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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The effects of fumaric acid on reproduction have been assessed in a number of older published studies. These data, combined with the role of fumaric acid in mammalian metabolism and the lack of reproductive effects in a study with the fumaric acid metabolite, maleic acid, provide sufficient information to determine that fumaric acid has a low toxicity profile and is not considered to be a reproductive toxicant.

In addition, data from the read-across partner maleic anhydride was used to assess the reproductive toxicity of fumaric acid. In a multigeneration reproductive toxicity study (similar to OECD TG 416) in rats treated with maleic anhydride, no treatment-related effects on reproduction were observed at doses of up to 55 mg/kg bw/day.

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
circa 1946
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer-reviewed study with sufficient detail to enable confident assessment of the method and interpretation of the results
Qualifier:
no guideline available
Principles of method if other than guideline:
Effects on reproduction or lactation were assessed after administration of 1% fumaric acid in the diet for 52 weeks.
GLP compliance:
no
Remarks:
Study predates establishment of GLP guidelines
Limit test:
no
Species:
guinea pig
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
Young guinea pigs weighing between 236 and 304 g were maintained for 52 weeks on a diet consisting of ground rabbit chow (Purina). One percent fumaric acid was added to the ration of the test group of animals. The guinea pigs were housed in groups of three in wire-bottom cages. During the first 16 weeks of the experiment, lettuce was given twice a week but the animals showed signs of ascorbic acid deficiency, with some deaths. At this time, cabbage was substituted for lettuce. In addition, each animal was given orally, once a week, a solution containing 50 mg ascorbic acid.
Route of administration:
oral: feed
Vehicle:
other: cod liver oil added to diet mix
Details on exposure:
The guinea pigs were fed 1.0% fumaric acid in the diet.
Details on mating procedure:
Twelve young pigs were cast by the two females which received fumaric acid in the ration. The fathers were also fed the fumaric-acid containing diet.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
52 weeks
Frequency of treatment:
Daily - ad libitum in diet
Details on study schedule:
Guinea pigs were fed fumaric acid in the diet for 52 weeks.
Remarks:
Doses / Concentrations:
1.0%
Basis:
nominal in diet
No. of animals per sex per dose:
Two females
Control animals:
not specified
Details on study design:
No further details on study design available.
Positive control:
A positive control was not included.
Parental animals: Observations and examinations:
Body weights were recorded over a period of 52 weeks. Animals was observed for signs of toxicity.
Oestrous cyclicity (parental animals):
Oestrus cyclicity was not examined.
Sperm parameters (parental animals):
Sperm parameters were not examined.
Litter observations:
The rate of increase in body weight was determined for the offspring.
Postmortem examinations (parental animals):
No information available.
Postmortem examinations (offspring):
No information available.
Statistics:
No statistical information available.
Reproductive indices:
Indices were not determined.
Offspring viability indices:
Indices were not determined.
Clinical signs:
no effects observed
Description (incidence and severity):
see comments below
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see comments below
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
see comments below
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
see comments below
There were too few female animals in each group to give a significant average value but fumaric acid does not appear to exert any detectable effect on the growth of guinea pigs. Average growth values for male rats, though quite irregular, are more or less coincident. No evidence of toxicity was found in offspring of guinea pigs fed a 1% fumaric acid diet from birth. There were no effects on reproduction or lactation.
Dose descriptor:
NOAEL
Effect level:
> 400 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No adverse effects were seen
Clinical signs:
no effects observed
Mortality / viability:
not examined
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
The rate of increase in body weight of the males was considerably greater than that of the parent control group. The authors attributed this to a diet adequate in ascorbic acid during the entire growth period of these animals.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 400 mg/kg bw/day (nominal)
Sex:
not specified
Basis for effect level:
other: No adverse effects were seen in offspring exposed to 1% fumaric acid (400 mg/kg bw/day) from birth.
Reproductive effects observed:
not specified

No evidence of toxicity was found in F1 generation guinea pigs fed a 1.0% fumaric acid diet from birth (400 mg/kg bw/day).

Conclusions:
No evidence of toxicity was found in F1 generation guinea pigs fed a 1.0% fumaric acid diet from birth (400 mg/kg bw/day).
Executive summary:

No evidence of toxicity was found in F1 generation guinea pigs fed a 1.0% fumaric acid diet from birth (400 mg/kg bw/day).

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
other: Safety assessment
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Peer-reviewed safety assessment by the Cosmetic Ingredient Review Expert Panel.
Qualifier:
no guideline required
Principles of method if other than guideline:
The paper provides a comprehensive review of data presented to support th use of malic acid as a ph-adjuster in cosmetic preparations. Malic acid can be prepared by hydration of fumaric acid and it forms part of the Krebs cycle. These similarities mean that read across to fumaric acid, an endogeneous, ubiqitous organic acid present in humans, is feasible.
GLP compliance:
not specified
Remarks:
published review
Limit test:
no
Species:
other: mice, rats and rabbits
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
Reproductive and developmental toxicity studies were carried out in mice, rats and rabbits.
Route of administration:
oral: gavage
Vehicle:
other: water used in some studies
Details on exposure:
Mouse study: Groups of 25 albino CD-1 mice were mated and dosed orally with 2.66, 12.4, 57.3, or 266 mg/kg malic acid on days 6 through 15 of gestation.
Rat study: Groups of 25 to 29 Wistar albino rats were mated and dosed orally with 3.5, 16.2, 75.4, or 350 mg/kg malic acid on days 6-15 of gestation.
Rabbit study: Groups of 15-23 Dutch-belted rabbits were inseminated artificially and dosed orally with 3, 14, 65 or 300 mg/kg malic acid on days 6 to 18 of gestation.
Details on mating procedure:
Mice and rats were mated, rabbits were artificially inseminated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Mice and rats: 10 days during gestation
Rabbits: 13 days during gestation.
Frequency of treatment:
Daily
Details on study schedule:
The animals were mated. Malic acid was administered by gavage on gestational days 6 through 15 in the case of mice and rats, for rabbits dosing was continued through to gestational day 18.
Remarks:
Doses / Concentrations:
2.66, 12.4, 57.3, or 266 mg/kg
Basis:
other: Mice: nominal concentration
Remarks:
Doses / Concentrations:
3.5, 16.2, 75.4, or 350 mg/kg
Basis:
other: Rats: nominal concentration
Remarks:
Doses / Concentrations:
3, 14, 65 or 300 mg/kg
Basis:
other: Rabbits: nominal concentration
No. of animals per sex per dose:
Mice: 25 females/dose
Rats: 25 to 29 females/dose
Rabbits: 15 to 23 females/dose
Control animals:
yes
Details on study design:
No further details available.
Positive control:
Mouse study: 150 mg/kg aspirin as positive control
Rabbit study: 6-aminonicotinamide as positive control
Parental animals: Observations and examinations:
Mouse study: All animals were observed daily. Body weights were determined on days 0, 6, 11, 15 and 17 of gestation.
Rat study: All animals were observed daily and body weights were recorded at regular intervals.
Rabbit study: All animals were observed daily. Body weights were determined on days 0, 6, 12, 18 and 29 of gestation.
Oestrous cyclicity (parental animals):
No information available.
Sperm parameters (parental animals):
No information available.
Litter observations:
Mouse and rat study: The body weights of live pups were recorded and all neonates were examined grossly.
Postmortem examinations (parental animals):
Uteri were examined.
Postmortem examinations (offspring):
The offspring were examined for soft tissue and skeletal abnormalities.
Statistics:
No information available.
Reproductive indices:
Mouse study: On day 17 of gestation, the number of implantation sites, resorption sites, and live and dead neonates were determined.
Rat study: On day 20 of gestation, the number of implantation sites, resorption sites, and live and dead neonates were determined.
Rabbit study: On day 29 of gestation, the number of corpora lutea, implantation sites, resorption sites, and live and dead fetuses were determined.
Offspring viability indices:
No information available.
Clinical signs:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
see comments below
Mouse study: At dose levels of 2.66, 12.4, 57.3 and 266 mg/kg malic acid, 19/25, 22/25, 21/25 and 21/24 animals were gravid, respectively.
Rat study: At dose levels of 3.5, 16.2, 75.4 and 350 mg/kg malic acid, 20/25, 21/29, 22/25, and 26/28 animals were gravid, respectively.
Rabbit study: At dose levels of 3, 14, 65 and 300 mg/kg malic acid, 12/15, 10/20, 13/15, and 13/23 animals were gravid, respectively.
Dose descriptor:
NOAEL
Effect level:
266 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no discernible effect on maternal toxicity
Remarks on result:
other: mouse
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no discernible effect on maternal toxicity
Remarks on result:
other: rabbit
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no discernible effect on maternal toxicity
Remarks on result:
other: rat
Clinical signs:
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
see comments below
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
see comments below
Histopathological findings:
not specified
Mouse, rat and rabbit studies: The number of abnormalities in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in sham-treated controls.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
266 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no discernible effect on fetal toxicity
Remarks on result:
other: mouse
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no discernible effect on fetal toxicity
Remarks on result:
other: rabbit
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
350 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no discernible effect on fetal toxicity
Remarks on result:
other: rat
Reproductive effects observed:
not specified

No further information available.

Conclusions:
This safety assessment supports the conclusion that malic acid,a metabolite of fumaric acid, is not a reproductive toxicant.
Similar results would be expected with the closely related chemical, fumaric acid, and no toxic effects on reproduction are likely to be seen.
Executive summary:

Malic acid administered to mice at up to 266 mg/kg bw, rats at up to 350 mg/kg bw, and rabbits at up to 300 mg/kg bw on days 6 to 15 or 18 of gestation had no discernable effect on nidation or on maternal or fetal survival. Similar results would be expected with the closely related chemical, fumaric acid, and no toxic effects on reproduction are likely to be seen.

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the read-across justification attached in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
With the exception of a few cases of respiratory rales, the clinical appearance and behaviour of all treated animals were not remarkably different from the controls.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality of adult males and females was 0 to 10 % in the low and mid dose group and 65 to 70 % in the high dose group. Intubation error was the cause of death for both low and mid dose rats and a single high dose male.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
P/F0 body weights in the high-dose group were significantly reduced by week 11 (males: -14.1 %; females: -10.4 %) in both sexes and this reduction increased as the generation progressed (males: -19.7 % on study week 32; females: -18 %). The mid-dose group means were low but not statistically significantly different from the controls, except at the end of the generation in the females. No effects in the low dose group in either sex during both generations. Mean maternal body weight gain during gestation and lactation during the Fla and Flb matings was unaffected by the administration of maleic anhydride at all treatment levels tested.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effects on food consumption were observed in any group during the study; a slight decrease in mean female food consumption (both g/rat/day and g/kg/day) was observed throughout the P/F0 generation in the 20 mg/kg/day group, but this was not considered treatment-related.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "details on results" below.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
Male and female fertility indices were reduced in the 20 and 150 mg/kg bw/day groups in the F1a mating when compared with the control group. The relation of these findings to treatment is doubtful since the F1b mating fertility indices were generally comparable at all treatment levels. No difficulties were observed at parturition among the treated and control females in either the F1a or F1b matings. There were no significant differences in the mean length of gestation between the 20, 55 and 150 mg/kg bw/day females and control group females in the F1a and F1b matings.
See above.
Key result
Dose descriptor:
NOAEL
Remarks:
(fertility)
Effect level:
55 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Dose descriptor:
LOAEL
Remarks:
(systemic)
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Dose descriptor:
LOEL
Remarks:
(local)
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: inflammatory changes in stomachs (it was not possible to conclude they were directly related to maleic anhydride)
Critical effects observed:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinically, in both parental generations (P0/P1), respiratory rales were observed with increased frequency among treated animals when compared to the control group. In addition, treated P1/F1 parental rats vigorously resisted the physical dosing procedure.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Most of these deaths were attributed to gavage-related injuries. If these deaths are omitted, then a 0 to 10 % mortality was observed in both the low and mid dose groups, and significant mortality was produced only in the high dose group (100 % among high-dose females). As a result of poor survival, the high dose group was terminated in the F1 generation, and the study was reduced from a three generation to a two-generation study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At the 20 mg/kg/d level, no effect on mean male body weight was observed throughout the F1 generation (percentage difference -2.6 on study week 61). The 55 mg/kg bw/d group exhibited moderate to slight decreases in mean male body weight which decreased in magnitude as the F1 generation progressed (i.e., percentage difference -10 and -5.4 on study weeks 41 and 61, respectively). Marked reductions in mean male body weight were observed at the 150 mg/kg/d level (percentage difference -12.9 on study week 41) prior to sacrifice of the remaining males.
Females in the 20 and 55 mg/kg bw/d groups showed no adverse effects regarding mean body weight throughout the F1 generation; values for these treated groups generally exceeded corresponding control group values. At the 150 mg/kg bw/d level, slight to moderate inhibition of mean female body weight was observed until study week 42 when mortality reached 100 %. Percent differences for these females ranged from -12.5 to -6.2 % on weeks 30 and 35, respectively. No statistical significance was observed at any of the F1 points of analysis.
Mean maternal body weight gain during gestation in the 20 and 55 mg/kg bw/d groups was comparable to the control group during the F2 matings (F2a and F2b). The 20 mg/kg/day group exhibited mean maternal body weight gain in excess of the control group during lactation in the F2a mating and mean loss in maternal body weight during lactation in the F2a mating. Slight reduction of mean maternal body weight gain and no gain in mean maternal body weight were observed during lactation in the F2a and F2b mating respectively, at the 55 mg/kg bw/d level.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the F1 generation, kidney weights were significantly increased in females from the low and mid dose group; however, there were no microscopic changes observed in these kidneys.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
Male and female fertility indices for the 20 and 55 mg/kg bw/d groups for the F2a and F2b mating were comparable to those of the control group. In addition, these values were generally within the range of historical control values. It was noted that fertility in this study was reduced in all groups including the control when compared to control groups of previous studies. However, this generalized reduction is not considered an effect of treatment since the control group also had reduced fertility indices. The general reduction in fertility observed throughout the P0 and P1 generations and mortality contribute to a significant reduction in the available sample size of the data with regard to reproductive and litter parameters. In the P1 generation, 17 litters were available at the 55 mg/kg bw/d level with 100 % mortality among the 150 mg/kg bw/d females by the time of the first F1 mating.
Findings with regard to parturition and length of gestation for the F1 generation were similar to the F0 generation. No dystocia was observed of the F2a and F2b matings and the mean length of gestation of the treated females was comparable to the control group during both matings of the F1 generation.
See above.
Key result
Dose descriptor:
NOAEL
Effect level:
55 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: Since 100% mortality was observed among female rats at 150 mg/kg bw/day.The high dose group was terminated in the F1 generation, and 55 mg/kg bw/day was the highest dose tested in the F1 generation.
Remarks:
The study was reduced from a three generation to a two generation study.
Key result
Dose descriptor:
LOAEL
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
- Pup viability (birth): There were no biologically meaningful or statistically significant differences between the treated and control rats in the mean numbers of viable or stillborn pups on lactation day 0 in the F1a and F1b litter.
- Pup survival to weaning: Treatment with maleic anhydride at levels of 20, 55 or 150 mg/kg bw/d had no apparent adverse effect on pup survival to weaning in the F1a or F1b litters.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In the F1a litters, mean pup body weight at birth was comparable to the control group at the 20 and 55 mg/kg bw/day levels but significantly reduced (p<0.01) in the 150 mg/kg/day group. This effect was not observed in the F1b litters; mean pup body weight at birth in all treated groups of the F1b litters was comparable to the control groups.
Pup growth during lactation was unaffected by treatment with Maleic anhydride at dosage levels of 20 and 55 mg/kg bw/day in both mating of the P0 generation. However, at the 150 mg/kg/day level, inhibition of pup body weight was observed throughout lactation [with statistical significance on days 7, 14 and 21 (by sex),] in the F1a litters and after day 7 of lactation in the F1b litters.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the F1 generation, the absolute kidney weights of adult females in the low- and mid-dose groups were significantly increased to 108 and to 111 %, respectively, of the control value.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
F1: Low incidence of mineralization (2/12 males; 3/21 females) and nephrosis (2/12 males; 5/21 females) in the kidney of animals receiving 150 mg/kg/d. There were no microscopic changes in these kidneys.
Histopathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on indices of fertility for males and females in the F1 generation. No adverse effects on litter size and on pup survival were observed at doses up to 150 mg/kg bw/day in the F1 litters, or at 55 mg/kg bw/day in the F2 litters.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
See above.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
55 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
sexual maturation
Remarks on result:
other: Since 100% mortality was observed among parental F1 female rats at 150 mg/kg bw/day. The high dose group was terminated in the F1 generation, and 55 mg/kg bw/day was the highest dose tested in the F1 generation.
Key result
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other: increased absolute kidney weights of adult females.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
- Pup viability (birth): Very slight reductions in the mean number of viable pups at birth in the F2a litters were observed at the 20 and 55 mg/kg bw/d levels; there was no similar increase in the mean number of stillborn pups. These very slight reductions were not considered to represent a test article-related effect since values for both the 20 and 55 mg/kg bw/d groups (12.2 and 12.0, respectively) were comparable to the historical control value (12.3) and no similar decreases were noted in the F2b litters. The mean numbers of viable and stillborn pups at birth in the 20 and 55·mg/kg bw/d groups were comparable to the control group in the F2b litters.
- Pup survival: There were no statistically significant differences in pup survival to weaning between treated and control litters in both matings of the F1 generation at doses of 55 mg/kg/d and less.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Mean pup body weight at birth of treated litters in both matings of the F1 generation was statistically comparable to the control group. In the F2a litters, mean pup body weights in the low and intermediate dose groups were generally comparable to the control through lactation. However, in the F2b litters, slight to moderate reductions in mean pup body weight were observed in the 20 and 55 mg/kg/d groups throughout lactation. These reductions were statistically significant on days 14 (combined weights) and 21 (females only) of lactation in the 20 mg/kg/d group and days 4 before reduction (females only) and 21 (females only) of lactation at the 55 mg/kg/d level.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
See above.
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
20 mg/kg bw/day
Treatment related:
no
Conclusions:
With respect to fertility, neither a dose-related reduction nor a pattern (during the two consecutive matings) within the parental (P0) generation suggested a treatment-related effect. In the F1 generation 100 % mortality was observed among female rats at 150 mg/kg bw/d. Therefore, the high dose group was terminated and 55 mg/kg bw/day was the highest dose tested in the F1 generation. No adverse effects on fertility were observed. Based on these observations the NOAEL(fertility) was derived at 55 mg/kg bw/d (highest dose tested under the conditions of this study).
Executive summary:

In a multigeneration reproduction study (similar to OECD guideline 416) maleic anhydride (purity 99 %) was administered to 10 male and 20 female rats/dose by gavage at dose levels of 0, 20, 55 and 150 mg/kg bw/d. The rats were mated to produce two generations, each with two litters. Groups of the same size from the second litter were used for subsequent generations and were given the same dose of maleic anhydride as were their parents. Since 100 % mortality was observed among parental F1 female rats at 150 mg/kg bw/d, the high dose group was terminated in the F1 generation and 55 mg/kg bw/d was the highest dose tested in the F1 generation. The study was reduced from a three generation to a two generation study.

Renal cortical necrosis occurred in high-dose P/F0 males and females. Increased kidney weights were observed in low- and mid-dose adult F1 females. Therefore, no NOAEL could be determined and the LOAEL (systemic) was regarded as 20 mg/kg bw/day. With respect to fertility, neither a dose-related reduction nor a pattern (during the two consecutive matings) within the parental (P0) generation suggested a treatment-related effect. No adverse effects on fertility was observed. Based on these observations the NOAEL (fertility) was derived at 55 mg/kg bw/d (highest dose tested under the conditions of this study).

This study is acceptable and satisfies the guideline requirement for a 2-generation reproductive study according to OECD 416 in rats.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
55 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Study performed similar to OECD TG 416.
Additional information

A number of older published studies investigating the reproductive toxicity of fumaric acid are available. In a two-year study using rats, slight testicular atrophy was observed after administration of 1.5% fumaric acid (approximately 750 mg/kg bw/day) in the diet. The authors of this study concluded that inanition was partly responsible for testicular atrophy. These effects were not seen in other studies carried out with rabbits and guinea pigs.

No treatment-related effects were observed in a one-generation study using guinea pigs maintained on a diet containing 1% fumaric acid for one year. No detectable toxic effects on growth, reproduction or lactation were observed. A NOEL of 400 mg/kg bw/day (1% dose group) was established for both the parental generation and F1 offspring.

Reproductive toxicity data on the closely-related fumaric acid metabolite, maleic acid, provides further assurance that additional testing is not needed. Malic acid administered to mice at up to 266 mg/kg bw, rats at up to 350 mg/kg bw, and rabbits at up to 300 mg/kg bw on days 6 to 15 or 18 of gestation had no discernable effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissue did not differ from controls.

In addition, data from read-across to maleic anhydride, which rapidly hydrolyses to maleic acid, a structural isomer of fumaric acid, were used to assess the reproduction toxicity endpoint.

In a multigeneration reproduction study (similar to OECD guideline 416) maleic anhydride (purity 99%) was administered to 10 male and 20 female rats/dose in by gavage at dose levels of 0, 20, 55 or 150 mg/kg bw/day.

The rats were mated to produce two generations, each with two litters. Groups of the same size from the second litter were used for subsequent generations and were given the same dose of maleic anhydride as were their parents. Since 100% mortality was observed among parental F1 female rats at 150 mg/kg bw/day, the high dose group was terminated in the F1 and 55 mg/kg bw/day was the highest dose tested in the F1 generation. The study was reduced from a three generation to a two-generation study.

No treatment-related effects on reproduction were observed with maleic anhydride at doses up to 55 mg/kg/day over two generations. Renal cortical necrosis occurred in high-dose P/F0 males and females. Increased kidney weights were observed in low- and mid-dose adult F1 females.

With reference to fertility, neither a dose-related reduction nor a pattern (during the two consecutive matings) within the parental (P0) generation suggested a treatment-related effect.

No significant reduction in the percentage of pregnant females or the percentage of fertile males was observed with maleic anhydride at doses up to 55 mg/kg/day over two generations. No adverse effects on litter size or pup survival were observed at doses up to 150 mg/kg/day in F1a and F1b litters or 55 mg/kg/day in F2a and F2b litters.

Fumaric acid occurs naturally in mammals and plays an essential role in metabolism. Dietary exposure to exogenous fumaric acid results from the large volumes used as a food acidulant in beverages, baking powders, and fruit drinks. The major route of exposure of the general population to exogenous fumaric acid, including pregnant women, is through consumption of food and beverages. The Joint FAO/WHO Committee on Food Additives and Contaminants (JECFA) concluded that there is no safety concern at current levels of intake when fumaric acid is used as a flavouring agent (1999).

When considered together, these data support the position that a separate 2-generation reproductive toxicity study is not warranted. A number of studies have shown a lack of adverse findings in reproductive organs in various species and the NOEL established in the one-generation reproductive study with guinea pigs is sufficient for risk assessment purposes. Additional studies in animals cannot be justified either scientifically or in terms of animal welfare.

Effects on developmental toxicity

Description of key information

The developmental effects of fumaric acid have been investigated in rats, guinea pigs and Drosophila cells.  These data, combined with the role of fumaric acid in mammalian metabolism and the lack of teratogenic effects in a study with the fumaric acid metabolite, maleic acid, provide sufficient information to determine that fumaric acid has a low toxicity profile and is not considered to be a developmental toxicant.

Additional information

Studies investigating the developmental toxicity of fumaric acid in rats, guinea pigs and Drosophila cells were located in the published literature. No evidence of toxicity was found in second generation guinea pigs fed a 1.0% fumaric acid diet from birth. The absence of gross or microscopic abnormalities observed in rats maintained on diets containing 0.1 or 1.0% fumaric acid, or 1.38% sodium fumarate, for one or two years suggests that developmental toxicity is unlikely with fumaric acid or its sodium salt.

The lack of developmental effects seen in studies described above is supported by data from an in vitro study. No significant differences in the number of myotubes or ganglia (used to determine cell and tissue differentiation) were seen in three different strains of Drosophila embryonic cells treated with 10-3 M fumaric acid. Fumaric acid was not considered to have a teratogenic effect. Although this is a non-standard study, it is useful in a weight-of-evidence approach and supports the position that fumaric acid is not a developmental toxicant.

Read-across to the closely-related fumaric acid metabolite, maleic acid, provides further assurance that developmental toxicity testing of fumaric acid is unnecessary. 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. No trends toward lesser or greater skeletal development were observed.

Fumaric acid occurs naturally in mammals and plays an essential role in metabolism. Dietary exposure to exogenous fumaric acid results from the large volumes used as a food acidulant in beverages, baking powders, and fruit drinks. The major route of exposure of the general population to exogenous fumaric acid, including pregnant women, is through consumption of food and beverages. The Joint FAO/WHO Committee on Food Additives and Contaminants (JECFA) concluded that there is no safety concern at current levels of intake when fumaric acid is used as a flavouring agent (1999).

The overall conclusion from a review of the data is that the developmental toxicity data requirement can be adequately fulfilled with a combination of public domain studies and consideration of the presence and role of fumaric acid in mammalian metabolism.  A separate developmental toxicity study is not proposed and cannot be justified either scientifically or in terms of animal welfare.

Justification for classification or non-classification

The available information on fumaric acid suggests no effects on reproduction or development. The existing data combined with the important role of fumaric acid in mammalian metabolism do not trigger classification according to Directive 67/548/EEC.

Additional information