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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive 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:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data from handbook or collection of data, read-across from malein anhydride

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Maleic anhydride (99.7%) Maleic anhydride hydrolyses under test conditions. As a result, it is believed that maleic acid and its salts were the test materials investigated in this study. See also SIDS Initial Assessment.

Test animals

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
no data
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Pre-mating and throughout mating, gestation and lactation
Premating exposure period: F0 and F1, a minimum of 80 days
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 55 and 150 mg/kg
Basis:
actual ingested
Control animals:
yes
Details on study design:
dose volume: 10 mL/kg

Examinations

Parental animals: Observations and examinations:
no data
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
no data
Postmortem examinations (parental animals):
no data
Postmortem examinations (offspring):
no data
Statistics:
no data
Reproductive indices:
no data
Offspring viability indices:
no data

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
mortalities at 150 mg/kg
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced at 55 and 150 mg/kg
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
reduced at 55 and 150 mg/kg
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
kidney, bladder
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
kidney, bladder

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
reduced at several timepoints, no dose-related pattern

Details on results (P0)

With the exception of a few cases of respiratory rales, the clinical appearance and behavior were not remarkably different from the controls. Significant mortality occurred in adults of both sexes from the 150 mg/kg group.
Body weights in the F0 high-dose group were significantly reduced by Week 11 and this reduction persisted for the remainder of the test. The mid-dose group means were low but not statistically significantly different from the controls.
Macroscopic and microscopic examination of tissues from F0 adults revealed compound-related changes in the kidneys and bladder of rats from all dose groups. However, renal cortical necrosis, present in 60% of the males and in 15% of the females from this group, was observed in the high-dose group only.

Effect levels (P0)

Dose descriptor:
LOEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
respiratory rales
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
mortality (females) in study week 42
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
most prominent in high dose males
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
absolute kidney weights (females, 20 and 55 mg/kg) increased
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

F1 clinical observations: Respiratory rates were also observed and the incidence and severity appeared to increase with dose. These rats often vigorously resisted handling at the time of dosing. Due to 100% mortality among the high-dose females by study week 42, the remaining high-dose males were terminated by study week 44.
F1 generation showed a similar pattern of depressed weight gain as the F0 generation; however, only the F1 males in the high-dose group had significantly significant body weight depression at 30 weeks. No fertility or offspring data are available from the high-dose animals.
In the F1 generation, the absolute kidney weights of adult females in the low- and mid-dose groups were significantly increased to 108 to 111%, respectively, of the control value. There were no microscopic changes in these kidneys.
Fertility was significantly reduced in the treatment groups at several timepoints; however, neither a dose-related reduction nor a pattern within a generation suggested a treatment-related effect
No adverse effects on litter size and on pup survival were observed at doses up to 150 mg/kg/day in the F1 litters, or at 55 mg/kg/day in the F2 litters. Microscopic examination of tissues from pups in the F2 liters revealed no treatment-related changes. Therefore, treatment up to 55 mg/kg/day for two generations had no adverse effect on pups.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: litter size, pup survival

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOEL
Generation:
F2
Effect level:
55 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: litter size, pup survival

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Since there was no significant reduction in the percentage of pregnant females or the percentage of fertile males, it is concluded that no adverse effects on fertility were observed with maleic anhydride at doses up to 55 mg/kg/day administered over two generations. Maleic anhydride was toxic to parental animals at all dose levels.
Executive summary:

A two-generation study similar to OECD 416 was performed with maleic anhydride in Sprague-Dawley rats. The test substance was administered orally at doses of 0, 20, 55 and 150 mg/kg body weight and day, on 7 days/week, at a dose volume of 10 mL/kg body weight.

Results:

F0 clinical observations: with the exception of a few cases of respiratory rales, the clinical appearance andbehaviorwere not remarkably different from the controls. Significant mortality occurred in adults of both sexes from the 150 mg/kg group.

F1 clinical observations: Respiratory rates were also observed and the incidence and severity appeared to increase with dose. These rats often vigorously resisted handling at the time of dosing.  Due to 100% mortality among the high-dose females by study week 42, the remaining high-dose males were terminated by study week 44.

Body weights in the F0 high-dose group were significantly reduced by Week 11 and this reduction persisted for the remainder of the test. The mid-dose group means were low but not statistically significantly different from the controls. F1 generation showed a similar pattern of depressed weight gain; however, only the F1 males in the high-dose group had significantly significant body weight depression at 30 weeks. No fertility or offspring data are available from the high-dose animals. 

Macroscopic and microscopic examination of tissues from F0 adults revealed compound-related changes in the kidneys and bladder of rats from all dose groups. However, renal cortical necrosis, present in 60% of the males and in 15% of the females from this group, was observed in the high-dose group only. In the F1 generation, the absolute kidney weights of adult females in the low- and mid-dose groups were significantly increased to 108 to 111%, respectively, of the control value. There were no microscopic changes in these kidneys.

Fertility was significantly reduced in the treatment groups at several timepoints; however, neither a dose-related reduction nor a pattern within a generation suggested a treatment-related effect.

No adverse effects on litter size and on pup survival were observed at doses up to 150 mg/kg/day in the F1 litters, or at 55 mg/kg/day in the F2 litters. Microscopic examination of tissues from pups in the F2 liters revealed no treatment-related changes. Therefore, treatment up to 55 mg/kg/day for two generations had no adverse effect on pups.

Since there was no significant reduction in the percentage of pregnant females or the percentage of fertile males, it is concluded that no adverse effects on fertility were observed with maleic anhydride at doses up to 55 mg/kg/day administered over two generations. Maleic anhydride was toxic to parental animals at all dose levels.