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EC number: 200-735-9 | CAS number: 70-47-3
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study without detailed documentation
Data source
Reference
- Reference Type:
- publication
- Title:
- A 90-day toxicity study of L-asparagine, a food additive, in F344 rats
- Author:
- M Yokohira, K Hosokawa, K Yamakawa, N Hashimoto, S Suzuki, Y Matsuda, K Saoo, T Kuno, K lmaida
- Year:
- 2 008
- Bibliographic source:
- Food and Chemical Toxicology 46; 2568-2572
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Asparagine
- EC Number:
- 200-735-9
- EC Name:
- Asparagine
- Cas Number:
- 70-47-3
- Molecular formula:
- C4H8N2O3
- IUPAC Name:
- asparagine
- Details on test material:
- Molecular weight: 132.12 g/mol
C4H8N2O3
isoelectric point: 5.41
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan (Atsugi, Japan)
- Age at study initiation: 5 weeks
- Housing: Five per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2°C
- Humidity (%): 60 ± 10%
- Photoperiod (hrs dark / hrs light): 12h light/12h dark
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): 1.25%, 25.%, 5% of asparagine were mixed with synthetic diet (AIN-93G, Oriental yeast Co., Ltd, Tokyo, Japan) containing minerals and vitamins and constarch substituted for L-asparagine.
- Analytical verification of doses or concentrations:
- yes
- Remarks:
- performed by the Institute of Life Sciences, Ajinomoto Co. Inc.
- Details on analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- continuously with diet
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1.25 other: % in diet
- Remarks:
- 753 mg/kg bw/d in males, 857 mg/ kg bw/d in females
- Dose / conc.:
- 2.5 other: % in diet
- Remarks:
- 1537 mg/kg bw/d in males, 1708 mg/kg bw/d in females
- Dose / conc.:
- 5 other: % in diet
- Remarks:
- 3242 mg/kg bw/d in males, 3466 mg/kg bw/d in females
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: once a week
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
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the 90 days study after 16 h starvation collection of blood samples from the abdominal aorta under deep anesthesia and subsequently the animals were exsanguinated
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Yes
- How many animals: 20
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the 90 days study after 16 h starvation the animals were exsanguinated
- Animals fasted: Yes
- How many animals: 20
- Parameters examined: TP, A/G, ALB, BIL, TC, GLU, PL, TG, BUN, CRN, Ca, P, Na, Cl, K, AST, ALT, ALP, γ-GT
CAGE SIDE OBSERVATIONS: Not specified
URINALYSIS: No
- Metabolism cages used for collection of urine: No
- Animals fasted: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. A complete autopsy was then performed. Macroscopic pathological findings were noted during autopsy and weights of the brain,lungs, heart, spleen, liver, adrenals, kidneys, testes, salivary glands and ovaries were determined and values relative to the body weights were calculated.
HISTOPATHOLOGY: Yes. In addition to the above-mentioned organs, organs and tissues including the esophagus, stomach, duodenum, jejunum, ileum (including Peyer’s patches), colon, cecum, rectum, pancreas, urinary bladder, trachea, thyroid gland, tongue, skeletal muscle, ischiatic nerve, spinal cord, aorta, nasal cavity, eyeballs, Harderian glands, Zymbal’s glands, skin, mammary gland, mesenteric and mandibular lymph nodes, bone marrow in femur and sternum, epididymis, prostate, seminal vesicles, uterus and vagina were fixed in 10% buffered formalin solution. Testes were fixed in 2% glutaraldehyde, 15% formalin and 3% acetic acid (GFA) solution overnight before being transferred to 10% buffered formalin solution. The pituitary, prostate, seminal vesicle and uterus were weighed at the time of processing. Paraffin sections of all tissues from the 5% treated group and control groups were stained with hematoxylin and eosin for histopathological assessment. - Statistics:
- Analysis of the data for body and organ weights, hematology and serum biochemistry was performed using the following general procedures as appropriate. Dunnett's multiple comparison (P < 0.05) was applied. If significant heterogeneity of variance was detected, the Student's t-test for comparing treatment and control groups was employed. The Spearman’s rank correlation test was applied to examine dose - response relationships. The Fisher's exact probability test was used for histopathological data to analyze increases in incidence between treated and control rats. incidences of differing severities of histopathological findings were also compared using the one-sided Mann - Whitney U-test.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Slight decrease of body weights was observed in L-asparagine treated groups of males at autopsy, but there were no significant differences in final body weights in either male or female groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- ALP was significantly decreased by 9.4% in 2.5% treated males but there was no dose - response relationship. In 5% treated females, GLU, PL, TG, K and ALT were significantly increased to 123%, 125%, 316%, 117% and 121%, respectively. In 2.5% treated females, TG was significantly increased to 300%. In 1.25% treated females, GLU and TG were also significantly increased to 113% and 246%, respectively, and CRN was significantly decreased to 11%. The other serum biochemical parameters were not affected by the treatment.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Final bodyweights of 1.25% and 5% treated males, 273 ± 15 and 271 ± 14 g, respectively, and these values were significantly decreased compared to the control value, 290 ± 8 g. Significant increases of relative organ weights of the brain, kidney and testes were observed in 5% treated males,
0.72 ± 0.04%, 0.56 ± 0.03% and 1.07 ± 0.05%, compared with controls, 0.66 ± 0.03%, 0.52 ± 0.03% and 1.00 ± 0.02%, respectively. Other organs in males did not demonstrate significant variation and final body - and organ weights of females did not significantly vary across groups. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Organs of 5% and 0% treated males and females were analyzed in line with the OECD Test Guideline. In some rats, inflammatory findings or leukemia in the lung, simple cysts of the ovaries and sebaceous adenomas in the Zymbal’s glands were observed. However, there were no significant intergroup differences by the Fischer's exact test and the Mann-Whitney U-test. Additional examinations of 2.5% and 1.25% treated rats were therefore not performed, in line with the OECD Test Guideline.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The monocytic lymphomas in the lungs and sebaceous adenomas observed in the present study as proliferative lesions in male or female 5% groups are known to occur spontaneously in this strain of rats
- Other effects:
- not examined
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 650 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 730 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1: Selected clinical chemistry and pathology findings
Doses (unit) |
0 |
1.25% |
2.5% |
5% |
0 |
1.25% |
2.5% |
5% |
male |
female |
|||||||
Number of animals/group |
10 |
10 |
10 |
9 |
10 |
10 |
10 |
9 |
Blood chemistry(day 90) |
|
|
|
|
|
|
|
|
- TP (g/dL) |
7.0±0.1 |
7.1±0.2 |
7.2±0.2 |
7.0±0.2 |
7.2±0.2 |
7.1±0.4 |
7.3±0.3 |
7.1±0.3 |
- A/G |
1.7±0.1 |
1.7±0.2 |
1.5±0.2 |
1.6±0.2 |
2.0±0.1 |
2.0±0.3 |
2.0±0.1 |
2.0±0.2 |
- ALB (g/dL) |
4.4±0.1 |
4.4±0.2 |
4.3±0.2 |
4.3±0.1 |
4.8±0.1 |
4.7±0.2 |
4.9±0.2 |
4.7±0.1 |
- BIL (mg/dL) |
0.05±0.01 |
0.050.01 |
0.04±0.00 |
0.04±0.01 |
0.05±0.00 |
0.05±0.01 |
0.05±0.01 |
0.05±0.01 |
- TC (mg/dL) |
70.1±3.8 |
66.8±12.9 |
61.2±9.2 |
72.6±14.0 |
63.2±9.2 |
69.9±10.2 |
68.6±13.5 |
78.4±18.4 |
- GLU (mg/dL) |
168±29 |
165±18 |
149±14 |
165±17 |
107±7 |
121±8 |
116±8 |
132±13 |
- PL (mg/dL) |
116±7 |
114±20 |
103±14 |
117±19 |
115±13 |
128±14 |
130±19 |
114±27 |
- TG (mg/dL) |
112±24 |
122±49 |
112±32 |
143±38 |
22±8 |
54±23 |
66±8 |
69±21 |
- BUN (mg/dL) |
15.2±0.9 |
16.9±1.6 |
15.5±1.6 |
17.3±2.3 |
16.1±1.4 |
16.3±1.8 |
16.2±0.9 |
17.1±1.6 |
- CRN (mg/dL) |
0.25±0.01 |
0.25±0.02 |
0.26±0.01 |
0.26±0.02 |
0.27±0.02 |
0.24±0.03 |
0.27±0.01 |
0.25±0.02 |
- Ca (mg/dL) |
10.6±0.3 |
10.6±0.5 |
10.8±0.2 |
10.5±0.2 |
10.3±0.3 |
10.4±0.2 |
10.7±0.1 |
10.9±1.5 |
- P (mg/dL) |
5.3±0.7 |
5.4±1.0 |
5.2±0.6 |
4.6±0.7 |
5.9±0.7 |
5.8±1.4 |
4.8±0.4 |
5±0.9 |
- Na (mEq/L) |
140±1 |
139±2 |
140±1 |
139±1 |
141±2 |
141±2 |
143±1 |
140±2 |
- Cl (mEq/L) |
102±1 |
101±1 |
101±1 |
101±1 |
104±2 |
104±1 |
103±1 |
101±5 |
- K (mEq/L) |
3.9±0.6 |
4.1±0.5 |
3.8±0.3 |
4.0±0.3 |
4.1±0.3 |
4.4±1 |
4.5±0.4 |
4.8±0.6 |
- AST (IU/L) |
61.2±7 |
65.7±6.3 |
65.4±4.7 |
68.3±9.2 |
68.6±4.6 |
69.3±5.5 |
69.3±5.5 |
77.2±12.2 |
- ALT (IU/L) |
33.4±5.4 |
3.3±6.4 |
38.2±5.1 |
39.6±7.9 |
26.8±2.4 |
27.7±2.6 |
28.5±2.0 |
32.4±3.4 |
- ALP (IU/L) |
437±23 |
432±39 |
397±27 |
424±34 |
307±44 |
340±50 |
339±58 |
349±49 |
- γ-GTP (IU/L) |
<2 |
<2 |
<2 |
<2 |
<2 |
<2 |
<2 |
2.4±1.3 |
Histopathology |
|
|
|
|
|
|
|
|
Lung bronchial |
|
|
|
|
|
|
|
|
- Accumulation, foam cell/slight lesion |
2 |
|
|
5 |
6 |
|
|
6 |
- Accumulation, foam cell/moderate lesion |
0 |
|
|
0 |
2 |
|
|
1 |
- Acute inflammation/slight lesions |
2 |
|
|
1 |
0 |
|
|
1 |
-Acute inflammation/moderate lesions |
0 |
|
|
0 |
1 |
|
|
0 |
- Acute inflammation/severe lesions |
0 |
|
|
0 |
0 |
|
|
0 |
- Granulation |
0 |
|
|
0 |
0 |
|
|
1 |
- Monocytic cell leukemia |
0 |
|
|
2 |
0 |
|
|
2 |
Ovary |
|
|
|
|
|
|
|
|
- simple cyst |
0 |
|
|
0 |
1 |
|
|
0 |
Zymbal´s gland |
|
|
|
|
|
|
|
|
- Sebaceuos adenoma |
0 |
|
|
1 |
0 |
|
|
0 |
Statistics: For clinical chemistry ANOVA + Dunnetts tests (two sided): * P < 0.05 ** P < 0.01 and for histopathology Fischer´s exact test.
Applicant's summary and conclusion
- Conclusions:
- In the present 90-days repeated dose study in rats the animals received either 0, 1.25, 2.5 or 5% L-asparagine via daily diet. There were no adverse effects observed except an increase in relative organ weight and some clinical biochemistry biomarkers at the 5% dose level. Therefore, significant effects of the 5% treatment were concluded and the NOAEL was determined to be 2.5%, i.e. 1650 mg/kg bw in males and 1730 mg/kg bw in females.
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