N-methylacetamide

Developmental toxicity / teratogenicity

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: see 'Remark'

Remarks:

Comparable to Guideline study with acceptable restrictions (treatment period gestation day 6-15; only one dose group but same experimental design than in BASF 1975, complement concerning mid dose level; partly limited documentation, e.g. no data about sex ratio of fetuses or uterine weight).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-methylacetamide

EC Number:

201-182-6

EC Name:

N-methylacetamide

Cas Number:

79-16-3

Molecular formula:

C3H7NO

IUPAC Name:

N-methylacetamide

Details on test material:

Purity 99.9% (analysed by GC)
no further details

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Source: Wiga, Sulzfeld, Germany
Acclimatisation: 7 days
Only females with sperm in vaginal smear used (gestation day 0 [GD0] )
Housing conditions:
2 animals per cage
temperature 20-24°C
rel. air humidity: 50-60%
dark/light cycle: 12/12 h
certified diet and tap water ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Constant application volume in control and treatment groups: 10 ml/kg bw (5 ml/kg bw in BASF 1975)
Dose related to the initial weight at GD0
Aqueous solutions prepared

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Mating with fertile, untreated males (4 females/1 male) for one night; only females with sperm in vaginal smear used (gestation day 0)

Duration of treatment / exposure:

Gestation day (GD) 6-15

Frequency of treatment:

once daily

Duration of test:

Termination at GD20, cesarean section

Doses / concentrations

Remarks:

Doses / Concentrations:
0 or 400 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

22-33 pregnant animals

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: data from acute oral toxicity in rats

Examinations

Maternal examinations:

Clinical symptoms recorded daily
Conception rate determined
Body weight measured thrice weekly and GD0, 6, 11, 15, 20
Necropsy at termination

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: no data
- placenta weight of living fetuses: yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- dead and living fetuses: yes

Fetal examinations:

weight, length, sex of fetuses
all living fetuses examined for external effects
2/3 of all fetuses processed for the study of skeletal effects (Dawsen-method; Alizarin staining)
1/3 of all fetuses processed for the study of visceral effects (fixation in Bouin's solution for 2 weeks, 15 transversal sections)

Statistics:

Fisher exact test
U-test
t-test
level of significance: p<=0.05

Indices:

see results

Historical control data:

no data available

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No clinical signs in the treatment group except vaginal bleeding in 1 dam.
Body weight gain significantly reduced at 400 mg/kg bw/day (possibly due to resorptions).
Necropsy: no effects in any group.
Conception rate 100% in all groups.

Effect levels (maternal animals)

Dose descriptor:

other: effective dose level

Effect level:

400 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

- Embryotoxic / teratogenic effects:yes
- Details on embryotoxic / teratogenic effects: No effects on number of implantations in any treatment group. Increased resorptions (mainly late). Reduced fetal and placental weight; reduced fetal length; no data about runts; increase in malformations and retardations & variations.
- Type of malformations: Cleaved vertebral bodies, bilateral wavy ribs, rotation of the heart, anasarca, cleft palate
- Details are presented in the Table below.

Effect levels (fetuses)

Dose descriptor:

other: effective dose level

Effect level:

400 mg/kg bw/day (nominal)

Basis for effect level:

other: embrytoxic (resorptions), reduced fetal weight and fetal length, reduced placental weight, increased incidence in malformations and variations

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Developmental toxicity in rats after oral application of 400 mg/kg bw/day N-methylacetamide

Parameter	Untreated control	Vehicle control	400 mg/kg bw/day
Pregnant rats	33	22	24
Conception rate	100%	100%	100%
Corpora lutea/dam	13.3	13.3	13.9
Implants per dam	11.5	9.6	11.1
% resorbed implants	4.0	11.2	35.4**
% living fetuses/ implants	96.0	88.8	64.6
Fetal weight	No data	No data	Reduced**
Fetal length in cm	No data	No data	Reduced**
Placental weight in g	No data	No data	Reduced**
% Living fetuses/litter with malformations	3.6	3.0	19.9**
% litter with malformations	30.3	13.6	71.4**
% Living fetuses/litter with variations & retardations	15.3	14.7	56.0**
% litter with variations & retardations	60.6	63.6	95.2*

*: significant, p 0.05; **: p 0.01

Data on standard deviation not given

Applicant's summary and conclusion

Conclusions:

Developmental toxicity and reduced maternal weight gain (possibly due to resorptions) was found in rats at a dose level of 400 mg/kg bw/day.

Executive summary:

Comparable to Guideline study with acceptable restrictions (treatment period gestation day 6-15; only one dose group but same experimental design than in BASF 1975, complement concerning mid dose level; partly limited documentation, e.g. no data about sex ratio of fetuses or uterine weight).

A group of 24 pregnant Sprague-Dawley rats were gavaged at gestation day (GD) 6 -15 with 400 mg/kg bw/day. Concurrent controls were untreated (n=33) or received vehicle (n=22). The study was terminated at GD20. At 400 mg/kg bw/day reduced body weight gain in dams might be related to resorption of implantations; vaginal bleeding was seen in 1 dam but no further clinical signs; the conception rate was 100% in all groups. In the treatment group increased resorptions were reported as well as decreased fetal and placental weight of living fetuses and decreased fetal length. Treatment related teratogenic effects were detected as well as an increase in variations and retardations.

Conclusion: Developmental toxicity and reduced maternal weight gain (possibly due to resorptions) was found in rats at a dose level of 400 mg/kg bw/day.