Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
Original report is only available in Japanese. The translation is in progress. Therefore, the report is cited by a peer-reviewed OECD SIDS.

Data source

Referenceopen allclose all

Reference Type:
other: summary report
Title:
Unnamed
Year:
1998
Reference Type:
publication
Title:
MHW, Japan (1998) Ministry of Health and Welfare, Toxicity Testing Reports of Environmental ChemicaIs 6, 539-568
Author:
Ministry of Health and Welfare, Japan
Year:
2003
Bibliographic source:
cited in: OECD SIDS, 2-Dimethylaminoethylmethacrylate, CAS No: 2867-47-2, 07/2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-dimethylaminoethyl methacrylate
EC Number:
220-688-8
EC Name:
2-dimethylaminoethyl methacrylate
Cas Number:
2867-47-2
Molecular formula:
C8H15NO2
IUPAC Name:
2-(dimethylamino)ethyl methacrylate
Test material form:
liquid
Specific details on test material used for the study:
TEST MATERIAL:
- Name of test material: 2-(dimethylamino) ethyl methacrylate

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
Males: 43 days (starting 14 days before mating)
Females: from 14 days before mating to day 3 of lactation (41 -52 days)
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: As the LD50 value of > 2000 mg/kg was known, a preliminary test to decide the highest dose level at 30, 100, 300, and 1000 mg/kg/day for 14 days was conducted. At 1000 mg/kg/day, decrease of body weight in males and suppression of body weight increase in females were observed. Then the highest dose level for the test was set at 1000 mg/kg/day.
- Premating exposure period: 14 days
- Duration of test: 41 -52 days
- Post-exposure period: 1 day

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

The compound had no effects on reproductive parameteres such as the mating index, the fertility index, numbers of corpora Iutea or implantations, the implantation index, the delivery index, the gestation index, gestation length or parturition. Three dams of the 1000 mg/kg group, however, lost all their pups in the lactation period.
Significant adverse effects were observed in animals of the 1000 mg/kg/day group, especially in females. These adverse effects observed in females were as follows:
- 3 females out of 12 died.
- By the observation, late onset of twitching, chronic convulsion, suppression of body weight gain and a decrease in food consumption in lactation period were observed.
- By the histopathological examination, the degeneration of nerve fibers in the brain and the spinal cord, and the hyperplasia of the mucosa in gastric tract, the oedema and inflammatory ceII infiltration in the forestomach, and the atrophy of the thymus were revealed. Also the increases in the weight of the kidney and the adrenals without histopathological changes were observed.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see remarks

Results: F1 generation

Details on results (F1)

On examination of neonates, the 1000 mg/kg dose was associated with a decrease in body weight and a low viability index. There were no significant differences in the number of offspring or live offspring, the sex ratio or the live birth index. No abnormalities ascribable to the compound were found for external features, clinical signs or necropsy findings for the offspring.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight of neonates and viability index

Overall reproductive toxicity

Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
not specified

Any other information on results incl. tables

Reproductive parameters:

 

Dose

(mg/kg)

0

40

200

1000

No. of pairs examined

12

12

12

10

No of pairs with successful mating

12

12

11

10

Mating index

(%)

100.0

100.0

91.7

100.0

No. of pregnant females

12

12

11

9

Fertility index

(%)

100.0

100.0

100.0

90.0

Pairing days until mating

(mean ± SD)

2.5 ± 1.0

3.1 ± 1.0

3.9 ± 3.0

2.8 ± 1.0

No. of estrous stages without mating

(mean ± SD)

0.0 ± 0.0

0.0 ± 0.0

0.1 ± 0.3

0.0 ± 0.0

 

Mating index (%) = (No. of pairs with successful mating / No. of pais examined) x 100

Fertility index (%) = (No. of prgnant animals / No. of pairs with successful mating) x 100

 

_

Developmental parameters:

 

Dose

(mg/kg)

0

40

200

1000

No. of females examined

12

12

11

8

Live birth index

(%)

98.03 ± 4.52

100.00 ± 0.00

93.18 ± 22.61

89.06 ± 12.64

No. of live pups on day 0

(mean)

1.6

1.2

5.1

3.7

No. of live pups on day 4

(mean)

1.5

1.2

3.7

4.2

Body weight of pups on day 0 (g)

Male (mean ± SD)

7.2 ± 0.4

6.6 ± 0.4

6.9 ± 0.7

6.4 ± 1.1*

Female (mean ± SD)

6.8 ± 0.6

6.3 ± 0.5

6.5 ± 0.7

6.0 ± 0.9*

Body weight of pups on day 4 (g)

Male (mean ± SD)

11.1 ± 1.1

10.4 ± 0.9

10.8 ± 2.0

10.2 ± 2.5

Female (mean ± SD)

10.7 ± 1.3

9.8 ± 1.0

10.4 ± 2.0

9.8 ± 1.8

 

* = Significantly different from control; p<0.05

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the NOAEL for the reproductive/developmental toxicity is considered to be 200 mg/kg/day. A lower body weight gain and a lower viability index were observed in the pups from females of the 1000 mg/kg/day group.
Executive summary:

The study was performed according to OECD TG 422 in compliance with GLP.

SD (Crj: CD) rats received gavage doses of 0 (vehicle; corn oil), 40, 200 and 1000 mg/kg/day, for males starting from 14 days before mating for 43 days and in females from 14 days before mating to day 3 of lactation. The female animals were sacrificed on day 4 of lactation.

There were no effects on the reproductive parameters such as the mating index, the fertility index, the number of corpora lutea or implantations, the implantation index, the delivery index, the gestation index and the gestation length or the parturition. Three females in the 1000 mg/kg/day group, however, lost all of their pups during the lactation period. Females in the 1000 mg/kg/day group showed the following adverse effects in the repeated oral dose test: death of 3 animals out of 12, late onset of twitching, chronic convulsion, the suppression of body weight gain, degeneration of nerve fibers in the brain and spinal cord, hyperplasia of the mucosa in die gastric tract, oedema and inflammatory cell infiltration in the forestomach, atrophy of the thymus, increase in the weight of the kidneys and the adrenals without histopathological changes.

The pups from the females in the 1000 mg/kg/day group showed lower body weights, and the viability index of the pups was decreased due to maternal nursery activity. By external inspection, no abnomalities were found.

Conclusion: Under the conditions of this study, the NOAEL for the reproductive/developmental toxicity is considered to be 200 mg/kg/day. The NOAEL for the parental toxicity is considered to be 200 mg/kg bw/d.