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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
OECD Preliminary Reproduction Toxicity Screening Test

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1996

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibutyl adipate
EC Number:
203-350-4
EC Name:
Dibutyl adipate
Cas Number:
105-99-7
Molecular formula:
C14H26O4
IUPAC Name:
dibutyl adipate
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Details on mating procedure:
Premating exposure period: male: 14 days; female: 14 days
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 42 days
Females: from 14 days before mating to day 3 of lactation.
Frequency of treatment:
Frequency of treatment: 7 day /week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Slight suppression of body weight gain was observed in males in 1,000 mg/kg group, while body weight change in females and food consumption in male and female animals in all compound treated groups were comparable to those in the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
pup weight on postnatal days 0 and 4 was slightly decreased along with viability on postnatal day 4.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

Copulation, ovulation, fertility, maintenance of pregnancy, and parturition and lactation were not affected by the test compound.

Reproductive parameters (i.e., duration of gestation, number of corpora lutea, implantations and resorptions, litter size, and sex ratio distribution) were comparable among all four groups including controls. In the 1,000 mg/kg group, pup weight on postnatal days 0 and 4 was slightly decreased along with viability on postnatal day 4. Thus the NOEL was considered to be 1,000 mg/kg/day for reproduction in male and female rats and 300 mg/kg/day for the F1 generation.

Concerning maternal and paternal general toxicity, no mortalities occurred in any group. There were no toxic effects of this chemical on the general condition of male and female animals. Slight suppression of body weight gain was observed in males in 1,000 mg/kg group, while body weight change in females and food consumption in male and female animals in all compound treated groups were comparable to those in the controls. Macroscopic findings at necropsy and histological findings for the internal genitalia showed no abnormalities,. Kidney weights were increased in males and females of the 1,000 mg/kg groups as compared to the control values. Thus the NOEL for general toxicity of this chemical in parent animals was considered to be 300 mg/kg/day.

Applicant's summary and conclusion

Executive summary:

Type: Fertility [ ]; One generation study [ ];

Two generation study [ ]; Other [X]

Species/strain: Rat/Crj: CD (Sprague-Dawley)

Sex: Female [ ]; Male [ ]; Male/Female [X]; No data [ ]

Route of Administration: Oral gavage

Exposure period: Males: 42 days

Females: from 14 days before mating to day 3 of lactation.

Frequency of treatment: 7 day /week

Postexposure observation periodi:

Premating exposure period: male: 14 days; female: 14 days

Duration of the test;

Doses: 0, 100, 300 or 1,000 mg/kg (13 /animals/sex/group)

Control group: Yes [X]; No [ ]; No data [ ];

Concurrent no treatment [ ]; Concurrent vehicle [X]; Historical [ ]

NOEL Parental: 1,000 mg/kg/day (reproductive effect)

300 mg/kg/day (general toxicity)

NOEL F1 Offspring: 300 mg/kg/day

NOEL F2 Offspring: N/A

Results: Copulation, ovulation, fertility, maintenance of pregnancy, and parturition and lactation were not affected by the test compound. Reproductive parameters (i.e., duration of gestation, number of corpora lutea, implantations and resorptions, litter size, and sex ratio distribution) were comparable among all four groups including controls. In the 1,000 mg/kg group, pup weight on postnatal days 0 and 4 was slightly

decreased along with viability on postnatal day 4. Thus the NOEL was considered to be 1,000 mg/kg/day for reproduction in male and female rats and 300 mg/kg/day for the F1 generation.

Concerning maternal and paternal general toxicity, no mortalities occurred in any group. There were no toxic effects of this chemical on the general condition of male and female animals. Slight suppression of body weight gain was observed in males in 1,000 mg/kg group, while body weight change in females and food consumption in male and female animals in all compound treated groups were comparable to those in the controls. Macroscopic findings at necropsy and histological findings for the internal genitalia showed no abnormalities,.

Kidney weights were increased in males and females of the 1,000 mg/kg groups as compared to the control values. Thus the NOEL for general toxicity of this chemical in parent animals was considered to be 300 mg/kg/day.

Method: OECD Preliminary Reproduction Toxicity Screening Test

GLP: Yes [X] No [ ] ? [ ]

Test substance: Commercial, purity > 99 %

Remarks:

Reference: MHW, Japan (1996a)