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Toxicological information

Toxicity to reproduction

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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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1998
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:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
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.