Carnosine

Endpoint summary

Description of key information

Acute Toxicity oral, mouse: LD₅₀> 14930 mg/kg bw

 

Acute toxicity, intravenous administration, rat: LD₅₀ > 2000 mg/kg bw, no adverse effect observed after administration of doses up to 2000 mg/kg bw (Please refer to study entry: acute toxicity: other routes (WoE_AT_rat_RL2))

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Acute oral toxicity of the test substance was tested after single oral administration at doses up to 15000 mg/kg bw in mice
- Parameters analysed / observed: death and clinical signs of toxicity

GLP compliance:

no

Species:

mouse

Strain:

other: dd strain mice

Sex:

male

Route of administration:

oral: unspecified

Vehicle:

other: physiological saline

Details on oral exposure:

VEHICLE
- Concentration in vehicle: physiological saline
- Amount of vehicle: 0.1 - 0.3 mL/10 g

Doses:

up to 15000 mg/kg bw (other doses were used, but not specified)

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: not specified at least 72 hours

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 14 930 mg/kg bw

Based on:

test mat.

Mortality:

One out of 10 animals died after 12 hours

Clinical signs:

other: No effects observed.

Interpretation of results:

other: no classification required according to Regulation (EC) 1272/2008.

Conclusions:

Under the condition of the acute toxicity test with the test substance one out of 10 mice died at a dose of 15000 mg/kg bw administered orally.
The available data on acute oral toxicity of the test substance do not indicate requirement of classification according to Regulation (EC) 1272/2008.

Executive summary:

Acute oral toxicity of the test substance was investigated at doses up to 15000 mg/kg bw in groups of ten male dd strain mice. Following oral administration death or other clinical signs of toxicity were determined. The observation period was at least 72 hours. One out of 10 animals died after 12 hours. A LD50 > 14930 mg/kg bw was computed by the Van der Waerden method based on the number of dead mice after 72 hours. No clinical signs of toxicity were observed. Under the condition of the acute toxicity test with the test substance one out of 10 mice died at a dose of 15000 mg/kg bw administered orally. The available data on acute oral toxicity of the test substance do not indicate requirement of classification according to Regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises two adequate and reliable studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity, mouse

Acute oral toxicity of the test substance was investigated at doses up to 15000 mg/kg bw in groups of ten male dd strain mice. Following oral administration death or other clinical signs of toxicity were determined. The observation period was at least 72 hours. One out of 10 animals died after 12 hours. A LD₅₀ > 14930 mg/kg bw was computed by the Van der Waerden method based on the number of dead mice after 72 hours. No clinical signs of toxicity were observed. Under the condition of the acute toxicity test with the test substance one out of 10 mice died at a dose of 15000 mg/kg bw administered orally. The available data on acute oral toxicity of the test substance do not indicate requirement of classification according to Regulation (EC) 1272/2008.

 

Other route, Acute toxicity, intravenous administration, rat

Acute toxicity of the test substance administered intravenously was investigated in male, adult Sprague-Dawley rats. Although the test substance was not administered via the oral route, the data can be used in a weight of evidence approach for acute oral toxicity of the test substance. Since the availability of the test substance via the intravenous route is assumed to be at a maximum of 100%, the data are considered adequate to cover and evaluate the acute oral toxicity of the test substance.

In the study, groups of 12 rats were administered the test substance at doses of 100, 500, 1000, or 2000 mg/kg bw. The rats were observed for a period of 14 days. Daily assessments of systemic signs of toxicity were performed and included measurements of body weight, food consumption, activity, analysis of organ-specific toxicity, histopathological evaluations at the end of the study period (bone marrow, cerebellum, cerebrum, brain stem, hippocampus, heart, lung, liver, and kidney in randomly selected animals) and mortality. No deaths were observed. Furthermore, no clinical signs of toxicity were observed and there was no difference found between control (saline-treated) and test item-treated groups both in body weight change and the amount of food consumption. Administration of the test substance did not induce signs of toxicity in any of the examined organs. Hence, a LD₅₀ greater than 2000 mg/kg bw was determined in this study. The available data on acute toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008. (Please refer to study entry: acute toxicity: other routes (WoE_AT_rat_RL2).

Supporting studies, Acute oral toxicity, rat and mouse with the structural analogue catena-(S)­ [µ-[N^α-(3-Aminopropionyl)histidinato(2-)-N1,N2,0:N^τ]- zinc], (CAS 107667 -60 -7)

Acute oral toxicity studies in rats (Sprague-Dawley) and mice (ICR mice [Crj:CD-1 (ICR)]) were conducted with the read-across (RA) substance catena-(S)­ [µ-[N^α-(3-Aminopropionyl)histidinato(2-)-N1,N2,0:N^τ]- zinc], (CAS 107667 -60 -7) and were used as supporting studies.

The RA substance was administered at doses of 0, 4823, 5787, 6944, 8333, 10000 mg/kg bw to rats (one male and one female per dose) and doses of 0, 566, 820, 1189, 1724, 2500 mg/kg bw to mice (one male and one female per dose). During a period of 14 days following administration, the animals were observed daily and individual body weights were recorded prior to dosing on Day 0 and on Days 1, 3, 7, 10 and 14 after dosing.

1, 3, 9 and 10 female mice were found dead at the applied doses of 820, 1189, 1724 and 2500 mg/kg bw, respectively. 3, 9 and 10 male mice were found dead at the applied doses of 1189, 1724 and 2500 mg/kg bw, respectively. Death was observed 4 h to 2 days after oral administration. The LD₅₀ value for mice was calculated to be 1250 - 1350 mg/kg bw.

3, 3, 4 and 7 female rats were found dead at the applied doses of 5787, 6944, 8333 and 10000 mg/kg bw, respectively. 3, 5, 5 and 9 male rats were found dead at the applied doses of 5787, 6944, 8333 and 10000 mg/kg bw, respectively. Death was observed 1 to 5 days after oral administration of the RA substance. The LD₅₀ value for rats was calculated to be 7000 -8500 mg/kg bw. Rats and mice showed a decrease in locomotor activity, ventral posture, crouching, hypothermia and/or respiratory depression after administration of the test substance. The signs disappeared 2 - 4 days after administration in surviving animals. In addition, loose feces and dirtiness of fur following oral dosing were observed in rats, only. These signs disappeared 5 - 6 days later in surviving animals. (Please refer to study entries: acute toxicity: Supporting study_CAS 107667-60-7_AOT_rat_RL2, Supporting study_CAS 107667-60-7_AOT_mouse_RL2)

Under the condition of the acute oral toxicity test with the RA substance zinc-carnosine (CAS 107667 -60 -7), the determined LD₅₀ value for mice meets the criteria for Acute Tox. 4 (H302) according to Regulation (EC) 1272/2008. Adverse effects observed in this study are most likely attributable to the zinc part, since these effects were not observed in studies with the substance for registration and were not considered relevant for classification. This is in line with data on several zinc compounds. For example, death was reported in mice that consumed 1110 mg zinc/kg/day as zinc sulfate in their diet for 13 weeks. The LD₅₀ of zinc ranges from 186 to 623 mg zinc/kg bw/day in rats and mice. Furthermore, mice appear to be more sensitive than rats to the lethal effects of zinc (ATSDR, 2015).

Under the condition of the acute oral toxicity test with the RA substance zinc-carnosine (CAS 107667 -60 -7), the determined LD₅₀ value for rats does not meet the criteria for classification according to Regulation (EC) 1272/2008. This is in line with the other studies summarized with the substance for registration in mice and rats.

Justification for classification or non-classification

Under the condition of the acute oral toxicity test with the substance for registration one out of ten mice died at a dose of 14930 mg/kg bw. In a further study where the test substance was administered to rats intravenously, no adverse effects or death were observed. The available data used in a weight of evidence approach for evaluation of acute oral toxicity of the substance for registration do not meet criteria for classification according to Regulation (EC) 1272/2008.