Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles. Reliability was adopted from OECD SIDS.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Objective of study:
distribution
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, maleic acid, respectively, were determined and the data analyzed by a nonlinear parameter estimation program.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
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:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 13-14 months
- Fasting period before study: 12 hrs
- Housing: in pens according to sex and dose
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 months

Administration / exposure

Route of administration:
oral: feed
Vehicle:
peanut oil
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet: weekly
- Storage temperature of food: The basal ration consisted of ground laboratory chow supplemented with 1% peanut oil. A premix composed of 5% maleic anhydride and the basal ration was used to prepare the test diets
Duration and frequency of treatment / exposure:
90 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 40, or 60 mg/kg
No. of animals per sex per dose:
4
Control animals:
yes, concurrent no treatment
Details on study design:
Four animals/sex/dose were used for this study. Body weights and food consumption were recorded, and the dogs were observed for signs of toxicity. Clinical parameters were evaluated by determination made prior to the beginning of the study and at intervals throughout the test period. These included hematological studies, urinalysis and various clinical chemistry studies. Gross examination was conducted at necropsy after the exposure period, organ weights were examined, and tissues were obtained for histopathological evaluation.

Results and discussion

Preliminary studies:
In a preliminary tolerance study, beagle dogs fed maleic anhydride in their diets at a concentration that provided 100 mglkg/day showed a considerable decrease in food intake along with a loss of body weight within one week. Dogs fed a dose of 20 mg/kg/day for 2 weeks, then 40 mq/kg/day for 2 weeks, and finally 60 mg/kg/day for 2 weeks showed no decrease in food consumption or body weight or other signs of toxicity. Based on these findings, dose levels of 20, 40, and 60 mg/kg/day maleic anhydride were selected for the 90-day study.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
An uptake rate constant of 0.00349 per day was calculated assuming an one-compartment model.
Details on excretion:
An elimination rate constant of 0.0832 per day was calculated assuming an one-compartment model.

Any other information on results incl. tables

mean maleic anhydride plasma levels in ppm
means 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

According to the one-compartment 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 the 90 day study.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
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.
NOEL = 60 mg/kg/day (highest dose tested)
Executive summary:

In a 90 day feeding study with Beagle dogs (7 days a week, ad libitum), no adverse effects were reported at all dose groups.

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.

Highest dose tested: NOEL = 60 mg/kg/day.