5-[(2-hydroxyethyl)amino]-o-cresol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 31 March 2004 to 21 December 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

17th December 2001

Deviations:

yes

Remarks:

animal room relative humidity was sometimes outside the target ranges (minor deviation not compromising the validity or integrity of the study)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

5-[(2-hydroxyethyl)amino]-o-cresol

EC Number:

259-583-7

EC Name:

5-[(2-hydroxyethyl)amino]-o-cresol

Cas Number:

55302-96-0

Molecular formula:

C9H13NO2

IUPAC Name:

5-[(2-hydroxyethyl)amino]-2-methylphenol

Test material form:

solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Analytical purity: 99.3% (HPLC; Area % without response factor, UV detection)
- Purity test date: August 2004
- Lot/batch No.: 0121442
- Expiration date of the lot/batch: September 2005
- Titre: 99.8% (based upon alkalinity in g/100g)
- Description: beige powder
- Trade name: IMEXINE OAG
- Labeling code: 2948

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at +4°C, protected from light and under nitrogen gas
- Stability under test conditions: test item dosage forms were prepared extemporaneously under nitrogen atmosphere and stored at room temperature, protected from light (using an aluminium foil) and under nitrogen atmosphere until treatment, for a maximum period of 4 hours according to the stability results obtained.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Rj: SD (IOPS Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 8 weeks old on the say of treatment
- Weight at study initiation (mean ± standard deviation): 206 ± 6 g
- Fasting period before study: overnight period of approximately 18 hours before dosing with free access to water. Food was given back approximately 4 hours after administration of the test item.
- Housing: animals were housed in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm). Each cage contained one to seven animals of the same sex during the acclimation period and one or four rats of the same group during the treatment period. Each cage contained autoclaved sawdust (SICSA, Alfortville, France). Sawdust was analysed by the supplier for composition and contaminant levels.
- Diet: ad libitum to A04 C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France), except during the fasting period. Each batch of food was analysed by the supplier for composition and contaminant levels (formula detailed in the study report).
- Water: ad libitum to drinking water filtered by a FG Millipore membrane (0.22 micron). Bacteriological and chemical analyses of water were performed regularly by external laboratories, including the detection of possible contaminants (pesticides, heavy metals and nitrosamines).
No contaminants were known to have been present in the diet, drinking water or bedding material at levels which may be expected to have interfered with or prejudiced the outcome of the study.
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30 to 70
- Air changes (per hr): 12 cycles of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals.

IN-LIFE DATES: From: March 2004 To: 28 April 2004

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

as 0.5% suspension in purified water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw. The volume administered to each animal was adjusted according to body weight determined on the day of treatment.

DOSAGE PREPARATION (if unusual): Before preparation, the vehicle was degassed by sonication for at least 15 minutes and then saturated with nitrogen gas, and kept under nitrogen atmosphere for 15 minutes. The test item was first ground using a mortar and pestle, then prepared at the chosen concentration in the vehicle. The test item dosage forms were prepared extemporaneously under nitrogen atmosphere and were stored protected from light (using a glass beaker covered with aluminium foil) and under nitrogen atmosphere until delivery. They were used within the 4 hours following the preparation according to the known stability results. The pH of the dosage form at the concentration of 200 mg/mL, measured at the testing laboratory, was approximately 6.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females (one female for the sighting test and one group of four females for the main experiment)

Control animals:

no

Details on study design:

- Sighting test: test item was administered at the dose of 2000 mg/kg. This dose was chosen according to information available on the test item. One female was used for this sighting test.
- Main experiment: As no mortality was observed at 2000 mg/kg in the sighting test, the test item was administered at the dose-level of 2000 mg/kg to one group of four females.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. Type, time of onset and duration of clinical signs were recorded for each animal individually. Animals were weighed individually just before the administration of the test item and then 7 days and 14 days following the administration. The body weight gain of the treated animals was compared to that of testing laboratory control animals with a similar initial body weight.
- Sacrifice: At the end of the observation period, all animals were killed by carbon dioxide asphyxiation.
- Necropsy of survivors performed: yes; macroscopic examination as soon as possible after death. A macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed. No organ samples were taken for preservation of tissues.

Statistics:

Not applicable

Results and discussion

Preliminary study:

- No mortality occurred at 2000 mg/kg.
- Hypoactivity or sedation and piloerection were observed on day 1 within the 2h45 following the treatment.

Effect levels

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality

Mortality:

No death occurred.

Clinical signs:

other: Hypoactivity or sedation, piloerection and dyspnea were observed in all animals on day 1 within the 2 hours following the treatment. No clinical signs were observed thereafter on day 1 but from day 2 up to day 5 and then on days 14 and 15, noisy breathing

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Other findings:

None.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, the maximum non-lethal dose of the test item 2-methyl-5-hydroxyethylamino-phenol is > 2000 mg/kg bw. Thus, the test material is not classified as hazardous for acute oral toxicity according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) criteria.

Executive summary:

This GLP-compliant study was performed to assess the acute oral toxicity of 2-Methyl-5-hydroxyethylaminophenol, according to fixed dose OECD Guideline 420 method (dated 17th December 2001).

Material and methods

The test material -diluted in 0.5 % carboxymethylcellulose- was administered by oral route (gavage) to a group of 5 female Sprague Dawley rats (one for the sighting test) at a single dose of 2000 mg/kg body weight. A preliminary test (sighting test) preceded the definitive test. Animals were observed for mortality, clinical signs and body weight for 2 weeks and were then subjected to necropsy.

Results

No death occurred during the study.

Hypoactivity or sedation and piloerection were observed on day 1 within the 2h45 following the treatment of the animal of the sighting test. Hypoactivity or sedation, piloerection and dyspnea were observed in all animals of the main test on day 1 within the 2 hours following the treatment. No other clinical signs were observed on day 1 but from day 2 up to day 5 and then on days 14 and 15, noisy breathing was observed in 1/4 animals. This clinical sign was associated with piloerection and swollen abdomen on days 14 and 15.

A body weight loss was seen in 1/4 females between days 1 and 15. The overall body weight gain of the other animals was similar to that of the testing laboratory historical control animals.

At necropsy, no apparent abnormalities were observed.

Conclusion

Under the experimental conditions of this study, the maximal non-lethal dose of the test item 2-methyl-5-hydroxyethylamino-phenol is > 2000 mg/kg. Thus, the test material is not classified as hazardous for acute oral toxicity according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) criteria.