Ethyl methacrylate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Read across from analogous category member
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1

3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters

4. DATA MATRIX
see attached category document, endpoint specific chapters

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1998

Reference 2

Reference Type:

other:

Title:

Initial submission: Letter from Methacrylates Producers Association Incorporation to USEPA RE summaries of methacrylate toxicity|studies conducted in Japan, with attachments and dated 8/2/1999, Ministry Hlth, OTS0559766

Author:

MPA (Methacrylate Producers Association)

Year:

1999

Bibliographic source:

Methacrylates Producers Associationents and dated|8/2/1999, Ministry Hlth, OTS0559766

Report date:

1999

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

Test material information

Constituent 1

Reference substance name:

Butyl methacrylate

EC Number:

202-615-1

EC Name:

Butyl methacrylate

Cas Number:

97-88-1

Molecular formula:

C8H14O2

IUPAC Name:

butyl methacrylate

Details on test material:

Mitsubishi Gas Chem. Co., Inc., Lot No. NG60912, Purity: 99.6 %, kept cool and dark until use

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

1) Age at study initiation: 9 weeks old for males and 8 weeks old for females 
2) Weight at study initiation: 340-373 g for males, 198-222 g for females  

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Duration of treatment / exposure:

Exposure period: Males; for 44 days
Females; from 14 days before mating to Day 3 of lactation

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0(vehicle), 30, 100, 300, 1000 mg/kg/day
Basis:

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

Reproductive function / performance (P0)

Reproductive performance:

effects observed, treatment-related

Details on results (P0)

(1) Copulation index and fertility index Copulation was accomplished in all animals in all groups within 5 days after the start of mating, and there was no significant change in the fertility index.
2) Number of corpora lutea, implantation sites and implantation index In the 1000 mg/kg group, significant decreases in the number of corpora  lutea and implantation sites were observed. There was no significant  change in the implantation index. See table below
(3) Delivery index and gestation period The delivery index was 100% in the control group and all the treated  groups. 
There was no significant change in the gestation period.
(4) Parturition and lactation For the condition of parturition, no abnormality was observed in any parent animals in any group. For lactation, one animal in the 30 mg/kg group showed no lactating behavior on Day 0 of lactation and cannibalized all neonates. In addition, one animal in the 300 mg/kg group also cannibalized a part of neonates but showed a lactating behavior on and after Day 2 of lactation, and 4 of 19 neonates survived. However, these abnormalities in lactating were not dose-dependent changes.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: decreases in the number of corpora lutea and implantation sites

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Gross pathological findings:

no effects observed

Details on results (F1)

(1) Viability and body weight  The total number of litters, the number of neonates, fertility index, body weight on Day 0 of lactation and viability index on Day 4 of lactation in all treated  groups were comparable to the control group. For the sex ratio, the number of  females in the 300 mg/kg group was slightly higher than that of males, and that in the  1000 mg/kg was the reverse. In addition, the body weight  of neonates on Day 4 
of lactation was slightly low in the 1000 mg/kg  group. However, these changes  showed no statistically significant  difference. There was no abnormality in the clinical signs of neonates.
(2) Morphology There was no morphological anomaly attributable to administration of the test compound. As the changes observed  sporadically, 
mulitiple anomalities from the external surface to visceral  organs (systemic edema, defect of the second finger and hypoplasia of the  fifth finger of the bilateral forelimbs, hypoplasia of the fifth finger  of the bilateral hindlimbs,  hypoplasia of the left lung, defect of the  right lung) were observed in one animal in the 100 mg/kg group. In  addition, as external anomalies, a kinked tail and systemic edema were  observed in one animal each in the control group. For the visceral  variations, thymic remnant in the neck or persistent left umbilical  artery was sporadically observed in all groups including the control  group, but the frequency was not different between groups.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no adverse effects observed

Target system / organ toxicity (F1)

Critical effects observed:

no

Overall reproductive toxicity

Reproductive effects observed:

no

Any other information on results incl. tables

NOAEL: 1000 mg/kg for the parental males and offspring
        300 mg/kg for the parental females

1) Effects on parent animals 

Number of corpora lutea, implantation sites and
implantation index
-----------------------------------------------------------
Dose level (mg/kg/day)
      0         30        100         300         1000
 No. of corpora lutea (Mean± SD)
   19.6±1.3  19.3±1.8   17.8±2.0    18.1±2.0     16.0±1.8**
 No of implantation sites (Mean± SD)
   18.8±1.4  18.3±1.1   17.6±1.9    17.8±1.8     15.9±1.7**

Significantly different from control (**: p < 0.01)
-----------------------------------------------------------

Applicant's summary and conclusion

Conclusions:

In a valid guideline study the reproductive and developmental toxicological NOAEL is considered as 1000 mg/kg/day for parental males and offspring; 300 mg/kg/day for parental females since decreases in the number of corpora lutea and implantation sites were observed in the 1000 mg/kg group.

Executive summary:

In a valid guideline study the reproductive and developmental toxicological NOAEL is considered as 1000 mg/kg/day for parental males and offspring; 300 mg/kg/day for parental females since decreases in the number of corpora lutea and implantation sites were observed in the 1000 mg/kg group.