Registration Dossier

Toxicological information

Toxicity to reproduction

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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:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1999
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:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity: 98.0%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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)

open allclose all
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.
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)

open allclose all
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.
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.