2-(4-bromophenyl)-2-methylpropionic acid methyl ester

Endpoint summary

Description of key information

The oral and dermal LD50 values were determined to be > 2000 mg/kg bw.

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

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed in accordance with validated guidelines and in GLP compliance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Rat, HanBrl: Wist (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST SYSTEM
Test system: Rat, HanBrl: Wist (SPF)
Source: RCC Ltd - Biotechnology and Animal Breeding Division - CH-4414 Fullinsdorf/Switzerland
Number of animals per group: 3 males or 3 females
Total number of animals: 3 males; 3 females
Age when treated: Males: 8 weeks
Females: 10 weeks
Identification: Unique cage card and corresponding color-coded spots on the tail.
Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.


HUSBANDRY
Room number: E16
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with target ranges for temperature 22 ± 3°C and for relative humidity between 30-70%. 12 hours fluorescent light/12 hours dark, music during the light period.

Accommodation: In groups of three per sex in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding.
Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet - batch no. 77/01 - ad libitum. Results of analyses for contaminants are archived.
Water: Community tap-water, from Itingen ad libitum. Results of bacteriological, chemical and contaminant analyses are archived.

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 300

Details on oral exposure:

The test item was suspended in vehicle (PEG 300) at a concentration of 0.2 g/mL and administered at a volume of 10 mL/kg.

Doses:

Dose levels were in terms of test item as supplied unless otherwise stated by the sponsor. The preparations were made shortly before each dosing. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The mixtures were prepared using a magnetic stirrer. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer. The animals received a single oral dose of the test item by gavage at 2000 mg/kg body weight. The application volume was 10 mL/kg body weight.

No. of animals per sex per dose:

3 males or 3 females

Control animals:

no

Details on study design:

TREATMENT
The animals received a single oral dose of the test item by gavage at 2000 mg/kg body weight after being fasted for 16 to 20 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing. The application volume was 10 mL/kg body weight.
Rationale: Oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.

OBSERVATIONS
Mortality/Viability: Daily during acclimatization and twice daily during days 1-15.
Body weights: On test days 1 (pre-administration), 8 and 15.

Clinical signs: Daily during acclimatization and at least four times (see table of Mortality/Clinical Signs) on test day 1 after the test item administration. Once daily during days 2-15. All abnormalities were recorded.

PATHOLOGY - NECROPSY
All surviving animals were killed at the end of the observation period by an intraperitoneal injection of NARCOREN at a dose of at least 2.0 mL/kg body weight(equivalent to at least 320 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.
Animals which died spontaneously during the observation period were neoropsied as soon as they are found dead and any abnormalities recorded.

Statistics:

No statistical analysis was used.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: median lethal dose

Mortality:

The following animals were treated and percentage of mortality was observed:
Males: 0% at 2000 mg/Kg
Females: 33% at 2000 mg/Kg
Female no. 3 was found dead on test day 2.

Clinical signs:

Lateral recumbency and marked sedation were noted in female no. 3 before it was found dead. Slightly ruffled fur (from day 1 to 4), hunched posture (day 1) and slight dyspnea (days 3, 4, 9, 10) were observed in female no. 2. Slightly ruffled fur was observed in female no. 1 and all males on test days 1 and 2.

Body weight:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

No macroscopic findings were observed at necropsy.

The details on individual findings are reported in the illustration attached below.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The median lethal dose of FEXO-03 after single oral administration to rats of both sexes, observed over a period of 14 days is: LD50 (rat) > 2000 mg/Kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The quality of database is judged as good because the test was performed in accordance with validated guidelines.

Acute toxicity: via inhalation route

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

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed in accordance with validated guidelines and in GLP compliance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (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

Details on test animals or test system and environmental conditions:

Body weight at the commencement of the study: male 223-249 g and female 209-220 g. 5 male and 5 female animals were used.
The animals were derived from a controlled full barrier maintained breeding system (SPF).

The animals were barrier maintained (semi-barrier) in an air conditioned room
- temperature: 22 ± 3 °C
- Rel. humidity: 55 ± 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x/hour
- Feeding ad libitum, ssniffRIM-H, 10 mm Vl534-000, complete diet for rats/mice- maintenance, totally-pathogen-free (TPF)
- Free access to tap water (drinking water, municipal residue control, microbiol. controlled periodically)
- The animals were kept in Macrolon cages on Lignocel bedding
- Certificates of food, water and bedding are filed at BSL Bioservice
- Adequate acclimatization period

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The test item was applied as a single dose, uniformly over an area which was approx. 10% of the total body surface. The test item was held in contact with the skin with a gauze-dressing and no-irritating tape and was fixed with additional dressing in a suitable manner.

Duration of exposure:

24 h

Doses:

The test item was applied at a single dose (2000 mg/kg bw) by applying uniformly over an area which was approx. 10% of the total body surface.

No. of animals per sex per dose:

5 male animals (HsdRccHan : WIST rats) and 5 female animals (HsdRccHan: WIST rats) were used.

Control animals:

not required

Details on study design:

Animals were observed for 14 days after dosing. A careful clinical examination was made at least twice on the day of dosing and once a day thereafter.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
At the end of the observation period the animals were sacrificed by an overdosage of pentobarbital.
All animals were subjected to gross necropsy. All gross pathological changes were recorded.
Individual reactions of each animal were recorded at each observation time. Toxic response data were recorded by sex and dose level. Nature, severity and duration of clinical observations were described. Body weight changes were summarized in tabular form. Necropsy findings were described.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

Signs of toxicity related to dose levels:
no treatment related effects observed

Body weight:

Weight gain of all animals was within the expected range

Gross pathology:

Effects on organs:
no treatment related effects observed

Other findings:

Signs of toxicity (local):
no treatment related effects observed

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Considering the reported data of this dermal toxicity test it can be stated that the test item FEXO-03 has no acute dermal toxic characteristics. The dermal LD50 was determined to be > 2000 mg/kg bw.

Executive summary:

The test item was administered topically at a single dose (2000 mg/kg bw) by applying uniformly over an area which was approx. 10% of the total body surface. 5 male animals (HsdRccHan : WIST rats) as well as 5 female animals (HsdRccHan: WIST rats) were used. The test item was held in contact by an occlusive dressing with the skin throughout a 24-hour period. The occlusive dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner. At the end of the exposure, residual test item was removed by using tap water. A careful clinical examination was made at least twice on the day of dosing and once a day thereafter. At the end of the observation period the animals were sacrificed and necropsy was carried out to record gross pathological changes. No clinical signs of toxicity were observed throughout the observation period. Except for acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection no special gross pathological changes were found in any animals. Weight gain of all animals was within the expected range (table 1). Therefore, according to the intemationally accepted guidelines, a sufficient estimation of the acute dermal toxicity of the test item FEX0-03 was provided.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The quality of database is judged as good because the tests were performed in accordance with validated guidelines.

Additional information

These studies followed procedures indicated by internationally accepted guidelines and recommendations.

Justification for selection of acute toxicity – oral endpoint
This endpoint is judged as reliable because the test was performed in accordance with validated guidelines.

Justification for selection of acute toxicity – dermal endpoint
This endpoint is judged as reliable because the test was performed in accordance with validated guidelines.

Justification for classification or non-classification

According to Regulation EC 1272/2008 and to Directive 67/548/EEC, the substance should not be classified for acute toxicity (both oral and dermal).