γ-butyrolactone

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD Guideline Method according to GLP, but serves only as a screening study and not all details of the study were available for review in English.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1999

Reference 2

Reference Type:

secondary source

Title:

OECD SIDS (1,4-Butanediol; CASRN 110-63-4)

Author:

OECD

Year:

2000

Bibliographic source:

OECD Screening Information Data Set (SIDS). UNEP Publications. OECD HPV Integrated Database (CAS #110-63-4)

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

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

Details on test material:

purity: 98.0%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Atsugi Breeding Center
- Age at study initiation: Not reported (7 weeks old when purchased)
- Weight at study initiation: ca. 297g (males); ca. 216g (females)
- Fasting period before study: none
- Housing: seperate raised metal cages; wood chips as bedding (White Flake, Charles River Japan (Ltd.)
- Diet (e.g. ad libitum): solid-type diet (CA-1, Claire Japan (Ltd.), ad libitum
- Water (e.g. ad libitum):tap water, water Waterworks Hadano, ad libitum
- Acclimation period: 1 wk


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1
- 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:

PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): CA-1, Claire Japan (Ltd.)
- Storage temperature of food: No data


VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable
- Amount of vehicle (if gavage): 5 ml/kg adjusted to body weight

Details on mating procedure:

no data

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:

no data

Doses / concentrations

Remarks:

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

No. of animals per sex per dose:

Males, 13; females, 13

Control animals:

yes, concurrent vehicle

Details on study design:

- Post exposure observation period: 1 day
- Dose selection rationale: 1 wk range finding study with 800 mg/kg selected as high dose then two half-steps below
- Rationale for animal assignment (if not random): grouped according to weight then randomly selected

Positive control:

no data

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, 1 or more times


DETAILED CLINICAL OBSERVATIONS: No information reported
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable


FOOD EFFICIENCY:
- Food intake was measured but details are unclear


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not applicable


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: After final exposure
- Anaesthetic used for blood collection: pentobarbital
- Animals fasted: No data
- How many animals: all


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After final exposure
- Animals fasted: No data
- How many animals: all


URINALYSIS: Reported data unclear
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No

Oestrous cyclicity (parental animals):

yes, but translated information is unclear

Sperm parameters (parental animals):

yes, but translated information is unclear

Litter observations:

yes, but translated information is unclear

Postmortem examinations (parental animals):

yes, but translated information is unclear

Postmortem examinations (offspring):

yes, but translated information is unclear

Statistics:

yes, but translated information is unclear

Reproductive indices:

yes, but translated information is unclear

Offspring viability indices:

yes, but translated information is unclear

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

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

Details on results (P0)

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.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Absence of developmental effects.

2

Dose descriptor:

NOEL

Effect level:

400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Slight but significant decrease in pup weights on day 4 of lactation at the 800 mg/kg bw/day dose level.

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Details on results (F1)

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).

Effect levels (F1)

1

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Absence of adverse effects on reproduction.

2

Dose descriptor:

NOEL

Generation:

F1

Effect level:

400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Repeated dose toxicity without negative effects on reproduction. See section 7.5.1 of IUCLID file.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The compound showed no effects on mating and fertility in dosed animals, and viability and morphogenesis in pups. The body weights of pups of 800 mg/kg on day 4 of lactation were slightly but significantly lower than those of controls. This change was considered to be secondary to maternal toxicity.