Tetramethylene dimethacrylate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

only original in Japanese and abstracts in English available

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1999

Reference 2

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2000

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:

Butane-1,4-diol

EC Number:

203-786-5

EC Name:

Butane-1,4-diol

Cas Number:

110-63-4

Molecular formula:

C4H10O2

IUPAC Name:

butane-1,4-diol

Test material form:

liquid

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan (Ltd.) Atsugi breeding center
- Age at study initiation: 7 weeks
- Weight at study initiation: male: 297-305 g; female: 256-277 g
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ±
- Humidity (%): 50-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

- Amount of vehicle (if gavage): 5 ml

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 15 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 42 days
Females: from 14 days prior to mating to day 3 of lactation

Frequency of treatment:

daily

Details on study schedule:

Exposure period:
Males: For 2 weeks prior to mating and 2 weeks of mating
Females: For 2 weeks prior to mating and 2 weeks of mating and throughout pregnancy antil day 3 postpartum

Doses / concentrations

Remarks:

Doses / Concentrations:
200, 400, 800 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

13 males, 13 females

Control animals:

yes, concurrent vehicle

Positive control:

no

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes /
- Time schedule: daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: once a week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): YES
P males during treatment period, P females during pre-mating period, pregnant period and lactation period
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Postmortem examinations (parental animals):

bladder, liver, kidney, heart, spleen, thymus, testes, epididymides and Haderian gland were observed

Postmortem examinations (offspring):

viablity, body weight on day 4, embodyment

Reproductive indices:

- number of mated pairs
-number of copulated pairs
-copulation index
-number og pregnat animals
-fertility index
-pairing days until copulation
- times of vaginal estrus

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gains were suppressed at 400 and 800 mg/kg during the early period of administration. Food consumption also decreased according to body weight gain

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Body weight gains were suppressed at 400 and 800 mg/kg during the early period of administration. Food consumption also decreased according to body weight gain

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Transient hyperactivity only just after administration was observed at 200 mg/kg/day. At 400 mg/kg, activities were rather suppressed than increased although hyperactivity was also observed after a few doses. At 800 mg/kg, toxic signs observed were more severe and some animals were even comatose after showing hypoactivity and recumbency. By 5 hours after dosing these signs disappeared and animals recovered to normal.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the histopathological examination, diffuse transitional epithelial hyperplasia and fibrosis in the lamina propria of the urinary bladder were observed in the 400 and 800 mg/kg groups.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

The parental animals exhibited no alteration in reproductive parameters including the copulation index, ferility index, gestation length, numbers of corpora lutea or implantation, gestation lenghth, numbers of corpora lutea or implantation index, gestation index, delivery index and behavior at delivery and lactation.

Effect levels (P0)

1

Dose descriptor:

LOEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

neuropathology

other: Hyperactivity/ transient neurotoxic signs in central nervous system. No alteration in reproductive parameters.

2

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Results: F1 generation

General toxicity (F1)

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other:

Remarks:

This change was considered to be secondary to maternal toxicity /reduced food consumption and body weight gain).

Overall reproductive toxicity

Reproductive effects observed:

no

Lowest effective dose / conc.:

800 mg/kg bw/day

Any other information on results incl. tables

For reproductive toxicity, in the observation items related to fertility of the parent generation, change to related test substance administration was observed. The pup weight of the offspring after 4 days of lactation was reduced in the 800 mg / kg dose group in m,ales and females. Although this decline might be the average body weight of nursing four days of the mother animal is due to the fact was a low value, toxicological significance is unknown.

Applicant's summary and conclusion

Executive summary:

An oral subacute toxicity study was performed in SD (Crj: CD) rats by an OECD 422 combined repeat dose and reproductive/developmental toxicity screening test. Administration was conducted at doses of 200, 400 or 800 mg/kg/day by gavage for 45 days in males and from 14 days before mating to day 3 of lactation in females. (MHW, Japan: 1999).

The parental animals exhibited no alteration in reproductive parameters including the copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation. Although neither the pup viability nor the incidence of morphological abnormalities was changed by administration of the compound, pup body weight was slightly but significantly decreased in the 800 mg/kg group. This change was considered to be secondary to maternal toxicity (reduced food consumption and body weight gain). LOAEL parental 200 mg/kg/day (male, female) due to neurotoxic effects (based on OECD SIDS review). NOAEL F1: 800 mg/kg.