Carnosine

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Safety and Efficacy Evaluation of Carnosine, An Endogenous Neuroprotective Agent for Ischemic Stroke

Author:

Ok-Nam Bae et al.

Year:

2013

Bibliographic source:

Stroke. 44(1): 205–212. doi:10.1161/STROKEAHA.112.673954.

Materials and methods

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Carnosine

EC Number:

206-169-9

EC Name:

Carnosine

Cas Number:

305-84-0

Molecular formula:

C9H14N4O3

IUPAC Name:

(2S)-2-(3-aminopropanoylamino)-3-(1H-imidazol-4-yl) propanoic acid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan
- Age at study initiation: adult
- Weight at study initiation: 250 - 300 g

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: saline

Details on exposure:

For toxicity assessment, saline or the test substance were administered over 5 min into an indwelling intravenous catheter in the left femoral vein.

Doses:

100, 500, 1000, or 2000 mg/kg bw

No. of animals per sex per dose:

12

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily assessments for systemic signs of toxicity was performed
- Necropsy of survivors performed: yes
- Other examinations performed: body weight, food consumption, activity, and mortality were evaluated, to examine organ-specific toxicity, histopathological evaluations were performed on bone marrow, cerebellum, cerebrum, brain stem, hippocampus, heart, lung, liver, and kidney in randomly selected animals.

Statistics:

Means and standard errors of means (SEM) were calculated for all treatment groups. The data were subjected to student t-test or one-way ANOVA followed by Duncan’s test to determine the significant differences between treatment groups. Statistical analysis was performed using SPSS software (Chicago, IL). In all cases, a p value of <0.05 was considered significant.

Results and discussion

Effect levels

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: absence of adverse toxic effects

Mortality:

No rat died.

Clinical signs:

No clinical signs of toxicity observed.

Body weight:

No significant differences were found between control (saline-treated) and carnosine-treated groups both in body weight change and the amount of food consumption.

Gross pathology:

Administration of the test substance did not induce signs of toxicity in any of the examined organs.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the conducted study in rats, the test substance did not induce death or other signs of toxicity at a doses of 100 - 2000 mg/kg bw (administered intravenously).
The available data on acute toxicity of the test substance do not meet criteria for classification according to Regulation (EC) 1272/2008.

Executive summary:

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 per sex per dose 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.