L-cysteine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions, article in Japanese has been translated into English.

Data source

Reference

Reference Type:

publication

Title:

Acute Toxicity Tests with Cysteine in Mice and Rats

Author:

Koichiro Takasaki, Masanobu Urabe, Ryuichi Yamamoto, Shyozo Ishibashi, Norizo Hashimoto

Year:

1973

Bibliographic source:

Ori Yakuri [Applied Pharmacology] (1973) 7 (9-10) 1251-1264 (Special Feature)

Materials and methods

Test guideline

Qualifier:

no guideline followed

Deviations:

yes

Principles of method if other than guideline:

Twenty-four hours after feeding was stopped, the LD50 in the rats (females: 62-122 g, males: 68-137 g) from the oral administration of the liquid drug was calculated using the Litchfield-Wilcoxon method. The L-cysteine (hereinafter abbreviated as the test sample) was suspended in a 1% CMC liquid; a 30% solution was orally administered to rats. Administration was made to nine to 14 rats in each group. The LD50 was found in rats from the number of deaths after 72 hours. The dose was the same for the control groups regardless of body weight. During the experiment, the general symptoms of all of the groups were observed.The number of surviving animals after 72 hours were sacrificed by decapitation, and these and the other dead animals were autopsied for macroscopic changes in the vital organs.

GLP compliance:

not specified

Test type:

other: multiple-dose study

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

L-cysteine

EC Number:

200-158-2

EC Name:

L-cysteine

Cas Number:

52-90-4

Molecular formula:

C3H7NO2S

IUPAC Name:

L-cysteine

Test material form:

other: solution in CMC

Details on test material:

Name: L-Cysteine

Test animals

Species:

rat

Strain:

other: SD-JCL

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats (SD-JCL) raised for one week in a room at constant temperature (18-25º) and constant humidity (50-65%) were used. The mice and rats used in the one-month and six-month prolonged tests were ordinarily placed two in a cage. They were allowed to consume their feed (CLEA Japan) and water (tap) ad libitum. weight females: 62-122 g, weight males: 68-137 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% CMC solution

Details on oral exposure:

L-Cysteine was suspended in a 1% CMC liquid; a 30% solution was orally administered.
Control animals: oral administration of 2 mL of vehicle, same dose regardless of body weight.

Doses:

The median dose for oral administration was 5 g/kg with 10 levels differing by 10%.

No. of animals per sex per dose:

9-14

Control animals:

yes

Details on study design:

Twenty-four hours after feeding was stopped, the LD50 in the rats (females: 62-122 g, males: 68-137 g) from the oral administration of the liquid drug was calculated using the Litchfield-Wilcoxon method. The L-cysteine (hereinafter abbreviated as the test sample) was suspended in a 1% CMC liquid; a 30% solution was orally administered to rats. Administration was made to nine to 14 rats in each group. The LD50 was found in rats from the number of deaths after 72 hours. The dose was the same for the control groups regardless of body weight. During the experiment, the general symptoms of all of the groups were observed.The number of surviving animals after 72 hours were sacrificed by decapitation, and these and the other dead animals were autopsied for macroscopic changes in the vital organs.

Statistics:

Twenty-four hours after feeding was stopped, the LD50 in the rats (females: 62-122 g, males: 68-137 g) from the oral administration of the liquid drug was calculated using the Litchfield-Wilcoxon method.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

LD50

Effect level:

5.85 other: g/kg

Based on:

test mat.

95% CL:

>= 5 - <= 6.17

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

6.35 other: g/kg

Based on:

test mat.

95% CL:

>= 5.87 - <= 6.98

Mortality:

Animals entering an anesthetic condition: respiration was suppressed and the body temperature dropped before they died.
Particularly with large dose administration, the large majority died within 4 hours. There was almost no difference in LD50 between the sexes.

Clinical signs:

other: Almost no detectable symptoms in the lower dose groups; In the 5.6 g/kg and higher groups there were many specimens with abnormal gait, respiratory symptomes and in some cases mild convulsion within 10-20 minutes until 1 hour after administration. In spe

Gross pathology:

Autopsy findings: although almost no changes were found in the surviving specimens, internal organ (abdominal and thoracic) and intracranial hemorrhaging, cerebral congestion, heart stoppage in the contracted position were observed in the dead specimens.

Other findings:

Almost no detectable symptoms appeared in the CMC-only control group and oral groups. The LD50 for oral administration was approximately 4 times that for other administration methods.
Autopsy findings: Although almost no changes were found in the surviving specimens in each of the administration routes, internal organ (abdominal and thoracic) and intracranial hemorrhaging, cerebral congestion, heart stoppage in the contracted position, and so on were observed in the dead specimens.

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

A 72 hour acute oral toxicity study with rats resulted in a LD50 of 5.85 g/kg bw (female) - 6.35 g/kg (male) bw.

Executive summary:

With a single administration of L-cysteine, temporary, mild central nervous agitation symptoms persisted from ataxic walking to small jumping, convulsive walking continued in the oral 5 g/kg and higher groups of rats. This transitioned to central nervous paralytic symptoms, going from calm to a sleeping or anesthetic condition. Specimens having strong such symptoms entered a deep anesthetic state and then died.

Toxicity of L-cysteine in rats is thought to be relatively weaker than general drugs, but at high-dose administration, it is thought that central [nervous] symptoms occur, accompanying in particular cerebral congestion and hemorrhaging. These, combined with changes due to congestion and hemorrhaging in the heart and other organs, are thought to result in a anesthetic condition, then weakening and death. In the light of the histological tests, the congestion and hemorrhaging of the internal organs may be due to dilation of the capillaries or to transudation of blood due to hyperpermeability

This 72 hour acute oral toxicity study with rats resulted in a LD50 of 5.85 g/kg bw (female) - 6.35 g/kg (male) bw.