Fumaric acid

Endpoint summary

Description of key information

Two older studies comparable to OECD guideline 452 showed no signs of toxic effects in rats administered fumaric acid at dietary concentrations of up to 1.2 % for one or two years. The NOAEL for systemic toxicity was estimated as 1.2 % fumaric acid, or 600 mg/kg bw/d. The worst-case risk associated with subchronic dermal toxicity and subchronic inhalation toxicity of fumaric acid can be assessed using the results of chronic oral studies and additional testing cannot be justified either scientifically or in terms of animal welfare.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer-reviewed study comparable to OECD guideline 452.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Principles of method if other than guideline:

Overview of chronic exposure studies completed prior to introduction of experimental test guidelines. The study design was similar in principle to the method subsequently published as OECD 452

GLP compliance:

no

Remarks:

Study pre-dates establishment of GLP guidelines

Limit test:

no

Species:

rat

Strain:

Osborne-Mendel

Sex:

male

Details on test animals or test system and environmental conditions:

Male weanling rats (21-days) were fed diets containing fumaric acid for two years. The basic diet consisted of ground commercial rat biscuits with 1% added cod-liver oil. Fumaric acid was mixed with the basic diet using a rotary batch mixer. All animals were kept in individual cages in a room with temperature and humidity controlled for the duration of the experiment. Animals were given free access to their respective diets and water.

Route of administration:

oral: feed

Vehicle:

other: cod liver oil added to moisten diet

Details on oral exposure:

The basic diet consisted of ground commercial rat biscuits with 1% added cod-liver oil. Fumaric acid was mixed with the basic diet using a rotary batch mixer. Animals were given free access to their respective diets.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

2 years

Frequency of treatment:

Daily in feed

Remarks:

Doses / Concentrations:
0.5, 1.0, and 1.5%
Basis:
nominal in diet

No. of animals per sex per dose:

7- 12 male rats per dose, 10-12 females per group

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: In a previous experiment, male and female rats were fed diets containing 0.1, 0.5, 0.8 and 1.2% fumaric acid for two years.
This study was initiated to examine the toxicity of fumaric acid more closely.

Positive control:

No data

Observations and examinations performed and frequency:

Individual animal weights and food consumption were determined at weekly intervals.

Sacrifice and pathology:

Gross pathology and histopathology of lung, heart, liver, spleen, pancrease, stomach, small intestine, kidney, adrenal and testis.
Additional structures examined by histopathology include colon, bone marrow, leg bones, leg muscles, lymph nodes, uterus, ovary, thyroid and parathyroid.

Other examinations:

No details

Statistics:

No details

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mortality in the high dose group was significant but low mortality rates evident in lower dose groups

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality in the high dose group was significant but low mortality rates evident in lower dose groups

Body weight and weight changes:

no effects observed

Description (incidence and severity):

weight gains recorded for males and females at each dose level showed no treatment related effects

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption over te first 26 weeks of the study andsecond 26 weeks were compared or each treatment group. No statistically significant changes observed.

Food efficiency:

not specified

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

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Sporadic findings reported but no treatment relationship established

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

At two years, there were only 2 animals living on 1.5% fumaric acid.; other dose levels had no effect on mortality rate. Animals fed 1.5% fumaric acid showed more atrophy of the testis and 2 rats fed 0.5% and 1.0% fumaric acid showed phlegmonous gastritis.

Dose descriptor:

NOAEL

Effect level:

ca. 600 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

1.2% test material inclusion level

Sex:

male

Basis for effect level:

other: Low incidence of mortality seen at a dose level of 1.5%

Critical effects observed:

not specified

Mean gain in weight of rats fed fumaric acid for a year (data from a previous experiment is also included)

Test material	Dosage (%)	No. of animals	Sex	Mean gain in weight (g)	Standard error of mean (+ g)
Fumaric acid	0.1	11	M	452.9	19.0
	0.1	10	F	288.0	10.0
	0.5	10	M	444.4	20.7
	0.5	12	F	269.7	9.6
	0.8	9	M	429.6	11.0
	0.8	12	F	265.2	5.7
	1.0	10	M	468.8	25.9
	1.2	11	M	466.9	14.6
	1.2	12	F	280.0	10.2
	1.5	7	M	459.9	23.2
Control		31	M	464.9	13.4
		22	F	274.4	9.8

Conclusions:

Signs of toxic effects were observed when rats were fed fumaric acid at high dietary concentrations - 1.5%.
Toxic effects occurred in rats fed diets containing 1.5% fumaric acid for two years. An increase in mortality rate and more atrophy of the testis were seen in rats fed 1.5% fumaric acid. Inanition seems at least partly responsible for atrophy of the testis.
No adverse effects on reproductive organs were reported in a previous study using female rats administered up to 1.2% fumaric acid in the diet for 2 years.
The NOAEL was 1.2% or circa 600 mg/kg bw/day.
A previous study conducted in a similar manner with female rats showed no adverse effects on reproductive organs after administration of up to 1.2% fumaric acid in the diet for 2 years. Based on the low incidence of mortality of male rats, 1.2% is very near a NOAEL for chronic exposure to fumaric acid (600 mg/kg bw). The 1.2% NOAEL (600 mg/kg bw/day) derived from the available long term rat toxicity data was confirmed as the appropriate point of departure by two reviews - The International Programme on Chemical Safety (WHO 1975 Food Additive Series 6) report and the findings ofthe European Commission DG C Report of the Scientific Committee on animal nutrition on the safety of fumaric acid (SCAN, 2003).
In the SCAN report, a safe use was established in piglets in the field at circa 1000 mg/kg bw/day and circa 2000 mg/kg bw/day in experimental data. For human psoriatic patients the safe use was 0.9g fumaric acid equivalent/d or circa 15 mg/kg bw/day.
The WHO report contains confirmation of the study in which groups of rats were dosed at 1.2% fumaric acid without adverse toxicological effects.

Executive summary:

In a two-year dietary study using male rats, a very slight increase in mortality rate and some testicular atrophy was observed after administration of 1.5% fumaric acid (approximately 750 mg/kg bw/day). Gross and microscopic examination of major organs revealed no abnormalities. The authors of this study concluded that inanition was partly responsible for testicular atrophy. A previous study conducted in a similar manner with female rats showed no adverse effects on reproductive organs after administration of up to 1.2% fumaric acid in the diet for 2 years. Based on the low incidence of mortality of male rats, 1.2% is very near a NOAEL for chronic exposure to fumaric acid (600 mg/kg bw). The 1.2% NOAEL (600 mg/kg bw/day) derived from the available long term rat toxicity data was confirmed as the appropriate point of departure by two reviews - The International Programme on Chemical Safety (WHO 1975 Food Additive Series 6) report and the findings of the European Commission DG C Report of the Scientific Committee on animal nutrition on the safety of fumaric acid.

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Peer-reviewed study of acceptable quality, with the following methodological deficiencies: the paper reports the results of two experiments conducted concurrently, employing different dosing regimens; information regarding control animals is poorly reported; examinations were limited to body weight, food consumption and histopathology of main organs; no detailed results are available.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline available

Principles of method if other than guideline:

The study was a chronic exposure feeding study (conducted prior to development of the guidelines), limited to the evaluation of body weight, food consumption and histopathology of the main organs.

GLP compliance:

no

Remarks:

Study pre-dates establishment of GLP guidelines

Limit test:

no

Species:

rat

Strain:

Osborne-Mendel

Sex:

male

Details on test animals or test system and environmental conditions:

The animals were male and female weanling rats (21-days) of the Osborn-Mendel strain. All animals were kept in individual cages in a room with temperature and humidity controlled for the duration of the experiment. Animals were given free access to their respective diets and water.

Route of administration:

oral: feed

Vehicle:

other: cod liver oil added to moisten diet

Details on oral exposure:

Weanling rats (21 days) were fed diets containing fumaric acid for two years. The basic diet consisted of ground commercial rat biscuits with 1% added cod-liver oil. Fumaric acid was mixed with the basic diet using a rotary batch mixer.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

2 years

Frequency of treatment:

Ad libitum in feed

Remarks:

Doses / Concentrations:
0, 0.1, 0.5, 0.8 and 1.2%
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
0, 0.5, 1.0, and 1.5%
Basis:
nominal in diet

No. of animals per sex per dose:

Experiment 1 (0, 0.1, 0.5, 0.8 and 1.2%): 12 males and 12 females per group.
Experiment 2 (0, 0.5, 1.0 and 1.5%): 12 males

Control animals:

yes, plain diet

Details on study design:

Two experiments were conducted concurrently, employing two different dosing regimens. The first experiment included both male and female rats, exposed to 0, 0.1, 0.5, 0.8 and 1.2% fumaric acid in the diet. The second experiment was conducted in order to compare the toxicities of fumaric and maleic acids more closely; male rats were fed diets containing 0, 0.5, 1.0 and 1.5% fumaric or maleic acid.

Positive control:

None

Observations and examinations performed and frequency:

Individual animal weights and food consumption were determined at weekly intervals.

Sacrifice and pathology:

Gross pathology and histopathology of lung, heart, liver, spleen, pancrease, stomach, small intestine, kidney, adrenal and testis.
Additional structures examined by histopathology include colon, bone marrow, leg bones, leg muscles, lymph nodes, uterus, ovary, thyroid and parathyroid.

Other examinations:

None

Statistics:

No details

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mortality in the high dose group was significant but low mortality rates evident in lower dose groups (detailed information not provided in study report)

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality in the high dose group was significant but low mortality rates evident in lower dose groups (detailed information not provided in study report)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

weight gains recorded for males and females at each dose level showed no treatment related effects (data were presented for 1 year only)

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption over the first 26 weeks of the study and second 26 weeks were compared for each treatment group. No statistically significant changes observed (no detailed information is included in the study report).

Food efficiency:

not specified

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

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Sporadic findings reported but no treatment relationship established

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

At two years, there were only 2 animals living on 1.5% fumaric acid.; other dose levels had no effect on mortality rate. Animals fed 1.5% fumaric acid showed more atrophy of the testis and 2 rats fed 0.5% and 1.0% fumaric acid showed phlegmonous gastritis.

Dose descriptor:

NOAEL

Effect level:

ca. 600 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

1.2% test material inclusion level

Sex:

male

Basis for effect level:

other: Low incidence of mortality seen at a dose level of 1.5%

Critical effects observed:

not specified

Mean gain in weight of rats fed fumaric acid for a year (data from a previous experiment is also included)

Test material	Dosage (%)	No. of animals	Sex	Mean gain in weight (g)	Standard error of mean (+ g)
Fumaric acid	0.1	11	M	452.9	19.0
	0.1	10	F	288.0	10.0
	0.5	10	M	444.4	20.7
	0.5	12	F	269.7	9.6
	0.8	9	M	429.6	11.0
	0.8	12	F	265.2	5.7
	1.0	10	M	468.8	25.9
	1.2	11	M	466.9	14.6
	1.2	12	F	280.0	10.2
	1.5	7	M	459.9	23.2
Control		31	M	464.9	13.4
		22	F	274.4	9.8

Conclusions:

Signs of toxic effects were observed when rats were fed fumaric acid at high dietary concentrations - 1.5%.
Toxic effects occurred in rats fed diets containing 1.5% fumaric acid for two years. An increase in mortality rate and more atrophy of the testis were seen in rats fed 1.5% fumaric acid. Inanition seems at least partly responsible for atrophy of the testis.
No adverse effects on reproductive organs were reported in a concurrent study using female rats administered up to 1.2% fumaric acid in the diet for 2 years.
The NOAEL was 1.2% or circa 600 mg/kg bw/day.
A concurrent study conducted in a similar manner with male and female rats showed no adverse effects on reproductive organs after administration of up to 1.2% fumaric acid in the diet for 2 years. Based on the low incidence of mortality of male rats, 1.2% is very near a NOAEL for chronic exposure to fumaric acid (600 mg/kg bw). The 1.2% NOAEL (600 mg/kg bw/day) derived from the available long term rat toxicity data was confirmed as the appropriate point of departure by two reviews - The International Programme on Chemical Safety (WHO 1975 Food Additive Series 6) report and the findings ofthe European Commission DG C Report of the Scientific Committee on animal nutrition on the safety of fumaric acid (SCAN, 2003).
In the SCAN report, a safe use was established in piglets in the field at circa 1000 mg/kg bw/day and circa 2000 mg/kg bw/day in experimental data. For human psoriatic patients the safe use was 0.9g fumaric acid equivalent/d or circa 15 mg/kg bw/day.
The WHO report contains confirmation of the study in which groups of rats were dosed at 1.2% fumaric acid without adverse toxicological effects.

Executive summary:

Groups of 12 male and 12 female rats were fed 0, 0.1, 0.5, 0.8 or 1.2% fumaric acid, and groups of 12 male rats were fed 0, 0.5, 1 or 1.5% fumaric acid for 2 years.

A very slight increase in mortality rate and some testicular atrophy was observed after administration of 1.5% fumaric acid (approximately 750 mg/kg bw/day). Gross and microscopic examination of major organs revealed no abnormalities. Two rats receiving 1% or 0.5% had stomach inflammation. The authors of this study concluded that inanition was partly responsible for testicular atrophy. In the study with female rats, no adverse effects on reproductive organs were observed after administration of up to 1.2% fumaric acid in the diet. Based on the low incidence of mortality of male rats, 1.2% is very near a NOAEL for chronic exposure to fumaric acid (600 mg/kg bw). The 1.2% NOAEL (600 mg/kg bw/day) derived from the available long term rat toxicity data was confirmed as the appropriate point of departure by two reviews - The International Programme on Chemical Safety (WHO 1975 Food Additive Series 6) report and the findings of the European Commission DG C Report of the Scientific Committee on animal nutrition on the safety of fumaric acid.

Endpoint conclusion

Dose descriptor:

NOAEL

600 mg/kg bw/day

Additional information

In a two-year dietary study using rats, a very slight increase in mortality rate and some testicular atrophy were observed after administration of 1.5% fumaric acid (approximately 750 mg/kg bw/day). Gross and microscopic examination of major organs revealed no abnormalities. The authors of this study concluded that inanition was partly responsible for testicular atrophy. Two animals fed fumaric acid at 1% and 0.5% showed phlegmonous gastritis. A NOAEL was not established in this study, however, the low incidence of mortality suggests that 1.2% is very near a NOAEL for chronic exposure to fumaric acid (600 mg/kg bw).

In another chronic study, eight groups of 14 weanling rats were kept on diets containing 0, 0.1 and 1.0% fumaric acid for one or two years. No adverse effect was noted on the rate of weight gain, haemoglobin, blood picture, calcium balance as shown by bone histology, or on the histopathology of liver, kidney, spleen and stomach. A NOAEL was not identified in this study.

The worst case risk associated with subchronic dermal toxicity of fumaric acid can be assessed using the results of the two oral studies described above which indicate a NOAEL of approximately 600 mg/kg bw/day. These data plus an assumption of 100% dermal absorption can be used to assess risk associated with systemic dermal exposure. This would greatly overestimate risk because fumaric acid will be readily ionized and thus, will be poorly absorbed by the dermal route. It should be noted that fumaric acid plays an essential role in metabolism, is formed in the skin during exposure to sunlight, and over the past 30 years, fumaric acid esters have been used safely in the treatment of psoriasis, both topically and orally.

The worst case risk associated with subchronic inhalation toxicity of fumaric acid can be assessed by converting the oral NOAEL of 600 mg/kg bw/day into a corrected inhalatory NOAEC according to guidance from ECHA. Based on human inhalatory exposure, the NOAEC for the general population is calculated as 522 mg/m3 for a 24-hour per day exposure. For workers, the NOAEC was calculated as 1.058 mg/m3 for an 8-hour per day exposure.

Based on the available information, no further testing is necessary for hazard identification or risk assessment purposes. A subchronic dermal toxicity study and a subchronic inhalation toxicity study are not proposed and cannot be justified either scientifically or in terms of animal welfare. Inhalation exposure following acute or repeated administration is highly umlikely given the particle size distribution which indicates less than 6% of particles are within the respirable range (< 10 micron diameter). The low potential exposure and ubiquitous endogenous presence of fumaric acid means that inhalation toxicity is unlikely.

Assessment of toxicity data available for Fumaric acid

Summary

Public domain studies and information on fumaric acid have been assessed with the objective of determining whether such information will satisfy various human health (hazard) data requirements in accordance with Annexes VII to X. The overall conclusion from a review of the data is that repeat dose toxicity, toxicokinetics and reproduction toxicity data requirements can be adequately fulfilled with a combination of older public domain studies, reference to therapeutic uses of fumaric acid and reference to the presence and role of fumaric acid in mammalian metabolism. Read-across to the closely-related fumaric acid metabolite, maleic acid, provides further assurance that repeat dose and reproductive toxicity testing of fumaric acid is unnecessary.

Background

Fumaric acid is naturally found in plants and animals and is ubiquitous in the environment due to release from gasoline and diesel engine exhaust as well as from aqueous effluents from pulp mills (HSDB). Dietary exposure also results from the large volumes of fumaric acid used as a food acidulant in applications such as beverages, baking powders, and fruit drinks. The major route of exposure of the general population to exogenous fumaric acid 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 used as a flavouring agent. The 1989 group ADI of "not specified" for fumaric acid and its salts was maintained at the fifty-third meeting (1999) of JECFA.

 

As noted in the Report of the Scientific Committee on Animal Nutrition (SCAN) on the Safety of Fumaric Acid (22 January 2003),Fumeria Officinalis ,the primary botanical source of fumaric acid, has been used in human therapy since ancient times. In 1959, the anti-inflammatory effects of fumaric acid were demonstrated and over the past 30 years fumaric acid esters have been used in the oral treatment of psoriasis. Fumaric acid esters are administered orally for up to 16 weeks and the fumaric acid equivalent dose used for therapeutic purposes is up to 900 mg/day.  Adverse effects occasionally observed from fumaric ester therapy are mild and reversible. According to the SCAN report, patients receiving therapy report gastrointestinal complaints, flushing and reversible elevations of transaminases, lymphocytopenia and eosinophilia.  SCAN concluded that about 0.9 g fumaric acid equivalent/d are safe for humans. It is important to note that fumaric acid is an intermediate in the tricarboxylic acid cycle and hence plays an essential role in aerobic respiration. In this cycle succinate is oxidized to fumarate by the flavoprotein succinate dehydrogenase. Fumarate is subsequently hydrated by to L-maleate by the enzyme, fumarase. The tricarboxylic acid cycle is regulated by the concentration of intermediates such as fumarate and various other factors.  It is noted that malic acid, the metabolite of fumaric acid and closely related dicarboxylic acid, shows little toxicity in chronic testing and no effects in reproductive toxicity testing in rats, mice or rabbits (Fiume, 2001).

Repeated dose toxicity

Short-term repeated dose toxicity study (28 days)

A number of oral repeated dose studies are available for fumaric acid, one chronic study in rats and three short-term studies in rabbits. In a long-term dietary study using rats, a very slight increase in mortality rate and some testicular atrophy were observed after administration of 1.5% fumaric acid (approximately 750 mg/kg bw/day) over a two-year period (Fitzhugh and Nelson, 1947). Gross and microscopic examination of major organs revealed no abnormalities. A NOAEL was not established in this study, however, the low incidence of mortality and testicular effects at 1.5% (in conjunction with data from a second investigation in females) suggests that 1.2% is an appropriate NOAEL for chronic exposure to fumaric acid (equivalent to 600 mg/kg bw).

A number of repeated dose toxicity studies have been conducted in rabbits using fumaric acid salts. Fourteen rabbits were fed 320-2080 mg/kg bw disodium fumarate daily for 28 days without any deaths (Locke et al, 1942). A further six rabbits received 2880-3680 mg/kg bw for 17 days with three deaths. Two rabbits were fed a daily diet containing 640 mg/kg bw for 36 days without consistent adverse effect on body weight, haematology, non-protein nitrogen or creatinine levels, or histopathological findings (Locke et al, 1942). These studies were summarized by JECFA (1974) and used to evaluate the toxicity of fumaric acid as a food additive.

Reproductive toxicity

Developmental toxicity study

Eight groups of 14 weanling rats were kept on diets containing 0, 0.1 and 1.0% fumaric acid and 1.38% sodium fumarate for one or two years (Levey et al, 1946). No adverse effect was noted on the rate of weight gain, haemoglobin, blood picture, calcium balance as shown by bone histology, or on the histopathology of liver, kidney, spleen and stomach. These data indicate an absence of gross or microscopic abnormalities, suggesting that developmental toxicity is unlikely with this substance.

The lack of developmental effects seen in the study described above is supported by data from an in vitro study. Fumaric acid was tested for teratogenesis using the Drosophila embryonic cell culture test (Bournias-Vardiabasis et al, 1983). Three different strains of embryonic cells were treated with 10^-3 M fumaric acid, which corresponds to 0.01 of the LD50 for adult female Drosophila. The number of myotubes and ganglia were used to determine cell and tissue differentiation. An interference (50% reduction in number of either myotubes and/or ganglia) in normal cell differentiation indicates a teratogenic response. Fumaric acid, tested in three separate trials using four replicates per trial, showed no teratogenic effect. This study provides useful weight-of-evidence information to address potential developmental toxicity.

Two-generation reproductive toxicity study

Two studies, one in rats and another in rabbits, have shown testicular atrophy following dietary administration of 1.5% fumaric acid over two years and ip administration of 60 mg/kg bw sodium fumarate over 17-29 weeks, respectively. However, these effects were not seen in additional studies carried out with rabbits and guinea pigs administered very high doses of fumaric acid in the diet.

Four groups of 15 rabbits were fed diets containing 0 or 6.9% sodium fumarate (equivalent to 5% fumaric acid) for 150 days. No compound-related toxicity was observed and histological examination showed no adverse findings attributable to the diet. In particular, spermatogenesis and testicular structure were unaffected (Packman et al, 1963).

Similar results were observed in a one-generation study using guinea pigs. Eight animals were maintained on a diet containing 0%, 1% and 10% fumaric acid for one year without any adverse effects on growth (Levey et al, 1946). The second generation from four mated animals was treated similarly without any adverse effect on growth, fertility or lactation. A NOEL of 400 mg/kg bw/day (1% dose group) was established for both the parental generation and F1 offspring.

Although a traditional two-generation reproductive toxicity study is not available, a number of studies, in various species, have investigated the effects of fumaric acid on growth, reproduction and lactation. While some studies show testicular atrophy after administration of high doses of fumaric acid, other studies show no adverse findings in reproductive organs. The NOEL established in the one-generation reproductive study with guinea pigs is sufficient for risk assessment purposes and additional studies in animals cannot be justified either scientifically or in terms of animal welfare.

Toxicokinetics

The distribution of fumaric acid in rat tissue has been studied and was found that blood contained 3 mg/l, brain tissue 150 mg/kg, kidney tissue 95 mg/kg, liver 78 mg/kg and muscle 23 mg/kg (Marshall et al., 1949). Fumaric acid is known to be poorly absorbed by the oral route of administration (SCAN).

Conclusion

Based on the available toxicity data for fumaric acid and the closely related compound, malic acid, background levels of exposure to fumaric acid due to its role in human respiration and as a food and feed additive, and experience gained from use as a human therapeutic agent, it can be concluded that fumaric acid is of low concern for human health and no further testing repeat dose, reproductive toxicity or toxicokinetics testing is necessary for purposes of REACH.

References

1. Bournias-Vardiabasis N, Teplitz RL, Chernoff GF, Seecof RL. 1983. Detection of teratogens in the Drosophila embryonic cell culture test: assay of 100 chemicals. Teratology 28: 190-22.

2. European Commission Health & Consumer Protection Directorate-General. 2003. Report of the Scientific Committee on Animal Nutrition (SCAN) on the Safety of Fumaric Acid. Adopted 22 Jan 2003.

3. Fitzhugh OG and Nelson AA. 1947. The comparative chronic toxicities of fumaric tartaric, oxalic, and malic acids. J Am Pharm Assoc 36: 217-219.

4. Fiume Z. 2001.Final report on the safety assessment of Malic Acid and Sodium Malate.

5. Int J Toxicol20; Suppl 1: 47-55.

6. Hazardous Substances Data Bank (HSDB). Fumaric Acid, CASRN 110-17-8. Accessed online athttp://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

7. Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1974. Toxicological Evaluation of some food colours, enzymes, flavor enhancers, thickening agents, and certain food additives. Fumaric acid. Eighteenth Report of the Joint FAO/WHO Expert Committee on Food Additives, Wld Hlth Org. Techn. Rep. Ser., 1974, No. 557. FAO Nutrition Meetings Report Series, 1974, No. 54.

8. Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1999. Fumaric acid. Summary of evaluations performed by the Joint FAO/WHO Expert Committee on Food Additives.

9. Levey S, Lasichak AG, Brimi R, et al. 1946. A study to determine the toxicity of fumaric acid.J Am Pharm Assoc35: 298-304.

10. Locke A, Locke RB, Schlesinger H, Carr H. 1942. The comparative toxicity and cathartic efficiency of disodium tartrate and fumarate, and magnesium for the mouse and rabbit, J Am Pharm Assoc 31:12-14.

11. Marshall, L. M., Orten, J. M. & Smith, A. H. 1949. J Biol Chem 179: 1127.

12. Packman EW, Abbott DD, Harrisson JW. 1963. Comparative subacute toxicity for rabbits of citric, fumaric, and tartaric acids. Toxicol Appl Pharmacol 5: 163-7.

Justification for classification or non-classification

The results of the available studies do not trigger classification according to Directive 67/548/EEC.