2,6-dibromo-4-cyanophenyl octanoate

Endpoint summary

Description of key information

WoE, M-185067-01-2; oral (rat, OECD 401, GLP): LD50 = 141 mg/kg bw (females)

WoE, M-253375-01-1; oral (rat, FIFRA: Federal Register, Vol. 43, No. 163, pre-GLP): LD50 = 400 mg/kg bw (males) and 238 mg/kg bw (females)

Key, M-226980-01-1; inhalation (rat, EPA OPP 81-3, GLP): LC50 = 0.81 mg/L (males) and 0.72 mg/L (females)

Key, M-185070-01-2; dermal (rat, OECD 402, GLP): LD50 > 2000 mg/kg bw (males and females)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

18 Jun - 15 Jul 1999

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:

adopted 1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Iffa Credo, L'Arbresle, France
- Females nulliparous and non-pregnant: not specified
- Age at study initiation:
approximately 6 weeks
- Weight at study initiation:
199 ± 12 g (males) and 165 ± 18 g (females)
- Fasting period before study:
overnight, approximately 18 h before dosing
- Housing:
5 per cage of the same sex in polycarbonate suspended cages containing sawdust bedding
- Diet: A04C pelleted diet (UAR, Villemoisson-sur-Orge, France), ad libitum
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron), ad libitum
- Acclimation period:
at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
21 ± 2
- Humidity (%):
30 - 70
- Air changes (per hr):
12
- Photoperiod (hrs dark / hrs light):
12/12

IN-LIFE DATES: From: 18 Jun To: 15 Jul 1999

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg bw
- batch no.: 107H1649 (Sigma, Saint-Quentin-Fallavier, France)

DOSAGE PREPARATION
On the day of treatment, the test substance was ground to a fine powder using a mortar and
pestle and the chosen concentrations in the vehicle were prepared. All preparations were made freshly on the morning of administration.

Doses:

50 (females), 100 (females) and 200 mg/kg bw (males and females)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Animals were observed frequently during the hours following administration and daily thereafter.
- Frequency of weighing: Animals were weighted before administration of the test substance on Day 1 and then on Days 8 and 15.
- Necropsy of survivors performed: yes, animals were killed by carbon dioxide asphyxiation

Statistics:

The LD50 value was calculated according to Probit-Analysis (Weber, 1972 and Bliss, 1938). The 70 to 95% confidence interval limits were calculated statistically according to Fieller's method (1944).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

141 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The toxicity was considered to be comparable in males based on the mortality at 200 mg/kg bw

Mortality:

50 and 100 mg/kg bw: no death occurred (only females were dosed)
200 mg/kg bw: 5/5 females and 3/5 males died on Day 2 following dosing
For details, please refer to attachment 1.

Clinical signs:

other: 50 and 100 mg/kg bw: no clinical signs were observed (only females were dosed) 200 mg/kg bw: No clinical signs were recorded in females before death. Hypoactivity was observed in all males on Day 1 and persisted on Day 2 in the surviving animals. For det

Gross pathology:

No apparent abnormalities were noted at necropsy in animals that survived to termination or died.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The study was performed in accordance with OECD TG 401 under GLP conditions and is considered reliable. Under the conditions chosen, the acute oral LD50 value was determined to be 141 mg/kg bw for female rats. As the male rats were only treated with the highest dose, the exact LD50 value was not determined. However, the toxicity for male rats was considered to be comparable to females based on the mortality at 200 mg/kg bw. According to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test substance for acute oral toxicity category 3 is warranted.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

04 Nov 1991 - 04 Mar 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Purity and batch number were not provided in the study report.

Qualifier:

according to guideline

Guideline:

other: FIFRA: Federal Register, Vol. 43, No. 163

Version / remarks:

adopted 1978

Deviations:

not specified

GLP compliance:

no

Remarks:

When the study was performed, GLP was not mandatory. However, it was stated that the study was carried out according to the principles of GLP.

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Hilltop-Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hilltop Lab Animals (Scottdale, USA)
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: approximately 5 - 7 weeks
- Weight at study initiation: 200 - 250 g
- Fasting period before study: overnight
- Housing: 2 to 5 rats were housed in cages with wire floors
- Diet: Agway certified rodent chow, ad libitum
- Water: ad lilbitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 25
- Humidity (%): 19 - 64
- Air changes (per hr): not provided
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 1%

DOSAGE PREPARATION
An appropriate amount of sample was measured and mixed with sufficient corn oil to give a 1% w/v solution. This solution was placed on a magnetic stirrer for approximately 1.5 h before dosing.

Doses:

males: 100, 200, 400 and 800 mg/kg bw
females: 100, 200 and 400 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: frequently on the first day of test and twice a day thereafter
- Frequency of weighing: on the day of dosing and at 7 and 14 days after dosing
- Necropsy of survivors performed: yes

Statistics:

LD50 was calculated by the moving average method (Thompson, 1947).

Preliminary study:

A trial test was first performed to determine approximate dose levels. Therefore 3 rats were treated orally with 2 dose levels.The trial test indicated that the LD50 value would be greater than 320 mg/kg bw.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

400 mg/kg bw

Based on:

test mat.

95% CL:

>= 236 - <= 679

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

238 mg/kg bw

Based on:

test mat.

95% CL:

>= 134 - <= 422

Mortality:

100 mg/kg bw: no death occurred
200 mg/kg bw: 0/5 males and 2/5 females
400 mg/kg bw: 3/5 males and 4/5 females
800 mg/kg bw: 4/5 males
Deaths were observed 1 to 2 days following treatment. For details, please refer to attachment 1.

Clinical signs:

other: Clinical signs included sluggishness, hyperactivity, unsteady gait and discharge from nose, mouth and genital areas. Survivors recovered within 1 to 6 day. For details, please refer to attachment 1.

Gross pathology:

Necropsy revealed several cases of hydronephrosis in 3/5 males at 100 mg/kg bw. Dark red lungs were observed in 2/5 and 3/5 females at 200 and 400 mg/kg bw, respectively. Dark red lungs were also observed at 100, 200, 400 and 800 mg/kg bw in 2/5, 2/5, 5/5 and 4/5 males, respectively. For details, please refer to attachment 2.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The study was performed according to FIFRA Federal Register (Vol. 43, No. 163) and to the principles of GLP. Under the conditions chosen, the acute oral LD50 value was determined to be 400 mg/kg bw and 238 mg/kg bw for male and female rats, respectively. According to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test item for acute oral toxicity category 3 is warranted.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

141 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 Jul - 30 Aug 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Version / remarks:

adopted 1984

Deviations:

not specified

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 2009

Deviations:

yes

Remarks:

limited information on materials provided (housing conditions not specified, no details on exposure provided); minor methodological deviatios (temperature in exposure chamber too high, body weight was only weekly noted)

GLP compliance:

yes

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Harlan Sprague Dawley. Inc., Texas, USA
- Females nulliparous and non-pregnant: yes
- Age at study initiation:
young adult
- Weight at study initiation:
226 - 300 g (males) and 188 - 245 g (females)
- Housing:
1-3 animals per cage (males separate from females) and during exposure period individually in suspended, wire bottom, stainless steel cages
- Diet:
Purina Formulab Chow #5008, ad libitum
- Water: Tap water, ad libitum
- Acclimation period:
at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: From: 29 Jul To: 30 Aug 1991

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

not specified

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

>= 1.84 - <= 2.33 µm

Geometric standard deviation (GSD):

>= 1.875 - <= 2.067

Remark on MMAD/GSD:

0.379 mg/L test substance: MMAD = 1.838 µm and GSD = 2.042
0.583 mg/L test substance: MMAD = 1.976 - 1.986 µm and GSD = 1.968 - 1.889
0.723 mg/L test substance: MMAD = 1.938 µm and GSD = 1.890
0.733 mg/L test substance: MMAD = 1.990 - 1.965 µm and GSD = 1.875 - 2.067
1.17 mg/L test substance: MMAD = 2.326 µm and GSD = 1.892

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:
dynamic flow inhalation chamber
- Exposure chamber volume: 200 L
- Method of holding animals in test chamber:
not specified
- Source and rate of air (airflow):
dried, heated and filtered air, 68 L/min
- Method of conditioning air:
not specified
- System of generating particulates/aerosols:
The aerosol was generated by pumping the test material into a pressure operated Spraying System Company air atomizer (1/4 JSS) and then elutriating the resulting aerosol through a baffling chamber. The concentrated aerosol was then diluted with dried, heated and filtered air and drawn into the exposure chamber.
- Method of particle size determination:
Particle size was determined at least once during each exposure, using an Andersen cascade impactor, at a rate of 28.3 L/min for a duration of 1 - 10 min.
- Treatment of exhaust air:
not specified
- Temperature, humidity, pressure in air chamber:
27.2 - 28.9 °C, 56 - 72% relative humidity, oxygen content was at least 19%

TEST ATMOSPHERE
- Brief description of analytical method and equipment used:
Analytical determination was made using a Tracor Model 560 gas chromatograph.
- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure
: 13.5 min

TEST ATMOSPHERE (if not tabulated)
Please refer to "Remark on MMAD/GSD"

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

nominal concentrations: 8.75, 7.74, 2.89, 7.70 and 11.7 mg/L
analytical concentrations: 0.379, 0.583, 0.723, 0.733 and 1.17 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: frequently on the day of exposure and at least once daily thereafter
- Frequency of weighing: prior to the inhalation exposure and on Days 7 and 14, or at the time of discovery after death
- Necropsy of survivors performed: yes

Statistics:

LC50 was calculated according to the method of Litchfield and Wilcoxon (1949).

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

0.809 mg/L air (analytical)

Based on:

test mat.

95% CL:

>= 0.612 - <= 1.07

Exp. duration:

4 h

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

0.721 mg/L air (analytical)

Based on:

test mat.

95% CL:

>= 0.589 - <= 0.883

Exp. duration:

4 h

Mortality:

0.379 mg/L test substance: 0/5 males and 0/5 females
0.583 mg/L test substance: 0/5 males and 2/5 females
0.723 mg/L test substance: 1/5 males and 2/5 females
0.733 mg/L test substance: 4/5 males and 2/5 females
1.17 mg/L test substance: 4/5 males and 5/5 females
Death occurred within 4.5 h to 3 days following exposure to the test substance.
For details, please refer to attachment 1.

Clinical signs:

other: decreased activity, lacrimation, nasal discharge, piloerection, polyuria, ptosis and salivation.

Remarks:

For details, please refer to attachment 2.

Body weight:

Animals that died following exposure to the test item, showed a weight loss of up to 26% when compared to the body weight at study initiation (Day 0). For details, please refer to attachment 1.

Gross pathology:

Gross necropsy findings included signs of nasal discharge, polyuria and salivation, discoloration of the contents of the gastrointestinal tract, gastrointestinal tract distended with gas, discolored fluid of the thoracic cavity, discoloration of the liver and lungs and swollen lungs. For details, please refer to attachment 1.

Other findings:

An attempt was made to reach a concentration of 5.0 mg/L with 25% of particles under 1 µm. However, due to the nature of the test material, a test level could not be generated containing at least 25% of particles under 1 µm to calculate an LC50 value.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The study was performed according to EPA OPP 81-3 (acute inhalation toxicity) and GLP. Therefore, the study is considered to be valid and reliable. Under the conditions of the test, the acute inhalation LC50 value was determined to be 0.81 mg/L for male and 0.72 mg/L for female rats. According to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test item for acute inhalation toxicity category 3 (H331) is warranted.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

0.72 mg/L air

Physical form:

inhalation: aerosol

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus, sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

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:

15 - 29 Jun 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 1987

Deviations:

no

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: IFFA Credo, L'Arbresle, France
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation:
approximately 8 weeks
- Weight at study initiation:
244 ± 10 g for males and 227 ± 10 g for females
- Housing:
During the acclimatization period, one to seven animals of the same sex were housed in polycarbonate cages (48 cm x 27 cm x 20 cm). During the treatment period, the animals were housed individually in polycarbonate cages (35.5 cm x 23.5 cm x 19.3 cm).
- Diet: A04C pelleted diet (UAR, Villemoisson-sur-Orge, France), ad libitum
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron), ad libitum
- Acclimation period:
at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
21 ± 2
- Humidity (%):
30 - 70
- Air changes (per hr):
12
- Photoperiod (hrs dark / hrs light):
12/12

IN-LIFE DATES: From: 15 Jun 1999 To: 29 Jun 1999

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: dorsal area
- % coverage: 10%
- Type of wrap if used: adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing: no; no residual test substance was observed at removal of the dressing
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Constant volume or concentration used: dose applied to each animal was adjusted according to body weight
- For solids, paste formed: test substance ground to a fine powder was placed on a hydrophilic gauze pad pre-moistened with 2 mL of water

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

On the day before treatment, the dorsal area (6 cm x 8 cm) of each animal was clipped using electric clippers. 5 male and 5 female rats with intact skin were treated with 2000 mg/kg bw of the test material.

- Duration of observation period following administration: 14 days
- Frequency of observations: at least once daily
- Frequency of weighing:
on day of treatment and weekly thereafter
- Necropsy of survivors performed: no (macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed)

Statistics:

No statistical analysis was performed.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No clinical signs and no cutaneous reactions were observed during the study.

Gross pathology:

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

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 12 72/2008

Conclusions:

The study was performed in accordance to OECD 402 under GLP conditions and is considered reliable. Under the conditions chosen, the acute dermal LD50 was determined to be > 2000 mg/kg bw/day for male and female rats. According to criteria of the CLP Regulation (EU) No. 1272/2008, no classification of the test item for acute dermal toxicity is required.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus, sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

To assess acute toxicity of the test substance, data after oral, inhalation and dermal exposure to the test substance are considered.

Acute toxicity: oral

Two acute oral toxicity studies are available (M-185067-01-2 and M-253375-01-1) to evaluate the toxicological properties, which are assessed following a weight-of-evidence approach. One acute oral toxicity study was performed according to OECD guideline 401 and in compliance with GLP (M-185067-01-2). Five male and female Sprague Dawley rats were exposed to single oral doses of 200 mg/kg bw. Further, 5 females per group were dosed at 50 and 100 mg/kg bw. Prior to compound administration, animals were fasted overnight and the test substance was administered by oral gavage as a suspension in corn oil at a volume of 10 mL/kg bw. Following dosing, no deaths occurred at 50 or 100 mg/kg bw. At 200 mg/kg bw 3/5 males and 5/5 females died on Day 2. All male rats at 200 mg/kg bw showed hypoactivity on the day of dosing until day 2. No clinical signs were recorded in females at this dose level or in animals at 50 or 100 mg/kg bw during the 14 days following dosing. There were no apparent effects on body weight gain during the observation period. Further, no apparent abnormalities were noted at gross necropsy in animals that survived to termination or died. Under the conditions chosen, the acute oral LD50 value was determined to be 141 mg/kg bw for female rats. As the male rats were only treated with the highest dose, the exact LD50 value was not determined. However, the toxicity for male rats was considered to be comparable to females based on the mortality at 200 mg/kg bw.

The second acute oral toxicity study was performed according to FIFRA: Federal Register, Vol. 43, No. 163 (M-253375-01-1). The study was not conducted in compliance with GLP, as this was not mandatory at that time. However it is stated that the study was carried out according to the principles of GLP. The test substance was administered in a 1% suspension in corn oil to groups of five Wistar rats by gavage. Male rats were given 100, 200, 400 or 800 mg/kg bw and female rats received 100, 200 or 400 mg/kg bw. Mortality occurred in 1 to 2 days following treatment as follows:

100 mg/kg bw: no deaths were observed

200 mg/kg bw: 0/5 males and 2/5 females

400 mg/kg bw: 3/5 males and 4/5 females

800 mg/kg bw: 4/5 males

Clinical signs included sluggishness, hyperactivity, unsteady gait and discharge from nose, mouth and genital areas. Survivors recovered within 1 to 6 days. Body weight gain of surviving animals was not affected by treatment with the test substance. Necropsy revealed several cases of hydronephrosis in 3/5 males at 100 mg/kg bw. Dark red lungs were observed in 2/5 and 3/5 females at 200 and 400 mg/kg bw, respectively. Dark red lungs were also observed at 100, 200, 400 and 800 mg/kg bw in 2/5, 2/5, 5/5 and 4/5 males, respectively. Under the conditions chosen, the acute oral LD50 value was determined to be 400 mg/kg bw for male and 238 mg/kg bw for female rats.

In conclusion, and following a weight-of-evidence approach, overall LD50 values of  141 and 400 mg/kg bw were derived for female and male rats, respectively. Based on these results, the test substance meets the classification criteria for acute oral toxicity, category 3 (H301).

 

Acute toxicity: inhalation

A GLP-conform acute inhalation toxicity study was performed according to EPA OPP 81-3 (M-226980-01-1).

Five male and five female Sprague Dawley rats were exposed to an aerosol generated from the undiluted test material for 4h at doses of 0.379, 0.583, 0.723, 0.733 and 1.17 mg/L (analytical concentration). The test article concentrations were determined by gas chromatography. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) corresponding to the dosage groups were (MMAD / GSD): 1.838 µm / 2.042 µm (0.379 mg/L), 1.976 – 1.986 µm / 1.968 – 1.889 µm (0.583 mg/L), 1.938 µm / 1.890 µm (0.723 mg/L), 1.990 – 1.965 µm / 1.875 – 2.067 µm (0.733 mg/L) and 2.326 µm / 1.892 µm (1.17 mg/L). Post exposure, all animals were observed for a period of 14 days. Following exposure to the test material, deaths occurred within 4.5 h to 3 days as follows:

0.379 mg/L test substance: 0/5 males and 0/5 females

0.583 mg/L test substance: 0/5 males and 2/5 females

0.723 mg/L test substance: 1/5 males and 2/5 females

0.733 mg/L test substance: 4/5 males and 2/5 females

1.17 mg/L test substance: 4/5 males and 5/5 females

Observed clinical signs included decreased activity, lacrimation, nasal discharge, piloerection, polyuria, ptosis and salivation. Animals that died following exposure to the test item, showed a weight loss of up to 26% when compared to the body weight at study initiation (Day 0). Gross necropsy findings included signs of nasal discharge, polyuria and salivation, discoloration of the contents of the gastrointestinal tract, gastrointestinal tract distended with gas, discolored fluid of the thoracic cavity, discoloration of the liver and lungs and swollen lungs. Under the conditions of the test, the acute inhalation LC50 value was determined to be 0.81 mg/L for male and 0.72 mg/L for female rats. In line with the harmonized classification and according to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test item for acute inhalation toxicity, category 3 (H331) is warranted.

 

Acute toxicity: dermal

A GLP-conform acute dermal toxicity study was performed according to OECD Guideline 402 (M-185070-01-2) which is considered as key study. A limit dose of 2000 mg/kg bw was topically applied for 24 h to the clipped skin of 5 male and female Sprague-Dawley rats under semi-occlusive dressing. Neither mortality nor clinical signs of toxicity or cutaneous reactions were observed until the end of the 14-day observation period. When compared to the laboratory historical control animals, the body weight gain of males was slightly reduced between day 1 and day 8. The body weight gain of females was not influenced by treatment. No gross internal findings were observed at necropsy. The dermal LD50 of the test compound in rats was determined to ≥ 2000 mg/kg bw.

A further acute dermal toxicity study was performed in rabbits in a non-GLP study according to FIFRA: Federal Register, Vol. 43, No. 163. Five male New Zealand White rabbits with abraded skin were tested at a single dose level of 2000 mg/kg bw. Groups of four female rabbits both with intact and abraded skin were treated with 1000, 1200, 1400 mg/kg bw or 1000, 1400 and 2000 mg/kg bw, respectively. Mortalities were observed as follows:

The skins of rabbits had erythema with instances of edema and ecchymosis. Mortality was observed as summarised: male rabbits (abraded skin) at 2000 mg/kg: 1/5 ; female rabbits (intact skin) at 1000 mg/kg: 0/4 at 1400 mg/kg: 0/4 at 2000 mg/kg: 4/4 ; females rabbits (abraded skin) at 1000 mg/kg: 0/4 at 1400 mg/kg: 1/4 at 2000 mg/kg: 3/4.

The only consistent necropsy finding was dark red lungs in the female rabbits that died. Under the conditions of this study, the acute dermal LD50 value of the test item was found to be > 2000 mg/kg bw for male rabbits with abraded skin and 1660 and 1310 mg/kg bw for female rabbits with abraded skin and intact skin, respectively. However, it has to be noted that the study was not performed according to GLP, as it was not mandatory at that time. Additionally, the test material was not specified. Therefore the study is considered of limited reliability.

In summary, two acute dermal toxicity studies are available. The acute dermal toxicity LD50 value in the key study was greater than 2000 mg/kg bw for male and female rats. According to criteria of the CLP Regulation (EU) No. 1272/2008, no classification of the test item for acute dermal toxicity is required.

Justification for classification or non-classification

The available data on acute oral toxicity and acute inhalation toxicity meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore sufficient for classification of the test substance for acute oral toxicity category 3 (Acute Tox. 3, H301) and acute inhalation toxicity category 3 (Acute Tox. 3, H331). Based on the available data on acute dermal toxicity, no classification of the test substance for acute dermal toxicity is required.

The substance is listed in Annex VI of Regulation (EC) 1272/2008 (608-017-00-0 ). Harmonised classification in regard to minimum classification was adopted according to the available experimental data if appropriate.