Maleic anhydride

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Plasma was obtained from dogs on a 90 day feeding study at 60 mg/kg/day of maleic anhydride. The plasma levels of maleic anhydride was determined and the data analyzed by a nonlinear parameter estimation program.

GLP compliance:

not specified

Radiolabelling:

no

Species:

dog

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

not specified

Duration and frequency of treatment / exposure:

90 days

Dose / conc.:

60 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

The plasma samples were obtained after a 12 hours fast at approximately 8 AM on days 3, 12, 29, and 90 of the 90 day feeding study.
Measurements of plasma concentration of maleic anhydride were made by gas chromatography/mass spectrometry using the method of Hermann and Braun .

Details on absorption:

An uptake rate constant (Ka) of 0.00349 per day was calculated assuming an one-compartment model.

Details on excretion:

An elimination rate constant (Ke) of 0.0832 per day was calculated assuming an one-compartment model.

Toxicokinetic parameters:

other: Ka

Remarks:

Uptake rate constant (Ka) = 3.49 x 10^-3 ± 6.82 x 10^-4 per day

Toxicokinetic parameters:

other: Ke

Remarks:

Clearance (Ke) = 8.32 x 10^-2 ± 2.00 x 10^-2 per day

Metabolites identified:

not measured

Table 1: Maleic anydride plasma concentration (ppm), dogs fed 60 mg/kg/day:

mean maleic anhydride plasma levels in ppm
mean	Day 1	Day 3	Day 12	Day 29	Day 90
males	0.44	0.84	1.35	2.03	2.43
females	0.39	0.69	1.65	2.33	2.8

Table 2: Time to "x" Percent of steady state:

x	Time (Days)
50	8.3 +/- 2.0
75	16.7 +/- 4.01
90	27.6 +/- 6.65
95	36.0 +/- 8.66
99	55.3 +/- 13.3
99.5	64.0 +/- 15.3

Table 3: Percentage of steady state after "x" Days:

x	%
20	81 +/- 7.6
40	96.4 +/- 2.9
60	99.3 +/- 0.80
90	99.94 +/- 0.10
100	99.976 +/- 0.04

Conclusions:

Under the conditions of the study, no bioaccumulation potential was observed. An uptake rate constant of 0.00349 per day and an elimination rate constant of 0.0832 per day were calculated assuming an one-compartment model.

Executive summary:

In a toxicokinetic study, dogs (n= 4/sex) were fed 60 mg/kg/day maleic anhydride for 90 days. The plasma levels of maleic anhydride were determined by gas chromatography/mass spectrometry using the method of Hermann and Braun. An uptake rate constant of 3.49 x 10^-3per day and an elimination rate constant of 8.32 x 10^-2per 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.

Description of key information

Under the conditions of the study, no bioaccumulation potential was observed. An uptake rate constant of 0.00349 per day and an elimination rate constant of 0.0832 per day were calculated assuming an one-compartment model.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The distribution of maleic anhydride in dogs was tested in a 90-day feeding study (60 mg/kg bw maleic anhydride). The plasma levels of maleic anhydride were determined by gas chromatography/mass spectrometry using the method of Hermann and Braun.

On day 1, the maleic anhydride plasma levels in the males ranged from 0.19 ppm to 0.78 ppm and in the females from 0.1 ppm to 0.88 ppm. Interpolation revealed that the blood concentration reached a plateau on day 55.After 90 days the plasma levels in the males ranged from 1.8 to 3.4 ppm and in the females from 1.9 to 3.5 ppm. The uptake rate constant (Ka) was calculated to be 0.00349 per day, the elimination rate (Ke) 0.0832 per day.

Considering the chemical structure of maleic anhydride, metabolism may consist of the hydrolysation to maleic acid in aqueous solutions and epoxidation of the double bond (hydrolysis; Bunton et al, 1963). These reactions lead to more polar and more water soluble products than the parent chemical (maleic acid is soluble in water (400 g/L at 20°C) and has a log Po/w of -2.61 at 25°C (experimental value; OECD SIDS, 2004) and are expected to be excreted predominantly via the urine. The epoxide is a reactive metabolite, but studies on genotoxicity (Ames test, chromosomal aberration test in vivo) were negative, i.e. there is no indication of a reactivity of maleic anhydride or its metabolites under the test conditions.

The toxicokinetic study showed, that maleic anhydride was ingested and distributed in the body. However, the elimination rate was considerably higher than the uptake rate. Taking also into account the log Po/w, the water solubility of the hydrolysation product maleic acid and the considerations on the metabolism, accumulation of maleic anhydride is considered to be unlikely.