Hexadecyl hydrogen maleate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

other: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

publication

Title:

Teratology and Multigeneration Reproduction Studies with Maleic Anhyride in Rats

Author:

Short RD, Johannsen FR, Levinskas GJ, Rodwell DE and Schardein JL

Year:

1986

Bibliographic source:

Fundamental and Applied Toxicology 7, 359-366

Materials and methods

Principles of method if other than guideline:

Teratology study in rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

2,5-Furandione

Test animals

Species:

rat

Strain:

other: CD-rats

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charkes River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: 12 wks
- Housing: individually housed, except during mating and lactation, in wire mesh cages or plastic cages with corn-cob bedding
- Diet: ad libitum. Purina Rodent Chow, Ralston-Purina, St. Louis, Mo
- Water: ad libitum
- Acclimation period: at least 10 days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

The test material was finely ground with a mortal and pestle and suspended in corn oil with the aid of a tissue homogenizer.
All doses were prepared daily in corn oil in order to minimize problems with stability. A 1 % w/v concentration was used to administer all doses

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

One male and one female were housed together for mating. The day of mating was determined by daily inspection for a copulatory plug for a sperm-positive vaginal smear. The day was designated Day 0 of gestation

Duration of treatment / exposure:

from day 6 through day 15 of gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

90 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

140 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25 mated females/group

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Body weights were recorded at intervals during gestation
Post-mortem examination: all females were sacrificed with carbon dioxide on Day 20 of gestation and the fetuses were delivered by cesarian section.

Fetal examinations:

All fetuses were weighed and examined for external abnormalities. Approximately 1/3 of the fetuses were placed in Bouin's fixative and examined for soft tissue abnormalities. The remaining fetuses were fixed in alcohol, cleared with potassium hydroxide, stained with Alizarin Red S and examined for skeletal abnormalities

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Description (incidence):

One adult died in each of the experimental groups, however, the overall survival in these groups was 96%

Description (incidence and severity):

Dams in the 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 weights at any of the times examined.

Description (incidence and severity):

The general appearance and behaviour of rats were not altered by treatment

Maternal developmental toxicity

Description (incidence and severity):

Dams from all test groups produced normal sized litters and there was no evidence of post-implantation loss.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

140 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse efects observed up the highest concentration

Results (fetuses)

Description (incidence and severity):

Compared with concurrent controls, fetal body weights were slighly reduced for all test groups but the reductions were statistically significantly significant only in the low- and high- dose groups. However, this is not considered to be compound-related, because fetal weights for concurrent control and all treated groups were slightly greater than the values for historical controls.

Description (incidence and severity):

Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group and three fetuses (three litters) from the high-dose group. Since each malformation was a singe occurence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation. the fetal variations were comparable both in type and frequency in the control and treated groups.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

Not teratogenic

Executive summary:

The effect of the substance on the development in CD rats were evaluated. Pregnant rats received 0, 30, 90 or 140 mg/kg/day of test material in corn oil orally from Days 6 -15 of gestation and fetuses were examined for gross soft tissue and skeletal effects. Maternal toxicity was demonstrated by the failure of dams to gain weight between Days 6 and 9 of gestation. Larger doses of test material would have had more severe effects on weight gain and probably would have produced mortality, thus compromising the present study. In the teratology study, dams were treated orally with up to 140 mg/kg/day from day 6 to day 15 of gestation. An examination of fetuses did not revealed any effects that were attributed to the test material. No increase in fetal malformations was observed, and the variations detected were similar in control and treated groups. Under the conditions of the study, no treatment-related effects on fetal development were observed and thus it is concluded that the substance is not teratogenic.