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EC number: 205-702-2 | CAS number: 147-85-3
- 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
L-proline did not show adverse effects in two independent 13 week oral toxicity studies up to high doses. All data from the oral route of administration suggest that they sufficiently cover the dermal and inhalative routes.
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:
- No exact period reported. Presumably 2009 / 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: Guidelines for Designation of Food Additives and for Revision of Standards for Use of Food Additives released by the MHLW (Standards and Evaluation Division Department of Food Safety, 1996)
- Deviations:
- not specified
- GLP compliance:
- not specified
- Remarks:
- GLP compliance not indicated in the publication.
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Fischer 344 (F344/DuCrlCrlj)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc., Kanagawa
- Age at study initiation: 5 weeks
- Weight at study initiation: no data
- Fasting period before study: no, but 1 week acclimatized to the control diet
- Housing: individually in stainless stell cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
according to guideline
IN-LIFE DATES: From: To: no data - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- L-Pro was admixed into a modified AIN-93G powder diet (Oriental Yeast Co., Ltd., Tokyo, Japan) to produce concentrations of 0% (control), 0.625%, 1.25%, 2.5% or 5.0% every 4 weeks (three time preparation for experimentation period). The diet was kept at 4 C and was given to the rat every week.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The L-Pro content in all experimental diets was analyzed at their preparation, and the actual values were 6.57 ± 0.48, 13.30 ± 0.39, 27.18 ± 0.71 and 54.04 ± 1.34 g/kg diet for the 0.625%, 1.25%, 2.5% and 5.0% doses, respectively.
- Duration of treatment / exposure:
- 90 d
- Frequency of treatment:
- The testing animals were allowed free access to food (and drinking water) throughout both the acclimation and experimentation periods.
- Remarks:
- Doses / Concentrations:
0 % = 0 g/kg diet (control)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
6.57 +/- 0.48 g/kg diet
Basis:
other: Analytically validated concentration in diet - Remarks:
- Doses / Concentrations:
13.30 +/- 0.39 g/kg diet
Basis:
other: Analytically validated concentration in diet - Remarks:
- Doses / Concentrations:
27.18 +/- 0.71 g/kg diet
Basis:
other: Analytically validated concentration in diet - Remarks:
- Doses / Concentrations:
54.04 +/- 1.34 g/kg diet
Basis:
other: Analytically validated concentration in diet - No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: high doses as low toxicity assumed
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: random
- Section schedule rationale (if not random): all animals - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily for clinical signs and mortality
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: After end of experimentaion period of 90 days
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: all
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After end of experimentaion period of 90 days
- Animals fasted: Yes
- How many animals: all
At the end of the experimentation period of 90 days, all rats were deprived of food (but not water) overnight. All rats were then lightly anesthetized and sacrificed by exsanguination after collecting blood samples via the abdominal aorta. Using the blood samples and subsequently prepared sera, hematological and serological examinations were performed. Hematological examination was carried out for the red blood cell count (RBC), hemoglobin concentration
(HGB), hematocrit level (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC) and platelet count (PLT). Differential counts of leukocytes were made by alight microscopic observation of smeared specimens stained with a routine May-Grünwald-Giemsa protocol. Serum biochemistry determination was performed with an automatic analyzer for the levels of total protein (TP), albumin (ALB), albumin/globulin ratio (A/G), glucose (GLU), total cholesterol (T-CHO), triglyceride (TG), total bilirubin (T-BIL), blood urea nitrogen (BUN), creatinine (CRE), uric acid (UA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), sodium (Na), potassium (K), chlorine (Cl) and calcium (Ca).
URINALYSIS: Yes
- Time schedule for collection of urine: After end of experimentaion period of 90 days
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
At the end of the experimentation period of 90 days, all rats were deprived of food (but not water) overnight, and fresh urine samples were obtained for urinalysis of urobilinogen, occult blood, bilirubin, ketone, glucose, protein, pH and nitrous acid using test papers.
NEUROBEHAVIOURAL EXAMINATION:No
OTHER: attitude (such as excitement or inanimation), behavior (such as exploration or grooming) or nervous system (such as tremor or convulsion) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- For numerical data such as body weight and hematological data, statistical evaluation of equality of means between the control and treated group values was assessed by Bartlett’s test. Homogeneity of variance was then analyzed by a one-way analysis of variance, and differences between the control and treated group values were evaluated by Dunnett’s test. If the Bartlett’s test was significant, the data were subjected to the Kruskal–Wallis test and the Dunnett’s type rank sum test. For contingent data such as incidences of histopathological lesions and urinalysis, differences between the control and treated group values were evaluated by the Fisher’s exact probability test. Statistical processing was conducted using StatLight software (Yukms Ltd., Tokyo, Japan). In all cases, statistical significance was set at p-value less than 0.05.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Average daily water intakes of the treated females were signif. increased compared to controls. These were slight changes and lacked dose-dependence and were probably due to the taste of diets containing L-Pro and thus without toxicologic significance.
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No rats died or became moribund until the end of the experiment. All treated rats showed no abnormal signs for general appearance.
BODY WEIGHT AND WEIGHT GAIN
There were no significant differences in average body weights.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no significant differences in average daily food intake.
FOOD EFFICIENCY
There were no significant differences in food efficiecy
HAEMATOLOGY
3 haemtological parameters (HGB, HCT, MCH) were statistically significant changed in the treated groups. These hematological changes were slight, and lacked dose-dependence, and no abnormalities were observed. The observed hematological changes can therefore be considered incidental and not treatment-related.
CLINICAL CHEMISTRY
The serum GLU (all treated males), BUN (0.625%, 1.25% and 5.0% females), CRE (5.0% both sexes) and UA (0.625% females, 2.5% males and 5.0% both sexes) levels were significantly lower than those of the control groups. However, the values in L-Pro-administered groups were within the range of the historic control values. Moreover, no corresponding pathological findings were observed. It is thus conceivable that the changes are toxicologically insignificant, even if they were treatment-related.
URINALYSIS
There were no treatment-related changes in the analyzed parameters.
NEUROBEHAVIOUR
All treated rats showed no abnormal signs for attitude (such as excitement or inanimation), behavior (such as exploration or grooming) or nervous system (such as tremor or convulsion) compared to the control rats during the study.
ORGAN WEIGHTS
The relative spleen (2.5% or greater males) and kidney (5.0% male) weights were significantly higher than those of the control groups.
The histological findings of the spleen showed no abnormalities. The hematological study revealed no significant differences between the control and the 2.5% or greater males. In the kidney weight, the increased changes were slight and lacked dose-dependence, and no abnormalities.
In the kidney weight, the increased changes were slight and lacked dose-dependence, and no abnormalities were observed in the urinalysis and histopathology. Moreover, the absolute spleen and kidney weights showed no significant differences between the control and the treated groups. It is suggested that the organ weight changes are toxicologically insignificant, even if they were treatment-related:
GROSS PATHOLOGY
There were no abnormal findings.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no abnormal findings.
HISTOPATHOLOGY: NEOPLASTIC
There were no abnormal findings. - Dose descriptor:
- NOAEL
- Remarks:
- males
- Effect level:
- 2 772.9 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Remarks:
- females
- Effect level:
- 3 009.3 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: see 'Remark'
- Critical effects observed:
- not specified
- Conclusions:
- A subchronic oral toxicity guideline study of L-proline with rats was conducted for 90 days. No treatment-related significant or toxicologiocally relevant findings were observed. The no-observed-adverse-effect-level (NOAEL) for L-Pro was determined to be a dietary dose of 5.0% (2772.9 mg/kg body weight/day for males and 3009.3 mg/kg body weight/day for females) under the present experimental conditions.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 773 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Study reliable without restrictions.
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 subchronic oral toxicity guideline study of L-proline with rats was conducted for 90 days. No treatment-related significant or toxicologiocally relevant findings were observed. The no-observed-adverse-effect-level (NOAEL) for L-Pro was determined to be a dietary dose of 5.0% (2772.9 mg/kg body weight/day for males and 3009.3 mg/kg body weight/day for females) under the present experimental conditions.
Another independent subchronic oral toxicity guideline study strongly supports these findings. The NOAELs estimated in this study were in the same range for both sexes of rats.
The mean human daily intake of alanine for all life stage and gender groups from food and supplements is approximately 5.2 g/d (Food and Nutrition Board, 2005). A dietary dose of 5.0% L-proline is significantly higher than the mean daily oral intake for humans.
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 selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study with Klimisch code 1
Justification for classification or non-classification
Based on the results of subchronic 90-day studies, L-proline acid is not classified for repeated dose toxicity according to DSD and CLP.
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