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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:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
No GLP

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2014

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Number of animals in tested group according the TG 414 should be 20 females. In present study, the number of animals was less than 12 in each group.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Semicarbazide hydrochloride
EC Number:
209-247-0
EC Name:
Semicarbazide hydrochloride
Cas Number:
563-41-7
Molecular formula:
CH5N3O.ClH
IUPAC Name:
hydrazinecarboxamide hydrochloride

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: Female S-D rats 230-260g
- Diet (e.g. ad libitum): diets containing 50% ground sweet pea seeds (Lathyrus odoratus) obtained locally and from Argentina and ground Purina Laboratory Chow at various times at gestation.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:Test substance was administrated to rats in aqueous solutions by oral intubation.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: Females were mated with fertile males overnight.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation.
Duration of treatment / exposure:
During the days of gestation
Frequency of treatment:
Daily
Duration of test:
During the gestation, after that, the females were killed.
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Remarks:
Group 1
Dose / conc.:
50 mg/kg bw/day
Remarks:
Group 2
Dose / conc.:
25 mg/kg bw/day
Remarks:
Group 3
Dose / conc.:
10 mg/kg bw/day
Remarks:
Group 4
Dose / conc.:
5 mg/kg bw/day
Remarks:
Group 5
No. of animals per sex per dose:
5 groups.
Group number 1: 9 animals (100 mg/kg bw/day)
Group number 2: 8 animals (50 mg/kg bw/day)
Group number 3: 3 animals (25 mg/kg bw/day)
Group number 4: 11 animals (10 mg/kg bw/day)
Group number 5: 4 animals (5 mg/kg bw/day)
Control animals:
not specified
Details on study design:
The administration tested substance in aqueous solution was performed during the days of gestation.
Group number 1, 4 and 5: 12-15 days
Group number 2 and 3: 10-16 days

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes:mortality

DETAILED CLINICAL OBSERVATIONS: Yes, mortality

Ovaries and uterine content:
Uterine content was examined after termination: Yes
Fetal examinations:
- External examinations: Yes:cleft palate and resorption
Fetuses were removed from the uterus 1 day before estimated term, examined for gross congenital malformations, and fixed in Bouin’s solution.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Three of six pregnant rats treated daily with test substance in doses 100 mg during the days of gestations 12-15 died.
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
not examined
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
not specified
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:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
LOAEL
Effect level:
ca. 100 other: mg/day
Based on:
test mat.
Basis for effect level:
mortality

Results (fetuses)

Fetal body weight changes:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Yes:
Doses: 100 mg/day 56% of resorption
50 mg/day- 38% of resorption
25 mg/day - 3 % of resorption
10 mg/day - 0 % of resorption
5 mg/day - 3% of resorption
Changes in sex ratio:
not examined
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, treatment-related
Description (incidence and severity):
At the dose of 100 mg of tested substance, litters produced by surviving females had resorptions and 100% cleft palate.
At the doses of 25 and 50 mg cleft palate and resorptions were observed also.
Skeletal malformations:
not examined
Visceral malformations:
not examined
Other effects:
not examined

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 10 other: mg/day
Based on:
test mat.
Sex:
not specified
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 25 other: mg/day
Based on:
test mat.
Sex:
not specified

Fetal abnormalities

open allclose all
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: face
Description (incidence and severity):
100 % Cleft palate - 100 mg/kg
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: face
Description (incidence and severity):
95% Cleft palate - 50 mg/kg
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: face
Description (incidence and severity):
43% Cleft palate - 25 mg/kg

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
25 other: mg/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Any other information on results incl. tables

Cleft palate and resorption produced by semicarbazide hydrochloride

No. Of females treated

Dose

mg/day

Days of gestation administrated

Resorptions

 

Cleft palate

No.                          %

No.                          %

6

100

12-15

28/50

56

22/22

100

8

50

10-16

26/68

38

40/42

95

3

25

10-16

1/29

3

12/28

43

11

10

12-15

0/107

0

0/107

0

4

5

12-15

1/33

3

0/32

0

3 animals from the first group (dose 100mg/day) died.

Applicant's summary and conclusion

Conclusions:
Test substance tested in pregnant S-D rats had teratogenic effects at doses 100, 50 and 25 mg/kg bw. At mentioned doses was observed cleft palate and resorption, althought the 100% cleft palate and resorption was observed at dose 100 mg/kg bw. The adverse effects were not seen in the mothers nor in the fetuses at the doses of 10 and 5 mg/day.
Executive summary:

Test substance was tested on pregnant S-D rats for teratogenic effects. Rats were fed with sweet peas. Female rats (230-260g) were mated with fertile males overnight and checked by vaginal smears for insemination the followong morning. Animals were divided into 5 groups, each one contained different amount of animals which were administrated by test substance in aqueous solution by oral intubatiion during the day of gestation. Test substance was administrated at doses 100,50,25,10 and 5 mg/day. Three animals from the first group administrated at dose 100 mg/day died, but the surviving animals produced litters with resorptions of 56% and 100% cleft palate. Cleft palate and resorptions were also observed at doses 25 and 50 mg/day. At the dose 50 mg/day was observed 38% of resorption and 95% of cleft palate and in dose 25 mg/day 3% of resorption and 43 % of cleft palate. The adverse effects were not seen at the doses of 10 and 5 mg/day.