Disodium L-cystinate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study from supporting substance (structural analogue)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1977

Report date:

1977

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

- Principle of test: The test materials cystenosine, inosine, an cystine were administered orally, and symptom and weight changes were observed.
- Short description of test conditions: Experiment was carried out on 4-week-old male and female rats fasted for 16 hours before drug administration via feeding tube. The animals still alive after seven days post-drug were sacrificed and autopsy was performed.
- Parameters analysed / observed: Symptom and weight changes were observed for seven days after drug administration.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Cystine

EC Number:

200-296-3

EC Name:

Cystine

Cas Number:

56-89-3

Molecular formula:

C6H12N2O4S2

IUPAC Name:

cystine

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

Test materials Cystenosine, Inosine, and Cystine were suspended in 5% gum arabic aqueous solutions
- Cystenosine is a blend of Inosine and Cystine at a weight ratio of 10:1

Test animals

Species:

rat

Strain:

Wistar

Remarks:

JCL

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan CREA
- Females (if applicable) nulliparous and non-pregnant: not reported
- Age at study initiation: 4 weeks
- Weight at study initiation: not reported
- Fasting period before study: 16 hours
- Housing: males and females housed separately; dose groups housed separately
- Diet (e.g. ad libitum): CA-1 pellets (Japan CREA) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): 55 ± 5%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: gum arabic aqueous solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 5% gum arabic aqueous solution
- Amount of vehicle (if gavage): 5 mL/100 g body weight
- Justification for choice of vehicle: not specified
- Lot/batch no. (if required): not reported
- Purity: not reported

MAXIMUM DOSE VOLUME APPLIED: 25,000 mg/kg body weight

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: 25,000 mg/kg body weight was the maximum allowable administration quantity.

Doses:

10,000 and 25,000 mg/kg of body weight

No. of animals per sex per dose:

10 males, 10 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: at least once a day
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

none

Results and discussion

Preliminary study:

none

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Remarks:

Cystenosine, Inosine, and Cystine (separately)

Effect level:

>= 25 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

One (female) rat died after 28 hours in the 25,000 mg/kg Cystine group

Clinical signs:

Drop in body temperature, dirtying around the lower abdomen, and a decrease in spontaneous exercise seen in 2 or 3 females 24-48 hours after administration of 25,000 mg/kg Cystine. One rat died, but remaining rats returned to normal by 72 hours.

Body weight:

In the 25,000 mg/kg Cystine group, suppression of weight increase was found 1 to 2 days after administration in males and females, but a progressive increase in body weight was subsequently exhibited.

Gross pathology:

In the 25,000 mg/kg Cystine group, the results of autopsy showed punctate bleeding on the stomach fundus and hematuria in the bladder, but there were no particularly abnormal findings in the living specimens.

Any other information on results incl. tables

Table 1. The acute toxicity of Cystenosine, Inosine, and Cystine

Compound	Doses (mg/kg)	Dead / Total Treated
		Male	Female
Cystenosine	10000	0/10	0/10
	25000	0/10	0/10
Inosine	10000	0/10	0/10
	25000	0/10	0/10
Cystine	10000	0/10	0/10
	25000	0/10	1/10

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

No particular abnormalities or all-encompassing adverse effects were seen in this 7-day acute toxicity test of Cystenosine, Inosine, and Cystine (administered separately). One female rat died during the observation period. The LD50 of each of three substances is at least 25,000 mg/kg body weight.

Executive summary:

Cystenosine, inosine and cystine were suspended in 5% gum arabic aqueous solutions and administered separately by oral gavage to four-week old Wistar JCL male and female rats at doses of 10,000 mg/kg or 25,000 mg/kg bw. No particular abnormalities or all-encompassing adverse effects were seen in this 7-day acute toxicity test of Cystenosine, Inosine, and Cystine (administered separately). One female rat died during the observation period. The LD50 of each of three substances is at least 25,000 mg/kg body weight.