Fumaric acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

other: Safety assessment

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Peer-reviewed safety assessment by the Cosmetic Ingredient Review Expert Panel.

Data source

Reference

Reference Type:

publication

Title:

Final report on the safety assessment of malic acid and sodium malate

Author:

Fiume MZ

Year:

2001

Bibliographic source:

Int J Toxicol 20 Suppl 1: 47-55

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Peer-reviewed safety assessment by the Cosmetic Ingredient Review Expert Panel.

GLP compliance:

not specified

Remarks:

published review

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Malic acid

EC Number:

230-022-8

EC Name:

Malic acid

Cas Number:

6915-15-7

IUPAC Name:

malic acid

Details on test material:

Malic acid is a metabolite of fumaric acid.

Test animals

Species:

rat

Strain:

not specified

Details on test animals or test system and environmental conditions:

No further animal information available.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Rats were fed 1000 or 10000 ppm malic acid for 9 weeks prior to mating for the F1A litter and through weaning of the F1B litter.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Rats were fed 1000 or 10000 ppm malic acid for 9 weeks prior to mating. One week after weaning of the last F1A litter, the P1 parents were remated to produce the F1B litter. Ten male and 20 female weanlings from each dose group were selected for the P2 generation and administered the appropriate diets. The animals were mated at 100 days of age to produce the F2A generation. One week after weaning of the F2A litter, the P2 parents were remated to produce the F2B litter.

Duration of treatment / exposure:

9 weeks

Frequency of treatment:

Daily in feed

Duration of test:

Multi-generation study

Doses / concentrations

Remarks:

Doses / Concentrations:
1000 or 10000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 males and 20 females per dose

Control animals:

yes, plain diet

Details on study design:

No further information available

Examinations

Maternal examinations:

Body weight gain, feed consumption, survival, appearance and behavior were evaluated.

Ovaries and uterine content:

Various indices and litter sizes were evaluated.

Fetal examinations:

Pup body weights were determined.

Statistics:

No information available.

Indices:

No information available.

Historical control data:

No information available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Body weight gain of female animals were comparable to controls prior to mating. Body weight gains of male animals in test groups were slightly decreased compared to controls. Feed consumption, survival, appearance and behavior were similar for P1 test and control rats. The P2 test and control animals were similar throughout the study and wheezing was observed in all groups during the F2B phase.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

> 10 000 ppm (nominal)

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
F1A: all necropsied pups from low dose group had rough surfaces on the spleen
F2A: the number of pups that were weak or had labored respiration during lactation was increased in the high dose group. No abnormal findings were reported at necropsy.
F2A: Renal discoloration, dark renal medullas and rough surfaces on the spleen where seen at both dose levels at necropsy. In addition, low dose animals had white foci on spleen. High dose animals also had dark red corticomedullary zones and a firm, enlarged, irregularly-shaped cecum with a hole penetrating it.
F2B litters delivered naturally showed weakness and labored respiration in the low dose group and the renal pelvis of one high-dose pup was dilated at necropsy.
F2B litters delivered by caesarean section showed no differences when compared to controls.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 10 000 ppm (nominal)

Remarks on result:

other: not determinable/no NOAEL identified

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The F2B generation showed no meaningful differences between test and control animals in the number and placement of implantation and resorption sites or in the number, weight, or length of live neonates, and none of the neonates died. The skeletal development of F2B neonates was similar between test and control animals. Slight differences in developmental indices were considered to be within the range of normal variations in fetal development and no trend toward lesser or greater skeletal development was observed.

Applicant's summary and conclusion

Conclusions:

This safety assessment supports the conclusion that malic acid, a metabolite of fumaric acid, is not a developmental toxicant.

Executive summary:

Malic acid was administered to rats at doses of 1000 or 10,000 ppm in the diet for 9 weeks prior to mating through weaning. Weanlings from this group were selected for the P2 generation and fed a similar diet. For all litters, various indices, litter sizes and pup body weights were comparable to controls and no significant differences in skeletal development were observed. Similar results would be expected with the closely related chemical, fumaric acid, and no toxic effects on the development of offspring are likely to be seen.