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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:
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

Constituent 1
Chemical structure
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.