Hydrazinium, 2-(3-methoxy-3-oxopropyl)-1,1,1-trimethyl-, bromide (1:1)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12.02.-23.06.2008.

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

other: Body responsible for the test

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

463-070-5

EC Name:

-

Cas Number:

106966-25-0

Molecular formula:

C7H17N2O2Br

IUPAC Name:

2-(3-methoxy-3-oxopropyl)-1,1,1-trimethylhydrazinium bromide

Test animals

Species:

other: Albino laboratory rat

Strain:

other: Wistar Han (outbred SPF quality)

Details on test animals or test system and environmental conditions:

SPF - Specified Pathogen Free

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: water for injection

Duration of treatment / exposure:

7 days/ week

Duration of test:

3 weeks

No. of animals per sex per dose:

Number of Dams Dose or Conc (mg/kg)
19 0
20 80
19 200
21 500

Control animals:

yes

Examinations

Maternal examinations:

CLINICAL OBSERVATIONS OF FEMALES: Yes
- Time schedule: daily during the administration period.


BODY WEIGHT: Yes
- Time schedule for examinations: on the 1st, 5th, 8th, 11th, 14th, 17th and 20th day of pregnancy


FOOD CONSUMPTION:
- Food consumption was measured on 5th, 8th, 11th, 14th, 17th and 20th day of pregnancy. In the given day the remainder of pellets of each cage was weighed, the new food was weighed out and the food consumption for one female and one day was computed (average value for each cage).

MORTALITY CONTROL, HEALTH CONDITION CONTROL : yes
- Time schedule: daily during the acclimatization, mating and pregnancy period.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No death during the study.
Administration of the substance affected clinical status, macroscopic structure of organs and fetal skeleton in treated maternal animals. These
effects manifested in results of health condition controls and clinical observations (watery excrements, flabby body, secretion from nostrils and eyes, piloerrections, apathy) during maternal animal necropcies (findings in stomach and duodenum) and examinations of ossification and structure of
fetal skeleton (decreased extent of skeletal ossification, higher occurence of skeletal variance) especially at the highest dose level. Changes of
maternal anymal clinical status at the middle dose level had only mild intensity and other signifficant adverse effects were not diagnosed at maternal animals and their foetuses of this dose level. Either at the lowest dose level no adverse effects in maternal animals and foetuses were detected.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Basis for effect level:

other: other:

2

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Effects on foetus (gross);
No statistically significant differences were detected in comparision with control group.
During examination the symmetry of fore and hind limbs, number of fingers, closing or opening of eye fissures and external auditory canal, symmetry of head, integrity of superior palatum, status of umbilicus and genital papilla no serious alteration were often observed.

Effects on foetus (soft tissue):
No serious alterations were observed.
In foetuses of females from the lowest and the highest dose level small punctiform haemorrhages on arachnopia were sporadic.

Effects on foetus (skeletal):
During examination of foetal cranium dalayed ossification of supraoccipital bone was observed in 5 foetuses of females of the lowest dose level and in 2 foetuses of females of the highest dose level.
Incomlete ossification of sternum was recorded in foetuses of all groups. Percentual portion of foetuses with this variation was mildly increased in trated groups compared with control and this difference was dependent on dose level. The highest percentual portion of litters with affected foetuses was at the highest dose level.
Anomaly of ribs - undulation along the length of a rib was detected only in foetuses of the highest dose level. More than 30% of examined foetuses at this dose level were affected and this finding occured in more than 60% of litters.

Effect levels (fetuses)

Dose descriptor:

other: dose or conc

Effect level:

>= 80 - <= 500 mg/kg bw/day

Basis for effect level:

other: incomplete ossification of sternum

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Administration of the test substance affected clinical status, macroscopic structure of organs and fetal sketeton in treated maternal animals. These effects manifested in results of health condition controls and clinical observations, during maternal animal necropsies and examinations of ossification and structure of fetal skeleton especially at the highest dose level. Changes of maternal animal clinical status at the middle dose level had only mild intensity and other significant adverse effects were not diagnosed at maternal animals and their foetuses of this dose level. Either at the lowest dose level no adverse effects in maternal animals and foetuses were detected.