Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication and study report which meets basic scientific principles. Reliability adopted from OECD SIDS Draft.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Teratology and multigeneration reproduction studies with maleic anhydride in rats
Author:
Short, R. D., Johannsen, F. R., Levinskas, G. J., Rodwell, D. E., and Schardein, J. L.
Year:
1986
Bibliographic source:
Fundam. Appl. Toxicol. 7: 359-366
Reference Type:
publication
Title:
Unnamed
Year:
1979
Report Date:
1979
Reference Type:
publication
Title:
Unnamed
Year:
1991
Report Date:
1991
Reference Type:
secondary source
Title:
Unnamed
Year:
1979
Reference Type:
secondary source
Title:
Teratology and multigeneration reproduction studies with maleic anhydride in rats
Author:
Short, R. D., Johannsen, F. R., Levinskas, G. J., Rodwell, D. E., and Schardein, J. L.
Year:
1986
Bibliographic source:
Fundam. Appl. Toxicol. 7: 359-366; cited in OECD SIDS Draft for CAS. Nos. 108-31-8/ 110-16-7, 2005
Reference Type:
secondary source
Title:
A 6-month multispecies inhalation study with maleic anhydride
Author:
Short, R.D., Johannsen, F.R., Ulrich, C.
Year:
1988
Bibliographic source:
Appl. Toxicol. 10: 517-524; cited in OECD SIDS Draft for CAS. Nos. 108-31-8/ 110-16-7, 2005
Reference Type:
secondary source
Title:
Teratogenic Study of Maleic Anhydride in Rats
Author:
Goldenthal, E. I., Jessup, D. C., and Rodwell, D. E.
Year:
1979
Bibliographic source:
cited in: EPA, Health and environmental effects profile of maleic anhydride, 06/1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(administered volume in the control and high dose group is higher (1.4 ml/100 g bw) than the advised maximum volume in the guideline (0.4 ml/100 g bw))
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): maleic anhydride
- Physical state: white briquettes
- Analytical purity: > 99%

Test animals

Species:
rat
Strain:
other: Charles River CD rats
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 12 weeks
- Housing: individually housed, except during mating
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Concentration in vehicle: 1% (w/v)
- Amount of vehicle (if gavage): 0.3-1.4 ml/100g bw
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
from gestation day 6 through day 15
Frequency of treatment:
daily
Duration of test:
day 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 90, 140 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes


BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, and 20

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: fetal swellings, number of viable and nonviable fetuses
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [1/3 per litter ]
- Skeletal examinations: Yes: [2/3 per litter ]
Statistics:
All statistical analyses compared the treatment groups with the control group, with the level of significance at p<0.05. Male to female fetal sex ratio and number of litters with anomalies were compared using the Chi-square test criterion with Yates correction for 2 x 2 contingency tables and/or Fisher's exact probability test as described by Siegel to Judge significance of differences. The proportion of lite resorbed fetuses and postimplantation losses were compared by the Mann-Whitney U-test as described by Siegel and Weil to judge significance of differences. Mean number of corpora lutes, total implantations and viable fetuses were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnett's multiple comparison table to judge significance of differences. Fetal body weights were compared by analysis of variance (hierarchal classification) and t-test as described by Steel and Torri using Dunnett's multiple comparison tables to judge significance of differences.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Respiratory involvement and red nasal discharge were observed in all dosage groups. The incidence of these was higher in the treated groups, though not in a dose-related pattern. No treatment-related deaths (one rat in each dosage group died during the first part of treatment; the cause of death was not determined) nor abnormal behavior was observed in any of the maleic anhydride treated groups. Mean body weight gain was reduced in the 30 mg/kg/day dosage group for the first three days of treatment. There was a slight mean body weight loss in the 90 and 140 mg/kg/day dosage groups for the first three days of treatment. These reductions in weight gains resulted in reduced mean body weight gains over the entire treatment period in all treatment groups compared to the control (however, mean weight of all groups was within 5% of control on days 15 and 20. No biologically meaningful differences in the mean number of viable fetuses, implantations, post implantation losses, corpora lutea, or in the male to female sex ratio between any of the maleic anhydride treated groups and the control group. The general appearance and behavior of rats were not affected by treatment.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 140 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Mean fetal body weights were lower in the treatment groups than in the control group. This was not considered compound related due to the unusually high mean fetal body weight in this concurrent control group (mean: 4 g). External evaluation, internal examination, and skeletal observations of fetuses from all three treatment groups showed no anomalies in fetal development which could be attributed to maleic anhydride (slight increase in fetal malformations in the 30 (2/23 litters) and 140 mg/kg/day dosage group (3/21 litters) when compared to the control group (1/23 litters) is considered due to random occurrence due to the variety of abnomalities observed).

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 140 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
>= 140 mg/kg bw/day
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion