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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Justification for type of information:
Peer-reviewed study of acceptable quality, with the following methodological deficiencies

Data source

Reference
Reference Type:
publication
Title:
The comparative chronic toxicities of fumaric, tartaric, oxalic and maleic acids
Author:
Fitzhugh OG, Nelson AA
Year:
1947
Bibliographic source:
Fitzhugh OG, Nelson AA

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: As mentioned below
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:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Fumaric acid
EC Number:
203-743-0
EC Name:
Fumaric acid
Cas Number:
110-17-8
Molecular formula:
C4H4O4
IUPAC Name:
Fumaric acid
Test material form:
solid
Details on test material:
IUPAC name:(2E)-but-2-enedioic acid
Mol. formula: C4H4O4
Molecular Weight: 116.0716 gm/mol

Test animals

Species:
rat
Strain:
other: 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.

Administration / exposure

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
Doses / concentrationsopen allclose all
Remarks:
0, 0.1, 0.5, 0.8 and 1.2% nominal in diet
Remarks:
0, 0.5, 1.0, and 1.5% 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

Examinations

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

Results and discussion

Results of examinations

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
Immunological 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, non-treatment-related
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.

Effect levels

Dose descriptor:
NOEL
Effect level:
ca. 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Low incidence of mortality seen at a dose level of 1.5%

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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  11 452.9  19.0 
   0.1 10  288.0  10.0 
   0.5 10   M 444.4  20.7 
   0.5  12 269.7  9.6 
   0.8 429.6  11.0 
   0.8 12  265.2  5.7 
   1.0 10  468.8  25.9 
   1.2 11  466.9  14.6 
  1.2  12  280.0  10.2 
  1.5  459.9  23.2 
 Control    31  M 464.9  13.4 
    22  274.4  9.8 

Applicant's summary and conclusion

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.