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Toxicity Summary

 

Data on maleic anhydride can also be used for maleic acid given that maleic anhydride is hydrolyzed to maleic acid in the body.

 

Acute oral toxicity:

LD50 data for maleic acid as well as for maleic anhydride are in the same range: 708, 1030, 1090 mg per kg body weight.

Acute dermal toxicity:

LD50 data for maleic acid are 1560 mg per kg body weight, whereas the LD50 data for maleic anhydride are between (practically) 400 and 100 mg/kg or above 2000 mg/kg (2620 mg/kg).

Acute toxicity, inhalation:

Inhalation is no relevant route of exposure, as the size particles are to large to inhale.

Repeated dose toxicity:

Results from various subchronic and chronic toxicity studies with maleic acid and maleic anhydride in rats and dogs with oral administration are available. Reported LOELs were between 32 and 250 mg per kg body weight and day, depending on study designs. Reported NOELs were 10 and 40 mg per kg body weight and day in rats and 60 mg per kg body weight in Beagle dogs.

In a 2-years toxicity study with maleic acid in rats, administration in the diet, no NOEL or LOEL was defined. The lowest dose was 0.5 % in feed (ca. 250 mg/kg and day). The main findings were increased mortality rate, reduced body weight/body weight gain and histopathological changes in liver, testis and kidneys.

In a 90-days toxicity study with maleic anhydride in rats, administration in the diet, the LOEL was at 100 mg/kg and day. At 600 mg/kg/day, there was slight proteinuria in both sexes, increased relative liver weight in males, increased relative/absolute kidney weights in both sexes. At 250 mg/kg/day, there was increased relative/absolute kidney weights in males. Grossly observed kidney changes were seen in males fed maleic anhydride 100, 250, and 600 mg/kg/day.The changes were characterized by increased size, pale discoloration, and evidence of dilated tubules in the cortex. Microscopically, the kidneys showed varying degrees of nephrosis, being most severe in the high-dose group. These changes consisted of diffuse tubular dilatation, hypertrophy, and degeneration and regeneration of the tubular cells in the cortical portion of the nephron. A decrease in severity of these changes was observed at lower dose levels, with the kidneys from the 100 mg/kg dose group showing minimal laterations. Similar changes were observed in the kidneys of females, but were generally limited to the high-dose group and were much less severe.

In a 90-days study with maleic anhydride in rats, administration in the diet, the NOEL was 40 mg/kg/day, which was the highest concentration tested.

In a 183-days toxicity study with maleic anhydride in rats, administration in the diet, the LOEL was 250 mg/kg and day. No statistically significant changes in mean body weights and food consumption between treated and control animals. Neither were there any meaningful (or significant) differences in hematology, urinalysis, urine concentration, or clinical chemistry tests. At the 90-day timepoint, the relative liver weight for the rats in the high-dose level and the absolute/relative kidney weights for both the 250 and 600 mg/kg groups were significantly higher compared to the controls. At 183 days, there was a significant increase in the absolute and relative liver and kidney weights for both treatment groups, increased relative testes weight, brain and heart, and decreased fasted body weights for rats at 600 mg/kg/day. Treatment-related changes were present in the kidneys of rats terminated at 90 and 183 days. The observed changes indicated a marked accentuation of the spontaneously occurring findings seen in the control animals. The changes in the controls and treated animals included: individual tubules that were dilated and contained eosinophilic staining casts, granular degeneration of the epithelial cells lining these tubules, tubular collapse and atrophy with peritubular fibrosis, focal mononuclear inflammatory cell infiltrates, glomeruli that showed thickening of the basement membrane, thickening and epithelialization of Bowmans Capsule, and occasionally showed either focal or diffuse sclerosis of the glomerular tufts. Both tubular and glomerular changes in treated animals were more severe than controls, and much more severe in the treated rats at 183 days compared to 90 days. In addition to the focal nature of the lesion (in controls), the tubules throughout the cortex of treated rats showed a generalized dilatation and hypertrophy. There were more degenerative tubules and tubules showing mitotic activity in treated versus controls. The degree of degenerative, hypertrophic, and regenerative changes was dose-related. In many of the 600 mg/kg dose group animals, there was a marked decrease in the amount of functional tissue in the kidney. Livers of maleic anhydride-treated rats at 183 days showed changes characterized by swollen individual hepatocytes having vacuolated cytoplasm.

In a 2-years toxicity study with maleic anhydride in rats, administration in the diet, the LOEL was 32 mg/kg and day, the NOEL was 10 mg/kg and day. There was only marginal toxicity which was evidenced by small, but dose-related, decrease in body weights of male rats fed 32 and 100 mg/kg/day compared to the controls. The female rats fed 32 and 100 mg/kg/day also had reduced body weights, but the reductions were smaller and of shorter duration than those observed in males. Food consumption was also slightly reduced during limited periods during the study for animals in the mid- and high-dose groups. Neither neurologic nor ophthalmologic evaluations revealed differences between treated and control animals. Hematology, clinical chemistry, gross or histopathological evaluations (including the kidneys) showed no differences between treated and control animals that were considered related to maleic anhydride exposure.

In a 90-days toxicity study with maleic anhydride in dogs, administration in the diet, the NOEL was 60 mg/kg and day.

Reproductive toxicity

Maleic anhydride has been tested in a two-generation reproductive toxicity study at oral gavage doses of 0, 20, 55 and 150 mg/kg/day. There was no significant reduction in the percentage of pregnant females or the percentage of fertile males. 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 up to 55 mg/kg/day in the F2 litters.  Maleic anhydride was toxic to parental animals in all dose groups. Significant mortality occurred in the F0 and F1 parental animals. During the second generation, the 150 mg/kg/day female group was terminated on study week 42 due to 100% mortality. Respiratory rales were observed in the F1 (and to minor extent in the F0) adults and the incidence and severity appeared to increase with dose. In the high-dose group F0 body weights were significantly reduced by Week 11, 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 statistically significant body weight depression at 30 weeks. Microscopic examination of tissues for F0 adults revealed compound-related changes in the kidneys and bladder of rats in all dose groups. However, renal cortical necrosis, present in 60% of the males and in 15% of the females was only observed in the high-dose F0 group. In the F1 generation, the absolute kidney weights of adult females in the low- and mid-exposure groups were significantly increased to 108 and 111%, respectively, of the control value. There were no microscopic changes in these kidneys. The NOAEL for reproductive effects was 55 mg/kg/day. For parental toxicity, however, the LOAEL was 20 mg/kg/day.

In female CD rats dosed orally (by gavage) to 0, 30, 90 or 140 mg/kg maleic anhydride in corn oil during days 6 to 15 of gestation had no developmental effects that were considered treatment-related. Dams in all experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation; however, the effect was reversible and there were no statistically significant effects on body weight gains at any interval. Dams from all test groups produced normal-sized litters, with no evidence of post-implantation loss. Fetal body weights in all treatment groups were slightly reduced compared to controls but the reductions were statistically significant only in the 30 and 90 mg/kg groups. This is not considered to be compound-related because fetal weights for concurrent control and all treated groups were slightly greater than the historical control values. There was no evidence of a dose-related increase in any specific malformation. Fetal variations were comparable both in type and frequency in the control and treated groups. There was, however, no maternal NOEL because females at 30 mg/kg failed to gain weight from gestation day 6-9 although this was not statistically significant. The NOAEL for both maternal and developmental toxicity was 140 mg/kg/day.

These effects are likely to reflect the toxicity of maleic acid since maleic anhydride is rapidly hydrolyzed to maleic acid in the body, particularly by the oral route of exposure.

Genetic toxicity

One Ames test and one in vitro gene mutation assay with maleic acid were negative andDNA sythesis was inhibited in another study.
One Ames test with maleic anhydride also gave negative results. One in vitro chromosome aberration study with maleic anhydride was performed only without a metabolising system and gave positive results, one other in vitro chromosome aberration study with maleic anhydride gave ambiguos results.Due to inadequate documentation on this study, it is unclear whether the results were due to the test material itself or a change in pH to an acidic environment, which could have resulted in a non-specific effect.

Toxicokinetic summary

 

Absorption / distribution

The data of acute and repeated toxicity studies clearly indicate absorption of maleic acid in the gastrointestinal tract and distribution in the body. Target organs are kidneys and possibly the liver.

In a study with dogs were fed 60 mg/kg/day maleic anhydride for 90 days the plasma levels were determined (although no analytical data was presented as to whether maleic anhydride or maleic acid was measured since maleic anhydride is rapidly hydrolyzed in aqeuous solutions). An uptake rate constant of 3.49x10E-3 per day and an elimination rate constant of 8.32x10 E-2 per day were calculated assuming a one-compartment model. According to the model, 99% of steady state was reached by day 55 of the study. The dogs were maintained at steady state for the final 35 days of study.

Dow Chemical Company (1984b) Plasma Levels of Maleic Anhydride in Dogs Fed 60 mg/kg/day for 90 Days. Unpublished Report (Secondary Source: SIDS Initial Assessment Report).

 

Maleic acid can penetrate the skin, as shown by acute dermal toxicity data, although the log Pow is very low (-1.29).

Metabolism

No relevant differences occurred in the three mutagenicity studies with and without the addition of a metabolising system. No indication of the importance of the metabolism of the test item was obtained from these studies. Influences on body weight developments in repeated dose toxicity studies may be caused by reduced palatability of the feed mixed with the test substance rather than by metabolic effects.

Biomechanical Mechanism

Maleic acid produces a condition in laboratory animals analogous to the human Fanconi syndrome. Marked changes in both renal tubular function and morphology occur within a period of 2 hours of maleate administration.  The most prominent features in morphological alteration are an enormous accumulation of vacuoles in the apical portion of proximal tubular cells and increased density of the cytosol. Target sites are mainly the late S2 segments of proximal tubules. Renal function changes are characterized by reduced glomerular filtration rate (GFR), single nephron glomerular filtration rate (SNGFR) of superficial nephrons, decreased fractional Na reabsorption, and increased amino acid, glucose and phosphate excretion.

Pfaller, W., Gstraunthaler, G., and Kotanko, P. (1985). Compartments and Surfaces in Renal Cells. In: Renal Biochemistry. Cells, Membranes, Molecules (Kinne, R. K. H., ed.), pp. 1-63, Elsevier Science Publishing Company, Inc, NY (Secondary Source: SIDS Initial Assessment Report)

Excretion

No information is available on excretion of the test item.