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EC number: 203-570-0 | CAS number: 108-30-5
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.
Table 1. Mortality and body weight of adult rats treated with maleic anhydride during a multigeneration reproduction study
Maleic anhydride (mg/kg/day)
Table 2. Fertility of rats treated with maleic anhydride during a multigeneration reproduction study
Table 3. Litter size of rats treated with maleic anhydride during a multigeneration reproduction study
Table 4. Body weight of pups from rats treated with maleic anhydride during a multigeneration reproduction study
In a two-generation study similar to OECD guideline 416, CD rats (10 males and 20 females/group) received 0, 20, 55, or 150 mg/kg/day maleic anhydride in corn oil orally and were mated to produce two generations, each with two litters. Treatment-related mortality in the F0 and F1 generations occurred primarily in the high-dose group. There were some gavage-related deaths in the F0 generation and mortality was observed at lower doses in the F1 generation but these were not related to treatment. Renal cortical necrosis occurred in high dose F0 males and females. Increased kidney weights were observed in the low- and mid-dose adult F1 females. No significant reduction in the percentage of pregnant females or the percentage of fertile males was observed with maleic anhydride at doses up to 55 mg/kg/day over two generations. At 150 mg/kg/day, maleic anhydride was toxic to parental animals. No adverse effects on litter size or pup survival were observed at doses up to 150 mg/kg/day in F1a and F1b litters or 55 mg/kg/day in F2a and F2b litters. Based on the results, the NOAEL (maternal & reproductive) can be considered to be 55 mg/kg bw/day.
Cyclic anhydrides, such as maleic anhydride and succinic anhydride, share structural and physicochemical properties. Reproductive toxicity data on maleic anhydride can be used to read-across to succinic anhydride and similar results would be expected. A separate study investigating reproductive toxicity of succinic anhydride is not proposed and cannot be justified based upon animal welfare considerations.
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