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Diss Factsheets

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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This is a GLP study conducted according to OECD guideline 422.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993

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)
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibutyl maleate
EC Number:
203-328-4
EC Name:
Dibutyl maleate
Cas Number:
105-76-0
Molecular formula:
C12H20O4
IUPAC Name:
dibutyl but-2-enedioate
Details on test material:
No data available

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
rats: Wistar, CRL:(WI)BR
Supplier: Charles River WIGA, D8741 Sulzfeld
Body weight: (M) mean 365 and (F) mean 245
Age: about 11 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
Doses for the combined test: 0 (control; treated with vehicle), 30, 95, and 300 mg/kg/day.
Dose range finding: 0, 100, 316, and 1000 mg/kg.
Details on mating procedure:
Mating was performed on an 1:1 base after 2 weeks of pre-mating period. Couples were separated after successful mating response at the end of a 10-days mating perido.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
Dosing of both sexes was started at beginning of pre-mating period and continued daily until the end of the study
Frequency of treatment:
Daily
Details on study schedule:
Day -10: receipt of animals
Day 1: First administration of the test substance
Day 15: Start of mating period
Day 16: First proven mating
Day 26: End of mating period
Day 37: First parturition
Day 41: Sacrifice of all males
Day 46: Last sacrifice
No. of animals per sex per dose:
12 female and 12 male Winstar rats per dose.
Details on study design:
Dams were allowed to litter normally and were sacrificed together with their offspring on day 4 of lactation. All males were necropsied together with the first dams.
Positive control:
no available

Examinations

Parental animals: Observations and examinations:
Clinical signs, body weight, feed consumption, mating results, time of parturition, hematology and clinical chemistry in males, necropry, organ weight analysis, histopathology examination.
Oestrous cyclicity (parental animals):
No data availabe
Sperm parameters (parental animals):
No data available
Litter observations:
Clinical signs, litter weight, number, sex and viability, necropsy.
Postmortem examinations (parental animals):
Histopathology of selected tissues.
Postmortem examinations (offspring):
No data
Statistics:
No specified
Reproductive indices:
Number of pregnancies, gestation length, number of implantations, copora lutea, and litter size.
Offspring viability indices:
Number of live births and post implantation loss, and number of pups with grossly visible abnormalities.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Albumin, total protein and bilirubin were significantly higher at teh high dose and urea lower in tyhe low and mid-dose groups.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
some renal changes at high dose but were not assumed to be test substncace realated due to their low incidence. One animal was severely affected in several organs.
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Number of pregnant females 11/11 control, 9/11 at 30 mg/kg/day; 10/10 at 95 mg/kg/day and 10/10 at 300 mg/kg/day.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

Observations in life revealed some unspecific signs of reduced well-being in both sexes and a higher incidence of dermal hyperaemia in males, altogether in the high dosed group only. Body weights of high dosed males were significantly lower than those of the controls towards the end of the dosing period. Clinical chemistry revealed significantly higher albumin, total protein and bilirubin in the high dosed males. A significant decrease in high dosed animals MCH (mean corpuscular haemoglobin) was found at haematological examination. Most prominent alterations at post mortem examination were renal tubular lesions in the high dosed males, i.e. tubular epithelial basophila, tubular dilatation, tubular epithelial proliferation and karyomegaly. Organ weight determination revealed increased absolute and/or relative liver and kidney weights in high dosed animals of both sexes. Individual effects were noted in a single female, suffering from different lesions (heart, kidney, liver) and loosing its whole litter due to lacking nursing behaviour. As this was single case, though being a high dosed animal, these effects cannot be related to the test substance without doubt. All but one fertility parameter remained without significant differences or dose relationships. The only exception was the number of dead pups at birth, which was significantly higher in both mid and high dosed groups.

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
95 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
organ weights and organ / body weight ratios

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
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:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Details on results (F1)

As all but one infant death in the high- dosed group were in the litter of the one severely affected dam mentioned above, those deaths cannot be attributed to an adverse effect on fertility of the test substance. Neither reproductive nor developmental effects were reported in the study.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
95 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Based on the lack of adverse effect in the mid-dose group of the study.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No adverse on reproductive performance were identified, therefore, it can be concluded that dibutyl maleate is neither a developmental nor reproductive toxicant.
Executive summary:

In a combined repeated-dose and reproductive/developmental screening study, dibutyl maleate was administered in arachis oil via gavage to Wistar rats (12/sex/dose) at 0, 30, 95 and 300 mg/kg BW/day during the premating (2weeks) and mating perids (10 days). Females delivered the litters normally and were sacrified with the offspring on day 4 of lactation. Males were also necropsied. Parental toxicity evaluation included clinical signs, body weight, feed consumption, mating results, time parturition; hematology and clinical chemistry in males, necropsy, organ weights, and histopathology of selected tissues. Offspring toxicity evaluation included clinical signs, litter weight, number, sex and viability and necropsy. At the high-dose (300 mg/kg), female and male rats showed unspecific signs of "reduce well-being" and increased absolute and/or relative liver and kidney weights. Also, male rats showed a higher incidence of dermal hyperremia, lower body weights, higher albumin, total protein, and bilirubin; and decreased mean corpuscular hemoglobin and renal tubular lesions including dilation, epithelial basophila, and epithelial proliferation and karyomegaly. A single female rat from the high-dose group lost its whole litter due to lacking nursing behavior. Limited information is available to assess the significance of the number of pup deaths in the mid and high-doses. The NOEL (reproductive toxicity) was determined to be 95 mg/kgBW/day. No adverse effects on reproductive performance were identified.