Semicarbazide hydrochloride

Developmental toxicity / teratogenicity

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

Test material information

Constituent 1

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:

semicarbazide 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 / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day

Remarks:

Group 1

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day

Remarks:

Group 2

Doses / concentrations 3

Dose / conc.:

25 mg/kg bw/day

Remarks:

Group 3

Doses / concentrations 4

Dose / conc.:

10 mg/kg bw/day

Remarks:

Group 4

Doses / concentrations 5

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)

1

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 10 other: mg/day

Based on:

test mat.

Sex:

not specified

2

Key result

Dose descriptor:

LOAEL

Effect level:

ca. 25 other: mg/day

Based on:

test mat.

Sex:

not specified

Fetal abnormalities

1

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

external: face

Description (incidence and severity):

100 % Cleft palate - 100 mg/kg

2

Key result

Abnormalities:

effects observed, treatment-related

Localisation:

external: face

Description (incidence and severity):

95% Cleft palate - 50 mg/kg

3

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.