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EC number: 230-022-8 | CAS number: 6915-15-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
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
- 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.
Reference
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).
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