L-cysteine

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Intraperitoneal administration

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

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 intraperitoneal 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; solutions were administered intraperitoneally at 16% for rats. For the rats, the intraperitoneal administrations were at least 1 g/kg with four or five levels differing by 20%. 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 control groups of rats were given intraperitoneal administrations of 1 ml. 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

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.

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1% solution in CMC

Details on exposure:

The L-cysteine (hereinafter abbreviated as the test sample) was suspended in a 1% CMC liquid; solutions were administered intraperitoneally at 16% for rats. For the rats, the intraperitoneal administrations were at least 1 g/kg with four or five levels differing by 20%. 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 control groups of rats were given intraperitoneal administrations of 1 ml. The dose was the same for the control groups regardless of body weight.

Doses:

The intraperitoneal administrations were at least 1 g/kg with four or five levels differing by 20%.

No. of animals per sex per dose:

Administration was made to nine to 14 rats in each group.

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 intraperitoneal 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; solutions were administered intraperitoneally at 16% for rats. For the rats, the intraperitoneal administrations were at least 1 g/kg with four or five levels differing by 20%. 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 control groups of rats were given intraperitoneal administrations of 1 ml. 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 intraperitoneal 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:

ca. 1.62 other: g/kg

Based on:

test mat.

95% CL:

> 1.46 - < 1.8

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 1.63 other: g/kg

Based on:

test mat.

95% CL:

> 1.46 - < 1.82

Mortality:

Particularly with large dose administration, the large majority died within 1-2 hours with intraperitoneal administration; while most died within 24 hours, a small number of specimens had a long quiescent or anesthetic condition and died within 4-72 hours. There was almost no difference in LD50 between the sexes or between intraperitoneal and subcutaneous administration, though the LD50 for oral administration was approximately 4 times that for other administration methods.

Clinical signs:

Almost no detectable symptoms appeared in the CMC-only control group and the test sample intraperitoneal groups, but mild walking confusion and a calm state were also seen in a number of specimens in the test sample groups that persisted for several hours. In the intraperitoneal 1.5 g/kg and higher, there were many specimens in which walking confusion, respiratory difficulty, and in some cases, mild convulsive walking appeared within 10-20 minutes and as late as about 1 hour. In specimens in which these symptoms were strong, there was a decrease in spontaneous exercise or a weakening or disappearance of self righting or other reflexes subsequently occurred, the animals become stationary in the abdominal position, and entered a quiescent, sleep or anesthetic condition; the muscles relaxed, respiration was suppressed, the body temperature dropped, and so on, and then they quickly died.

Body weight:

no data

Gross pathology:

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

Conclusions:

This 72 hour acute toxicity study with rats (intraperitoneal administration) resulted in a LD50 of 1.62 g/kg bw (female) - 1.63 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 intraperitoneal 1.25-1.5 g/kg 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 toxicity study with rats (intraperitoneal administration) resulted in a LD50 of 1.62 g/kg bw (female) - 1.63 g/kg (male) bw.