Cyclopropanecarboxylic acid, 1-amino-2-ethenyl-, ethyl ester, (1R,2S)-, sulfate (2:1)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2011-11-03 to 2011-12-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented GLP study performed according to OECD guideline N°425, EPA OPPTS 870.1100 and a guideline of the Japanese Ministry of Agriculture, Forestry and Fisheries (Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000). .

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau , November 24, 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

bis(ethyl (1R,2S)-1-amino-2-ethenylcyclopropane-1-carboxylate); sulfuric acid

EC Number:

689-958-4

Cas Number:

1173807-85-6

Molecular formula:

C8H13NO2.0.5H2SO4

IUPAC Name:

bis(ethyl (1R,2S)-1-amino-2-ethenylcyclopropane-1-carboxylate); sulfuric acid

Details on test material:

- Name of test material (as cited in study report): JNJ-31052047-ABI or T003325
- Substance type: isolated process intermediate
- Physical state: solid
- Analytical purity: 100.1% w/w
- Purity test date: 6 July 2011
- Lot/batch No.: 00549620
- Storage condition of test material: At room temperature (approximately 15-25°C)

Test animals

Species:

rat

Strain:

other: CD (Crl:CD 'SD')

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: 8-12 weeks
- Weight at study initiation: from 201 to 231 g
- Fasting period before study: overnight prior to and approximately four hours after dosing
- Housing: one animal per cage, in a barriered rodent facility kept at a positive pressure
- Diet (e.g. ad libitum): ad libitum except overnight prior to and approximately four hours after dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5, 7 or 12 days before treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG 400, 1.2 eq NaOH 10 N and 0.3 eq HCl 12N

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 35, 110 and 400 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Justification for choice of vehicle: no

MAXIMUM DOSE VOLUME APPLIED: 400 mg/mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As no previous toxicological information was available, the initial dose level was 175 mg/kg, in compliance with the study guidelines.

Doses:

175, 550 and 2000 mg/kg

No. of animals per sex per dose:

1 rat for 175 mg/kg
2 rats for 550 mg/kg
4 rats for 2000 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality : Cages of rats were checked at least twice daily for any mortalities
Clinical signs : Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, surviving animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only)
Body weights : The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15 or at death. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: yes (macroscopic evaluation of opened cranial, thoracic and abdominal cavities).

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

One female (animal number K3) dosed at 2000 mg/kg died on Day 2.

Clinical signs:

other: Concerning the dead animal, clinical signs seen prior to death comprised unsteady gait, flat posture, irregular breathing, underactivity, reduced body temperature, piloerection, reduced body tone, hindlimbs splayed, convulsion, shallow breathing, partiall

Gross pathology:

Macroscopic examination of the animal number K3 revealed congestion (darkened tissues/organs) of the subcutaneous tissue, pallor of the liver, spleen and kidneys, a small stomach and fluid (yellow or green) in the stomach, duodenum and small and large intestines.

Macroscopic examination of the surviving animals on Day 15 revealed pallor of the liver and kidneys of one female (animal number K5) dosed at 2000 mg/kg.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The 2000 mg/kg LD50 determined within the study allows to conclude on the classification of the substance JNJ-31052047-ABI as acutely toxic, category IV.