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EC number: 206-126-4 | CAS number: 302-72-7
- 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
One 26 -wk study is available for DL-alanine showing a NOAEL at 6800 mg/kg bw/day (10% in diet); at 20% body weight gain was slightly reduced, some effects on clinical chemistry were seen and relative kidney weight was increased. Other dietary studies (2 -wk, 3 -wk, 4 -wk or 13 -wk studies) with other structurally related amino acids all showed high NOAELs, viz. no adverse effects at the highest dose tested which varied from 2000 up to 6200 mg/kg bw/day.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
- Principles of method if other than guideline:
- Scientific investigation on long-term effects of DL-alanine after oral intake
- GLP compliance:
- no
- Remarks:
- study performed prior to implementation of GLP
- Limit test:
- no
- Specific details on test material used for the study:
- Delivered by Teklab Mills, Madison, Wisconsin, USA
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Hilltop Laboratory, Inc., Scottdale, Pennsylvania, USA.
- Age at study initiation: rats of weanling age
- Weight at study initiation: no data
- Caging: metabolic cage (during urine collection)
- Diet (e.g. ad libitum): basal diet
- Water (e.g. ad libitum): during urine collection: only water
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- no data - Route of administration:
- oral: feed
- Vehicle:
- other: basal diet
- Details on oral exposure:
- Male and female Wistar rats of weanling age, were acclimated for 1 week before being randomly divided into four groups with eight male and eight female rats in each group. They were fed a basal diet containing 0, 5, 10, or 20% DL-alanine. The basal ration was a purified ration consisting of the following ingredients: 12% soy protein, 10% casein, 33% sucrose, 33% corn starch, 5% Alphacel, 2% Hawk Oser salt mixture, 2% VitamDiet Fortification Mixture and 3% corn oil. In the rations containing alanine, sucrose and corn starch in equal amounts were substituted by alanine.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 26 weeks
- Frequency of treatment:
- Diet was provided daily.
- Remarks:
- Doses / Concentrations:
0% (w/w) (control)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
5% (w/w)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
10% (w/w)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
20% (w/w)
Basis:
nominal in diet - No. of animals per sex per dose:
- 8
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: no data
- Rationale for animal assignment (if not random): random - Positive control:
- Not applicable
- Observations and examinations performed and frequency:
- GENERAL CONDITION OF THE RATS: Yes
- Time schedule: no data
BODY WEIGHT: Yes
bodyweight determined biweekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
food consumption determined biweekly
- 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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- water consumption determined biweekly
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: after 26 weeks
- Anaesthetic used for blood collection: Yes (metophane)
- Animals fasted: No data
- How many animals: all
After 26 weeks, rats were anesthetized with metophane and blood samples were collected by cardiac puncture. Fresh heparinized blood samples were used for analysis of ammonia, pyruvate, and lactate. Serum from each rat was stored at -20°C for analysis of amino acids, triglycerides, and cholesterol.
URINALYSIS: Yes
- during week 13-14 and week 25-26
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
During the experiment, pooled urine samples from each group were collected twice: once during week 13-14 of the experiment and once just prior to termination, Week 25-26. In order to eliminate feed contamination during urine collection, only water was provided to the rats. Therefore, each rat was kept in a metabolic cage for only 4 hr and the average urine void per day per rat was estimated by extrapolation. The pH of the collected urine was measured and samples were stored at -20°C for further analysis.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- ORGAN WEIGHTS: liver and kidneys
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No - Statistics:
- Bartlett’s tests, level of significance p < 0.05
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN
Rats of all groups appeared healthy and gained weight throughout the experiment. However, rats fed 20% alanine ration gained 20-30% less weight than those fed 0, 5, and 10% alanine.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no significant differences in water consumption; however, there were slight increases in mean food consumption with increasing dietary alanine.
CLINICAL CHEMISTRY
Serum amino acid concentrations were the means of the eight rats from each group. The major amino acids present were alanine, glutamate, and lysine. Serum alanine was increased only in the rats fed rations containing 20% alanine. Linear variation of all other amino acids following the increase of alanine intake was not observed.
The effect of various levels of dietary alanine on blood components developed the following statistically significant changes in male rats:
Ammonia: increase (high dose); Pyruvate: decrease (high dose); Lactate: none; Cholesterol: decrease (mid dose only); Triglycerides: decrease (mid and high dose, not dose-related)
The effect of various levels of dietary alanine on blood components developed the following statistically significant changes in female rats:
Ammonia: none; Pyruvate: decrease (high dose); Lactate: decrease (all doses); Cholesterol: none; Triglycerides: decrease (mid and high dose, not dose-related)
URINALYSIS
Increasing dietary alanine increased urinary alanine in the first collection of both males and females and in the second collection of the female rats. However, only a slight increase of urinary alanine was observed in the second collection from the males fed with 20% alanine. The addition of alanine in the ration had no apparent effect on urine acidity. The urine pH of all samples ranged from 6.5 to 8.9, with the majority in the region of 8.
ORGAN WEIGHTS
Increase of alanine intake had no significant effect on the weight of liver. The average percentage liver (dry weight/body weight) of all groups was 0.84% +/- 0.11%. The kidney dry weight was unaffected by increasing alanine intake: male rats 0.76 g +/- 0.05 g and female rats 0.45 g +/- 0.05 g. However, the percentage kidney (dry weight/body weight) of both male and female rats fed 20% alanine showed an increase (0.17% +/- 0.02%) compared to that of the rats in all the other groups (0.13 % +/- 0.02%).
GROSS PATHOLOGY
Gross examination of all organs at necropsy showed no abnormalities and lesions. - Dose descriptor:
- NOAEL
- Effect level:
- 10 other: %
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: effects on body weight gain; serum chemistry and increased relative kidney weight at the high dose of 20%
- Critical effects observed:
- not specified
- Conclusions:
- DL-alanine, fed at dietary levels up to 20% for 26 weeks, did not show effects on the general health of male and female rats; however, body weight gain was slightly reduced, some effects on clinical chemistry were seen and relative kidney weight was increased. As such the NOAEL was set at 10%, corresponding to 6800 mg/kg bw.
Reference
The following intakes were calculated based on average food intake and body weight gain:
5%
males: 5% = 50 mg/g diet, mean food intake 25 g, thus 1250 mg/rat; average BW 450 g, thus mean intake 2800 mg/kg bw/day
females: 5% = 50 mg/g diet, mean food intake 24 g, thus 1200 mg/rat; average BW 250 g, thus mean intake 4800 mg/kg bw/day
10%
males: 10% = 100 mg/g diet, mean food intake 27 g, thus 2700 mg/rat; average BW 400 g, thus mean intake 6800 mg/kg bw/day
females: 10% = 100 mg/g diet, mean food intake 17 g, thus 1700 mg/rat; average BW 250 g, thus mean intake 6800 mg/kg bw/day
20%
males: 20% = 200 mg/g diet, mean food intake 31 g, thus 6200 mg/rat; average BW 350 g, thus mean intake 18000 mg/kg bw/day
females: 20% = 200 mg/g diet, mean food intake 25 g, thus 5000 mg/rat; average BW 225 g, thus mean intake 22000 mg/kg bw/day
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 6 800 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- GLP guideline study with Klimisch Code 2.
- Organ:
- kidney
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
A 26 -wk dietary study with DL-alanine as well as other dietary studies with L-alanine and L-alanine-L-glutamine. The pharmacokinetic behaviour of L-alanyl-L-glutamine (L-AG) justifies the approach of read-across from L-AG to L-alanine. Dipeptides such as L-AG are readily degraded into constituent amino acids during transport from the small intestine (Minami et al., 1992; Herzog et al., 1996; Klassen et al., 2000). Levels of alanine and glutamine in blood rise within 15–30 min of oral administration to both rats (Rogero et al., 2006) and humans (Klassen et al., 2000).
The 26 -wk studie with DL-alanine resulted in a NOAEL of 6800 mg/kg bw (10%). A subchronic oral toxicity guideline study of L-alanyl-L-glutamine (L-AG) with rats was conducted for 90 days. No treatment-related significant or toxicologically relevant findings were observed. The no observed adverse effect level (NOAEL) was determined to be at least a dietary dose of 5.0% (3129 mg/kg bw/day in males and 3601 mg/kg bw/day in females) under the present experimental conditions.
The mean human daily intake of alanine for all life stage and gender groups from food and supplements is approximately 3.6 g/d (Food and Nutrition Board, 2005). A dietary dose of 6800 mg/kg bw/day of DL-alanine is equivalent to about 130 times the mean daily oral intake for a 70 -kg human.
Minami, H., Morse, E., Adibi, S.A., 1992. Characteristics and mechanism of glutamine dipeptide absorption in human intestine. Gastroenterology 103 (1), 3–11.
Birgit Herzog, Brigitte Frey, Karin Pogan, Peter Stehle, Peter Fürst (1996). In vitro peptidase activity of rat mucosa cell fractions against glutamine-containing dipeptides. J. Nutr. Biochem. 7, 135–141.
Petra Klassen, Manolo Mazariegos, Noel W. Solomons and Peter Fürst. The Pharmacokinetic Responses of Humans to 20 g of Alanyl-Glutamine Dipeptide Differ with the Dosing Protocol but Not with Gastric Acidity or in Patients with Acute Dengue Fever. Journal of Nutrition. 2000; 130: 177-182.
Rogero MM, Tirapegui J, Pedrosa RG, Castro IA, Pires IS. Effect of alanyl-glutamine supplementation on plasma and tissue glutamine concentrations in rats submitted to exhaustive exercise. Nutrition. 2006 May; 22(5): 564-71. Epub 2006 Feb 10.
Food and Nutrition Board (2005): Dietary reference intakes for energy, carbohydrate, fiber, fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington DC, National Academic Press
Justification for classification or non-classification
Based on the results of a 26 -wk dietary study with DL-alanine and supporting studies, DL-alanine should not be classified for repeated dose toxicity according to CLP.
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