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Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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:
other: well documented study similar to OECD guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Beijing Weitonglihua experimental animal technique Co. Ltd
- Age at study initiation: 6 weeks
- Housing: 5 animals were housed in a bottom-meshed stainless cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-22°C
- Humidity (%): 40-70%
- Air changes (per hr): ~15 changes/h
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
individual dose volume of 10 ml/kg was calculated according to the latest measured body weight.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
test article was administered daily by gavage
Remarks:
Doses / Concentrations:
500, 1500, 3000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the experimental period
- Anaesthetic used for blood collection: Yes (phenobarbital sodium)
- Animals fasted: Yes
- Parameters checked: RBC, HGB, HCT, MCV, MCH, MCHC, WBC, PLT, differential counts of leukocytes, reticulocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the experimental period
- Animals fasted: Yes
- Parameters checked: TP, ALB, GLU, T-CHO, TG, T-BIL, BUN, CRE, IP, AST, ALT, ALP, Na, K, Cl, Ca

URINALYSIS: Yes
- Time schedule for collection of urine: during the last 4 days of the administration period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: urobilinogen, occult blood, bilirubin, ketone body, glucose, protein, pH, nitrite, specific gracity, leukocytes, sodium, potassium, chloride

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Variance in data for urinary quantitative data, hematology, serum biochemistry, body weights, food consumption, and absolute and relative organ weights was checked for homogeneity by Bartlett’s test. If the variance was homogeneous, the data were further analyzed by one-way analysis of variance. If not, the Kruskal–Wallis test was applied. When statistically significant differences were observed, the Dunnett’s multiple test was employed to compare between control and treatment groups. The urinary qualitative data and histopathological changes were analyzed with the Kruskal–Wallis test followed by Mann–Whitney’s U-test. Probability values of p < 0.05 were considered significant.
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
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Dose descriptor:
NOEL
Effect level:
3 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
The NOEL for the test item is 3000 mg/kg bw.
Executive summary:

In a subchronic toxicity study similar to OECD TG 408 L-serine was administered to 10 Sprague-Dawley rats/sex/dose by oral gavage at dose levels of 0 (control), 500, 1500 and 3000 mg/kg bw. Even the highest dose of 3000 mg/kg bw produced no adverse effects and is therefore regarded as the NOEL.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3 000 mg/kg bw/day
Study duration:
subchronic
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

In a subacute toxicity study according to OECD TG 407 L-serine was administered to 10 Sprague-Dawley rats/sex in a dose of approximately 1000 mg/kg bw. This dose and the resulting chemical intake of 799.9 and 903.0 mg/kg bw for male and female respectively resulted in no adverse effects and is regarded as the NOEL.

In a subchronic toxicity study similar to OECD TG 408 L-serine was administered to 10 Sprague-Dawley rats/sex/dose in diet at dose levels of 0 (control) 0.06, 0.5, 1.5 and 5%. Even the highest dose used (5%) resulting in an average intake of 2765 and 2905.1 mg/kg bw for male and female, respectively produced no adverse effects and is therefore regarded as the NOAEL.

In a further subchronic toxicity study similar to OECD TG 408 L-serine was administered to 10 Sprague-Dawley rats/sex/dose by oral gavage at dose levels of 0 (control), 500, 1500 and 3000 mg/kg bw. Even the highest dose of 3000 mg/kg bw produced no adverse effects and is therefore regarded as the NOEL.

All repeated dose toxicity studies consistently demonstrate the very low toxicity of L-serine. In the reported studies the test animals tolerate L-serine administrated in very high doses (well above the proposed limit dose according to OECD TG 408) and showed no signs of toxicity.

There are no studies available regarding repeated dose toxicity via the dermal route and via the inhalative route. However, although oral intake is not the most appropriate route of exposure it represents a worst case scenario in terms of bioavailability. No evidence for local effects is given. Therefore and due to animal welfare there is no need for further inhalative or dermal repeated dose testing.

Justification for classification or non-classification