N-[(1R)-2-[(Methylsulfonyl)oxy]-1-phenylethyl]carbamic acid 1,1-dimethylethyl ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 February - 3 March 2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl N-[(1R)-2-(methanesulfonyloxy)-1-phenylethyl]carbamate

EC Number:

855-580-5

Cas Number:

102089-75-8

Molecular formula:

C14H21NO5S

IUPAC Name:

tert-butyl N-[(1R)-2-(methanesulfonyloxy)-1-phenylethyl]carbamate

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

A total of 5 animals were used for each dose level. This includes the animal from the sighting study administered the same dose and an additional four animals. Food was removed overnight prior to dosing and returned approximately 2-3 hours after dosing. Then, food was available ad libitum. Body weights were observed on days 1, 7, and 14 and clinical observations were made on days 1-14.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

The test material was administed as a single dose via oral gavage with a 14 day observation period according to OECD 420 Acute Oral Toxicity - Fixed Dose Procedure. The formulation was composed of 0.5% hydroxpropylmethylcellulose (HPMC). The dose volume was 10 mL/kg (all concentrations).

Doses:

Sighting study: 300 mgkg, 2,000 mg/kg
Main Study: 2,000 mg/kg

No. of animals per sex per dose:

Not specified

Control animals:

not specified

Details on study design:

Sighting Study: The purpose of the sighting study was to determine the starting dose for the main study. The test article was administered to one animal at a time in a sequential manner with at least 24 hours between the dosing of each animal. Animals are maintained for a period of at least 14 days. Dose levels are fixed at 5, 50, 300, and 2,000 mg/kg. The first animal was dosed at a level expected to produce toxicity based on available in vivo or in vitro data; or at 300 mg/kg when no toxicity information is available. Depending on signs of toxicity, the next animal was dosed at the next higher or next lower dose level. Dosing continued until a dose level for the main test was determined determined or death was seen at the lowest fixed dose.

Main Test: The main test dose was determined by the sighting study. A total of 5 animals were used for each dose level. This included the animal from the sighting study administered the same dose and an additional four animals. The course of the study depended on the response of the animals at the dose level for the main test; either the testing was stopped and the appropriate hazard classification class was assigned; or the tesitng continued at a higher fixed dose level; or testing continued at a lower fixed dose level. If additional dose levels were tested, the time interval between them was determined by the onset, duration, and severity of toxic signs.

After dosing, the animals were returned to their cages and supplied with feed and water ad libitum. Clinical observations were made at least once during the first 30 minutes with special attention given during the first 6 hours and then at least daily for a period of 14 days. The frequency was determined by the response of the test animals to the treatment. However, the duration of observation was not fixed rigidly. It was determined by the toxic reactions, rate of onset and length of recovery period, and was therefore be extended when considered necessary. The time at which signs of toxicity appeared and disappeared and the time of death were important, especially if there was a tendency for deaths to be delayed. All observations were recorded, and individual records were maintained for each animal. Cageside observations included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic, and central nervous system, and somatomotor activity and behavior pattern. Particular attention was directed to observations of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma. The time of death was recorded as precisely as possible. Moribund animals that were killed for humane reasons were considered in the same way as animals that died on test.

Animals were weighed weekly and at the end of the observation period and then were sacrificed by exsanguination under deep anesthesia with intraperitoneal ketamine and xylazine. Changes in weights were calculated and recorded when survival exceeded one day. Any animal found dead was necropsied as soon as possible, but in no case later than 12 hours after discovery. A gross necropsy was performed on all animals whether found dead, sacrified in extremis, or sacrified at the end of the study and all gross pathological changes were recorded.

An evaluation of acute toxicity data included the relationship, if any, between the animals exposed to the test article and the incidence and severity of all abnormalities, including behavioral and clinical abnormalities, gross lesions, body weigh changes, effects on mortality, and any other toxic effects.

Results and discussion

Preliminary study:

Animal 1002 was dosed at 300 mg/kg of the test material as there was no information available on toxicity. Starting approximately 30 minutes after dosing clinical signs including piloerection and mildly decreased activity were observed, which lasted until the 4 h timepoint. In addition, animal 1002 showed increased consumption of the wooden bedding pellets one hour after dosing which might have been a sign of distress or abdominal pain but could also be related to the stress caused by the procedure itself, especially considering the fasting and the single housing. At the 3 hour observation point, walking on toes was obseved in this animal. To gain more information on the toxicological profile of the test material, animal 1004 was dosed the next day at the next higher dose of 2,000 mg/kg. Approximately 20 minutes after dosing mildly decreased activity was observed. Starting approximately 2 hours after application, clinical signs including partial palpebral closure, pilo-erection, hunched posture and decreased activity were observed, which lasted until the 6 hour timepoint. All clinical signs in animal 1004 were resolved 24 hours after dosing and the animal appeared normal. Based on the observations 2,000 mg/kg was chosen for the main study.

Four additional animals (1006, 1008, 1010, and 1012) were dosed at 2,000 mg/kg of the test material

Effect levels

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: All four animals showed clinical signs of decreaesd activity and rough hair starting 1 hour post dose. Animals 1006, 1008, and 1012 also showed piloerection and partial palebral closure. All clinical signs were reslved 4 hours post dose.

Gross pathology:

There were no findings during gross necropsy in any of the main animals at the end of the study; all tissues appeared normal.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The test item was determined to have an estimated LD50>2,000 mg/kg and was therefore classified as a Hazard Category 5 according to GHS, but because category 5 is not implemented in the EU, GHS criteria was considered to be not met.