Malic acid

Endpoint summary

Description of key information

A 2 year chronic study in the rat with malic acid gave a NOEL of 5000 ppm (approximately 260 mg/kg/day).  
A 2 year chronic study in the rat with fumaric acid gave a NOAEL of approximately 600 mg/kg/day.
Read across between malic acid and fumaric acid is considered valid as metabolism of fumaric acid to malic acid occurs as a key part of the Krebbs Cycle

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Experimental data published in peer reviewed journal

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Inc.
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: None ?
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Continuous (in feed)

Remarks:

Doses / Concentrations:
0, 500, 5000, 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

Treatment groups - 30 Males / 30 Females
Control group - 60 Males / 60 Females

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included - Mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly for first 26 weeks, very 2 weeks for second 26 weeks and monthly threafter

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for first 26 weeks, very 2 weeks for second 26 weeks and monthly threafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, weekly for first 26 weeks, very 2 weeks for second 26 weeks and monthly threafter
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 males / 5 females / group
- Parameters examined: No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to study start, Weeks 13, 26, 52 and at termination
- Animals fasted: No data
- How many animals: 5 males / 5 females / group
- Parameters examined: No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data, assumed to be as for clinical chemistry and haematology assessments
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: No data.

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

Interim sacrifice of 5 males and 5 females / test group and 10 male and 10 female conttol animals after 26 and 52 weeks
Terminal sacrifice of remaining animals after 104 weeks

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

No daa

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Reduced at 50000 ppm

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Reduced at 50000 ppm

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Incidental changes thyroid, testes, spleen, liver, kidney and heart

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY - Physical appearance, behaviour, and survival were similar for test and control animals.

BODY WEIGHT AND WEIGHT GAIN - Significantly decreased in both males and females treated at 50000 ppm (high-dose) during Weeks 0 to 52. Terminal body weights were similar to controls for male animals and decreased, but not significantly, for female animals.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) - . Feed consumption was statistically significantly decreased in males treated at 50000 ppm (high-dose) during Weeks 0 to 52. For females of this group, as compared to controls, feed consumption was significantly decreased during Weeks 0 to 26 and decreased, but not significantly, during Weeks 27 to 52. These differences were less distinct during the second year.

FOOD EFFICIENCY – No data

OPHTHALMOSCOPIC EXAMINATION – No data

HAEMATOLOGY – No significant changes observed.

CLINICAL CHEMISTRY – No significant changes observed.

URINALYSIS – No significant changes observed.

NEUROBEHAVIOUR – No data

ORGAN WEIGHTS – Males treated at 50000 ppm: relative thyroid weights significantly decreased at Week 26; relative testes weights significantly increased and liver weights significantly decreased at Week 52; spleen weights significantly increased and relative kidney weights significantly decreased at study termination, all relative to control animals.
Females treated at 50000 ppm: heart and body weights significantly decreased at Week 26; body weights significantly decreased at Week 52; thyroid gland weights significantly decreased at study termination, all relative to control animals.
These differences were considered incidental.

GROSS PATHOLOGY – No significant lesions found.

HISTOPATHOLOGY: NON-NEOPLASTIC – No significant lesions found.

Dose descriptor:

LOEL

Effect level:

50 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight and food consumption

Dose descriptor:

NOEL

Effect level:

5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Lack of observed effect

Critical effects observed:

not specified

Conclusions:

A chronic toxicity study, in which rats were exposed to malic acid, via their feed, for 104 weeks, resulted only in weight gain changes and changes in feed consumption at the highest level investigated, 50000 ppm.

Executive summary:

Chronic toxicity has been investigated in rats using methods similar or equivalent to those described by OECD TG 452. Rats were exposed to malic acid at levels of 500, 5000 or 50000 ppm, via their feed, for 104 weeks. Changes in body weight and feed consumption wre noted at the highest level investigated, 50000 ppm.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

260 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The chronic toxicity of malic acid has been investigated in both the rat and dog. The NOEL in the rat was judged to be 5000 ppm and in the dog 50000 ppm.

Data are also available on sub-acute and chronic studies on fumaric acid. The chronic NOAEL in the rat was approximately 600 mg/kg body weight/day. Read across between malic acid and fumaric acid is considered valid as metabolism of fumaric acid to malic acid occurs as a key part of the Krebbs Cycle.

There are uncertainties in the estimation of exposure, converting from dietary concentration to mg/kg/day, in the study on malic acid, one reviewer estimating a range of 2 -200 mg/kg/day and another a (more probable) 25 -2500 mg/kg/day. In view of this uncertainty, conversion factors described by EFSA (Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data, EFSA Journal 2012; 10(3): 2579) have been used to arrive at a NOAEL of 260 mg/kg/day.

Justification for classification or non-classification

On the basis of the data available, classification of malic acid is not justified according to the criteria given in Directive 67/548/EEC (CLP) or Regulation 1272/2008 (GHS).