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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Teratology and multigeneration reproduction studies with maleic anhydride in rats
Author:
Short RD, Johannsen FR, Levinskas GJ, Rodwell DE, and Schardein JL.
Year:
1986
Bibliographic source:
Fundamental and Applied Toxicology 7: 359-66

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
White briquettes with a purity of greater than 99%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Weanling rats were acclimated to the laboratory for at least 10 days prior to study initiation. Rats were individually housed, except during mating and lactation, in wire mesh cages or plastic cages with corn-cob bedding. All animals were maintained in environmentally controlled rooms with 12-hr photoperiods and given free access to feed (Purina Rodent Chow) and water.

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
corn oil
Details on exposure:
Briquettes of maleic anhydride were finely ground with a mortar and pestle and suspended in corn oil with the aid of a tissue homogenizer. All doses were prepared daily in corn oil in order to minimize problems with stability. The concentration of maleic anhydride was varied so that the desired dose could be administered orally in a volume of 10 mL/kg.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
Each generation was dosed a minimum of 80 days with maleic anhydride before its members were mated.Rats in groups of 10 males and 20 females were treated at 0, 20, 55 or 150 mg/kg bw/day (F0), Treatment began when the F0 rats were 5-6 weeks old, continued for at least 80 days prior to mating and continued to termination. For the F1 animals treatment began on Day 22, continued for at least 80 days prior to mating and then continued to termination
Frequency of treatment:
Daily
Duration of test:
Each generation was dosed a minimum of 80 days with maleic anhydride before its members were mated.Rats in groups of 10 males and 20 females were treated at 0, 20, 55 or 150 mg/kg bw/day (F0), Treatment began when the F0 rats were 5-6 weeks old, continued for at least 80 days prior to mating and continued to termination. For the F1 animals treatment began on Day 22, continued for at least 80 days prior to mating and then continued to termination
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
low dose
Dose / conc.:
90 mg/kg bw/day (nominal)
Remarks:
mid dose
Dose / conc.:
140 mg/kg bw/day (nominal)
Remarks:
high dose
No. of animals per sex per dose:
25 mated females per group
Control animals:
yes, concurrent vehicle
Details on study design:
No further information

Examinations

Maternal examinations:
no details
Ovaries and uterine content:
no details
Fetal examinations:
no details
Statistics:
no details
Indices:
no details
Historical control data:
no details

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
The general appearance and behavior of rats were not altered by treatment. While one adult died in each of the experimental groups, the overall survival in these groups was 96%. Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
140 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss. Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups, However, this is not considered to be compound-related, because fetal weights for were slightly greater than the values for historical controls. Malformations were observed in one fetus (one litter) from the con-
trol group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation. The fetal variations were comparable both in type and frequency in the control and treated groups.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
140 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects were observed

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In the teratology study, pregnant rats received 0, 30, 90, or 140 mg/kg/day maleic anhydride in corn oil orally from Days 6-15 of gestation and fetuses were examined for gross soft tissue and skeletal defects. Based on the result, the maternal and developmental NOAEL can be considered to be 140 mg/kg bw.
Executive summary:

In a developmental toxicity study (equivalent to OECD 414), CD rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day of maleic anhydride from Day 6 through Day 15 of gestation. Mated females in the control group were treated in a similar manner with 14 mL/kg of corn oil. All females were sacrificed with carbon dioxide on Day 20 of gestation, and the fetuses were delivered by cesar-

ean section. All fetuses were weighed and examined for external abnormalities. Approximately one-third of the fetuses were placed in Bouin’s fixative and examined for soft tissue abnormalities (Wilson, 1965). The remaining fetuses were fixed in alcohol, cleared with potassium hy-droxide, stained with Alizarin Red S (Dawson, 1926), and examined for skeletal abnormalities.

Results showed, that the general appearance and behavior of rats were not altered by treatment. While one adult died in each of the experimental groups, the overall survival in these groups was 96%. Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.

Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss. Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups, However, this is not considered to be compound-related, because fetal weights for were slightly greater than the values for historical controls. Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation. The fetal variations were comparable both in type and frequency in the control and treated groups.

Based on the results obtained, the maternal and developmental NOAEL can be considered to be 140 mg/kg bw/day.