(2S)-5-amino-2-[(aminoacetyl)amino]-5-oxopentanoic acid

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1992-11-19 to 1992-12-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted 24 February, 1987

Deviations:

yes

Remarks:

only 2 dose levels but dose levels are sufficient for evaluation, maximum dose volume applied was 21.5 mL/kg bw

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-(2-aminoacetamido)-4-carbamoylbutanoic acid

EC Number:

700-144-0

Cas Number:

13115-71-4

Molecular formula:

C7H13N3O4

IUPAC Name:

(2S)-2-(2-aminoacetamido)-4-carbamoylbutanoic acid

Test material form:

solid

Test animals

Species:

rat

Strain:

other: Bor: WISW (SPFCpb)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann Versuchstierzucht GmbH & Co. KG, Borchen, Germany
- Age at study initiation: males 8 weeks; females 9 weeks
- Weight at study initiation: males 150 - 164 g; females 138 - 146 g
- Fasting period before study: 16 hours before treatment
- Housing: individually in Macrolon cages type II
- Diet: standard diet, ad libitum (ssniff R, special diet for rats)
- Water: drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 21.6
- Humidity (%): 40 - 69
- Photoperiod (per hr): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5% (w/v)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 110 mg/mL (2370 mg/kg bw dose) and 237 mg/mL (5110 mg/kg bw dose)
- Amount of vehicle (if gavage): 21.5 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 21.5 mL/kg bw

DOSAGE PREPARATION : The test item was suspended in the vehicle immediately before dosing, using a homogenizer and by shaking.

Doses:

2370 mg/kg bw (test item glycyl-L-glutamine monohydrate), equivalent to 2177 mg/kg bw anhydrous glycyl-L-glutamine
5311 mg/kg bw (test item glycyl-L-glutamine monohydrate), equivalent to 4879 mg/kg bw anhydrous glycyl-L-glutamine

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: at 4 to 6 h after dosing and once daily thereafter
- Frequency of weighing: day 0 (prior to dosing), thereafter at weekly intervals up to the end of the study
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopical examination included external appearance, body orifices, thoracic and abdominal cavities. Histopathology was carried out on the testes and epididymes of males, and the ovaries of females.

Statistics:

no

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 110 mg/kg bw

Based on:

test mat.

Remarks:

test item glycyl-L-glutamine monohydrate

Effect levels 2

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 879 mg/kg bw

Based on:

other: anhydrous glycyl-L-glutamine

Mortality:

2370 mg/kg bw: no deaths
5110 mg/kg bw: 0/5 males and 2/5 females died 3 h post-application.

Clinical signs:

other: 2370 mg/kg bw: slight hypokinesia and decrease of muscle tone was observed in 1/5 males and 2/5 females. 5110 mg/kg bw: slight to severe hypokinesia, slight clonic convulsions, decrease of muscle tone, and loss of righting reflexes, restrained gait, piloe

Gross pathology:

2370 mg/kg bw: In 2/5 male animals the testes appeared reduced in size.
5110 mg/kg bw: In 1/5 male animals the testes appeared reduced in size. A reddened lung was noted in the 2 deceased females.
The observations were considered toxicologically relevant and attributed to treatment.

Other findings:

Testes:
The testes were affected by focal and/or diffuse atrophy of the seminiferous epithelium. In minimal to moderate cases degenerative changes were observed in spermatocytes and spermatids, resulting in a reduction or absence of these cells in specific stages of the seminiferous epithelium. Spermatocytes were predominantly affected in the zygotene stage of the meiotic cell division. Degenerative changes and a delay in the maturation of spermatids occurred in the first five stages of the cycle of the seminiferous epithelium. Affected tubules often had multinucleated giant cells. In marked to massive cases the epithelium of the seminiferous tubules consisted only of spermatogonia and Sertoli-cells or was characterized by the Sertoli-only change.
Diffuse atrophy of the seminiferous epithelium occured in 2/5 rats treated with 5110 mg/kg bw and in 5/5 rats treated with 2370 mg/kg bw. The finding was graded as marked to massive in animals of the high dose group and minimal to moderate in animals of the low dose group. Focal atrophy was observed in 1/5 and 3/5 animals treated with 5110 and 2370 mg/kg bw, respectively. It was graded slight to marked.

Epididymides:
The epididymides of animals of both dose groups had a treatment-related reduction of spermatosoma. This finding was associated with the occurrence of immature, multinucleated and degenerated speratids / spermatozoa. Four/5 and 5/5 animals treated with 5110 and 2370 mg/kg bw were affected by this change. It was graded slight to massive.

Ovaries:
The examined ovaries did not show any treatment-related findings.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

After oral application of the test substance the LD50 was above 5110 mg/kg bw (test item glycyl-L-glutamine monohydrate), equivalent to 4879 mg/kg bw anhydrous glycyl-L-glutamine, for male and female rats.
CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.