Registration Dossier

oral LD50 (male/female) > 2000 mg/kg bw (reference 7.2.1 -1)

inhalative LC50 (male/female) > 22 mg/L air (reference 7.2.2 -1)

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

02-1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Ltd., Manston, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5 to 8 weeks
- Weight at study initiation: 145 – 162 g
- Fasting period before study: overnight before dosing and 2 hours after treatment
- Housing: groups of 5 by sex in solid-floor PP cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 – 24
- Humidity (%): 40 – 66
- Photoperiod (hrs dark / hrs light): 12 hour light - 12 hour dark regimen

IN-LIFE DATES: From days 1 to 15

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Dose volume: 1.13 mL/kg

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 m / 5 f

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: days 0, 7, 14 or at death
- Necropsy of survivors performed: yes (gross pathology)

Statistics:

Standard statistical methods have been applied for data processing.

Preliminary study:

Yes: Range-finding with dose levels of 1000 or 2000 mg/kg, 1 m / 1 f for each dose level

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

1/5 m, 0/5 f

Clinical signs:

other: The dosing caused common signs of lethargy. Additional signs of toxicity noted in females were hunched posture, decreased respiratory rate and red/brown stains around eyes and snout. An isolated incident of ataxia was also noted in one female. Surviving m

Gross pathology:

Abnormalities noted at necropsy of the male that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

For regulatory purposes, the median lethal dose (LD50) can be declared as > 2000 mg/kg.

Executive summary:

The undiluted test item was tested for acute toxicity in rats after single oral administration of 2000 mg/kg body weight. The study was performed according to the OECD Guideline for Testing of Chemicals, No. 401. The surviving animals were observed for fourteen days after the day of dosing and were then killed for gross pathological examination.

One male was found dead one day after dosing. Lethargy was commonly noted. Additional signs of toxicity noted in females were hunched posture, decreased respiratory rate and red/brown stains around eyes and snout. An isolated incident of ataxia was also noted in one female. Surviving males appeared normal one day after dosing while females appeared normal two to five days after dosing.

Surviving animals showed expected gain in bodyweight during the study.

Abnormalities noted at necropsy of the male that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals killed at the end of the study.

For regulatory purposes, the median lethal dose (LD50) can be declared as > 2000 mg/kg.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

OECD TG 401

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 06, 1998 to September 24, 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 12, 1981

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

December 29, 1992

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Füllinsdorf, Switzerland
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 7 – 9 weeks
- Weight at study initiation: 194 – 232 g
- Fasting period before study: no
- Housing: Groups of 5 per sex in type IV Makrolon cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1
- Humidity (%): 46 – 86 %
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From days 1 - 15

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

The test article was used as supplied by the Sponsor. A test atmosphere was generated in ambient conditions using a nebuliser connected to a syringe pump. Insertion of an aerosol-retaining filter before the exposure system facilitated exposure of the animals to the vapour phase of the test article only.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

20 mg/L (nominal)

No. of animals per sex per dose:

5 m / 5 f

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: days 1, 4, 8 and 15
- Necropsy of survivors performed: yes. The animals were examined macroscopically and any abnormalities would have been recorded. The lungs, trachea, larynx and the head containing the nasopharyngeal tissues were collected from all animals and fixed in neutral phosphate buffered 4 % formaldehyde solution. The lungs were instilled with the fixative at a hydrostatic pressure of 30 cm H2O. All collected organs/tissues are available for histopathological examinations, if requested by the Sponsor.

Statistics:

Standard statistical methods have been applied for data processing.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 22.23 mg/L air

Exp. duration:

4 h

Mortality:

0 / 5 m, 0 / 5 f

Clinical signs:

other: The principal clinical signs were the findings of decrease in locomotion activity, excitement and ruffled fur seen in all animals, whole-body tremor in two of five male and one of five female animals, and hunched posture in two of the male and all female

Body weight:

Transient, slight losses of body weight were evident in all animals from test day 1 (prior to exposure) to test day 4 (three days after exposure). Afterwards, all animals gained body weight normally.

Gross pathology:

Necropsy of each animal did not reveal any macroscopically findings.

Interpretation of results:

GHS criteria not met

Conclusions:

For regulatory purposes, the median lethal dose (LC50), after an observation period of 15 days can be declared as > 22.23 mg/L air.

Executive summary:

The purpose of this GLP study performed according to OECD GL 403 was to assess the acute inhalation toxicity of the vapour phase of the test item when administered to rats for a single continuous 4-hour period at a target concentration of 20 mg/L air. Groups of five male and five female Albino Wistar rats were exposed by nose only, flow-past inhalation to the vapour phase of the test article at a mean concentration of 22.23 mg/L air. All animals were observed for clinical signs and mortality during and following the inhalation exposure over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8, and 15. All animals underwent necropsy and any gross macroscopically changes would have been recorded.

There were no deaths. The principal clinical signs were the findings of decrease in locomotion activity, excitement and ruffled fur seen in all animals, whole-body tremor in two of five male and one of five female animals, and hunched posture in two of the male and all female animals. All of these findings, except that of excitement, were seen on the day of exposure and disappeared within one to four days afterwards. The finding of slight excitement occurred from two days after exposure (test day 3) until five days afterwards (test day 6). As from six days after exposure (test day 7) until the scheduled necropsy fourteen days afterwards (test day 15), all animals were free from clinical signs. Transient, slight losses of body weight were evident in all animals from test day 1 (prior to exposure) to test day 4 (three days after exposure). Afterwards, all animals gained body weight normally. Necropsy of each animal did not reveal any macroscopically findings.

The LC50 of the vapour phase of the test item was estimated to be greater than 22.23 mg/L air (analytical mean value).

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

22 000 mg/m³ air

Quality of whole database:

OECD TG 403

Endpoint conclusion:

no study available

Oral

The undiluted test item was tested for acute toxicity in rats after single oral administration of 2000 mg/kg body weight. The study was performed according to the OECD Guideline for Testing of Chemicals, No. 401. The surviving animals were observed for fourteen days after the day of dosing and were then killed for gross pathological examination.

One male was found dead one day after dosing. Lethargy was commonly noted. Additional signs of toxicity noted in females were hunched posture, decreased respiratory rate and red/brown stains around eyes and snout. An isolated incident of ataxia was also noted in one female. Surviving males appeared normal one day after dosing while females appeared normal two to five days after dosing.

Surviving animals showed expected gain in bodyweight during the study.

Abnormalities noted at necropsy of the male that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals killed at the end of the study.

For regulatory purposes, the median lethal dose (LD50) can be declared as > 2000 mg/kg (reference 7.2.1 -1).

Inhalative

The purpose of this GLP study performed according to OECD GL 403 was to assess the acute inhalation toxicity of the vapour phase of the test item when administered to rats for a single continuous 4-hour period at a target concentration of 20 mg/L air. Groups of five male and five female Albino Wistar rats were exposed by nose only, flow-past inhalation to the vapour phase of the test article at a mean concentration of 22.23 mg/L air. All animals were observed for clinical signs and mortality during and following the inhalation exposure over a 15-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 4, 8, and 15. All animals underwent necropsy and any gross macroscopically changes would have been recorded.

There were no deaths. The principal clinical signs were the findings of decrease in locomotion activity, excitement and ruffled fur seen in all animals, whole-body tremor in two of five male and one of five female animals, and hunched posture in two of the male and all female animals. All of these findings, except that of excitement, were seen on the day of exposure and disappeared within one to four days afterwards. The finding of slight excitement occurred from two days after exposure (test day 3) until five days afterwards (test day 6). As from six days after exposure (test day 7) until the scheduled necropsy fourteen days afterwards (test day 15), all animals were free from clinical signs. Transient, slight losses of body weight were evident in all animals from test day 1 (prior to exposure) to test day 4 (three days after exposure). Afterwards, all animals gained body weight normally. Necropsy of each animal did not reveal any macroscopically findings.

The LC50 of the vapour phase of the test item was estimated to be greater than 22.23 mg/L air (analytical mean value) (reference 7.2.2 -1).

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data for acute oral and inhalative toxicity are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not classified for acute toxicity under Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) 2019/521.