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Administrative data

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
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1975
Report date:
1975
Reference Type:
review article or handbook
Title:
Maleic Anhydride and Maleic Acid, SIDS Initial Assessment Report For SIAM 18
Author:
OECD SIDS
Year:
2004
Bibliographic source:
OECD SIDS Initial Assessment Report For SIAM 18, Paris, France, 20-23 April 2004

Materials and methods

Objective of study:
distribution
Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Maleic anhydride
EC Number:
203-571-6
EC Name:
Maleic anhydride
Cas Number:
108-31-6
Molecular formula:
C4H2O3
IUPAC Name:
furan-2,5-dione
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Maleic anhydride- Physical state: white crystalline solid- Analytical purity: >/= 99.5%
Radiolabelling:
no

Test animals

Species:
dog
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
not specified

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
not specified
Duration and frequency of treatment / exposure:
90 days
Doses / concentrations
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 .

Results and discussion

Toxicokinetic / pharmacokinetic studies

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 parametersopen allclose all
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

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.

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