attributable to systemic toxicity. Incidence was not increased in the top-dose group. There is an indication of lower body weight gain, correlating to a lower food consumption, but that was not statistical significant and in the high-dose goup not different from the mid-dose group. Blackish content in stomack and intestines is indicative of local corrosive effects of test substance.

- NO(A)EL maternal toxic effects:
3 mg/kg bw/day. There seems to be a dose-response related increase in necropsy findings in stomach, intestine and liver. Dilated gallbladder incidence was not increased in highest dose group compared to mid-dose.

- LO(A)EL embryotoxic / teratogenic effects:
Based on the number of foetuses presenting malformations or variations and in the absence of a treatment-related increase of such observation, the embryo-fetal development was not considered to be affected by treatment.
- NO(A)EL embryotoxic / teratogenic effects:
30 mg/kg bw/day, being the highest tested dose.

Applicant's summary and conclusion

Conclusions:
Under the study conditions, the rabbit NOAEL for maternal toxicity was 3 mg a.i./kg bw/day while the rabbit NOAEL for embryo-foetal development was considered to be 30 mg a.i./kg bw/day.
Executive summary:

A study was conducted to determine the developmental toxicity and teratogenicity of the test substance according to OECD Guideline 414 and US EPA OPPTS 870.3700, in compliance with GLP. The substance was administered to pregnant rabbits by gavage from Day 6 to 28 post-coitum at the dose-levels of 3, 10 or 30 mg a.i./kg bw/day. The dose of 30 mg a.i./kg bw/day caused the death of three females, severe clinical condition or abortion in two other females and transient, lower maternal body weight gain. Necropsies revealed in 8/22 females accentuated lobular patterns in the liver, whitish areas and/or blackish deposits in the stomach mucosa and dilated intestines. At 10 mg/kg bw/day, relevant necropsy findings were noted in 5/22 females (dilated gall bladder, accentuated lobular pattern, pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa). No maternal toxicity or effects on litter data parameters or embryo-foetal development were noted at 3 mg/kg bw/day. Moreover, there were no effects on litter data parameters and no treatment-related findings upon external, visceral or skeletal observation in any of the dose groups up to 30 mg a.i./kg bw/day. Under the study conditions, the rabbit NOAEL for maternal toxicity was 3 mg a.i./kg bw/day while the rabbit NOAEL for embryo-foetal development was considered to be 30 mg a.i./kg bw/day (Gaoua, 2005).