L-cysteine

Endpoint summary

Description of key information

L-Cysteine was found to be practically non-toxic after oral and dermal application.

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:

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.

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

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

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.

Sex:

female

Dose descriptor:

LD50

Effect level:

5.85 other: g/kg

Based on:

test mat.

95% CL:

>= 5 - <= 6.17

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.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 850 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Type of coverage:

semiocclusive

Vehicle:

other: aqua ad injectionem

Details on dermal exposure:

Species/strain: healthy rats, WISTAR rats Crl: WI(Han) (full barrier)
Source: Charles River, 97633 Sulzfeld, Germany
Sex: male and female
Number of animals: 5 male and 5 female
Age at the beginning of the study: males: 8 - 9 weeks old; females: 12- 14 weeks old
Body weight on the day of administration: males: 233 - 257 g; females: 210-217 g.

Full barrier in an air-conditioned room
Temperature: 22 ± 3 °C
Relative humidity: 55± 10%
Artificial light, sequence being 12 hours light, 12 hours dark
Air change: 10 x/ hour
Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 0906) Free access to tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
The animals were kept individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 300512). Adequate acclimatisation period (at least five days) under laboratory conditions

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

The animals were marked for individual identification by tail painting. Approximately 24 hours before the test, the fur was removed from the dorsal area of the trunk using an electric clipper. Care was taken to avoid abrading the skin, and only animals with healthy intact skin were used.
No less than 10% of the body surface was cleared for the application. Prior to the application a detailed clinical observation was made of all animals.

The test item was applied at a single dose, uniformly over an area which was approximately 10% of the total body surface. The test item was held in contact with the skin by a dressing throughout a 24-hour period. The dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: The test item showed no signs of acute dermal toxicity but signs of dermal irritation after a single dose application.

Gross pathology:

With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The substance is not toxic to rats under the conditions of this study.

Executive summary:

An actute dermal toxicity study was performed with L-Cysteine according to OECD Guideline 402. The substance was administered at a single dose, uniformly over an area which was approximately 10% of the total body surface. The test item was held in contact with the skin by a dressing throughout a 24-hour period. The dressing consisted of a gauze-dressing and non-irritating tape. Under the conditions of the present study, single dermal application of the test item L-Cysteine to rats at a dose of 2000 mglkg body weight was associated with neither mortality nor signs of toxicity but signs of irritation. The dermal LD5O was determined to be > 2000 mg L-Cysteine /kg body weight. No clear signs of toxicity were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

LD50 > 2000 mg/kg

Additional information

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

The dermal LD50 was determined to be > 2000 mg L-Cysteine / kg body weight.

Justification for selection of acute toxicity – oral endpoint
Comparable to guideline study with acceptable restrictions: article in Japanese has been translated into English.

Justification for selection of acute toxicity – inhalation endpoint
Study scientifically unjustified.

Justification for selection of acute toxicity – dermal endpoint
Guideline study under GLP consitions.

Justification for classification or non-classification

The oral LD50 in an acute rat study was found to be 5850 - 6350 mg/kg and results in non-classification for the endpoint.

The dermal LD50 in an acute rat study was found to be > 2000 mg/kg and results in non-classification for the endpoint.