1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole

Endpoint summary

Description of key information

- Oral: LD50 = 550 mg/kg bw, female, rat, according to OECD TG 425, Tavazsi 2010

- Inhalation: LD50 > 5836 mg/m3, male/female, rats, according to OECD TG 403, Hartmann 1988

- Dermal: LC50 > 5000 mg/kg bw, male/female, rats, according to OECD TG 402, Zelenak 2010

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:

24 Aug 2010 to 23 Sep 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2008

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

December 2002

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

other: RjHan:WI

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult rats, 8-11 weeks old
- Weight at study initiation: 189 - 230 g
- Housing: Individual caging in type II polypropylene/polycarbonate cage; lignocel bedding for laboratory animals was available to animals during the study to allow digging and other normal rodent activities
- Diet: Autoclavable complete feed for rats and mice – breeding and maintenance; ad libitum
- Water: tap water, ad libitum
- Acclimation period: At least 5 days under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study
- Method of randomisation in assigning animals to test and control groups: Selected by hand at time of delivery

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 %
- Air changes: 15-20 air exchanges/hour
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: 24 Aug 2010 to 23 Sep 2010

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2%

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2 %
- Batch no.: 1414646
- Amount of vehicle: 10 mL/kg bw

DOSAGE PREPARATION: test substance was formulated for treatment doses at 175, 550 and 2000 mg/kg (dose volume of 10 mL/kg). The test substance was formulated in 2% CMC.

Doses:

175, 550 and 2000 mg/kg

No. of animals per sex per dose:

175 mg/kg: 1 animal;
550 mg/kg: 3 animals;
2000 mg/kg: 2 animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: surviving animals were observed individually after dosing at 30 minutes, 1, 2, 3, 4, and 6
hours after dosing and once each day for 14 days thereafter; body weights were recorded on Day -1 and Days 0 (beginning of the experiment) 7 and 14 (surviving animals)
- Necropsy of survivors performed: yes
- Clinical signs including body weight : individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern; particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Other examinations performed: All animals were subjected to macroscopic examination. Surviving animals were exsanguinated under pentobarbital anaesthesia. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross pathological changes were recorded for each animal on the post mortem record sheets.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

550 mg/kg bw

Based on:

test mat.

Mortality:

The test substance caused mortalities at 2000 mg/kg bw (2/2) and at 550 mg/kg bw (1/3). No deaths occurred in any animals treated at 175 mg/kg bw.

Clinical signs:

other: Clinical signs including decreased activity, prone position, incoordination, lateral position and hunched back were observed in both animals treated at 2000 mg/kg bw. Additionally one animal dosed at 2000 mg/kg showed decreased body temperature and noisy

Other findings:

No treatment related macroscopic findings were observed. Macroscopic findings were seen in animals dosed at 2000 mg/kg and 550 mg/kg. These findings included dark/red discoloration and/or non-collapsing of the lungs. Additionally, dark grey foci in the lungs was observed in one animal dosed at 550 mg/kg. No findings were observed either the other animal dosed at 550 mg/kg bw or in the animal dosed at 175 mg/kg bw.

Table 2. Acute oral toxicity of the test substance in the rat, application scheme and mortality data

Dose (mg/kg body weight)	Volume given (mL/kg body weight)	Survival
2000	10	Killed on day 1
550	10	Survived
2000	10	Found dead (day 2)
550	10	Found dead (day 2)
175	10	Survived
550	10	Survived

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Under the conditions of this study performed in compliance with GLP and following the OECD 425 guideline, the acute oral median lethal dose (LD50) of the test subtance was calculated to be 550 mg/kg bw in female RjHan:WI rats.

Executive summary:

In the study performed in compliance with GLP and following the OECD 425 guideline a single oral (gavage) dose was administered followed by a 14 day observation period. The animals were fasted overnight prior to treatment. Animals were weighed before dosing and food was returned 3 hours after dosing. Single animals were dosed sequentially at no less than 24 hour intervals. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Limit test was not performed. The starting dose of the main test was 2000 mg/kg. Surviving animals were observed individually after dosing at 30 minutes, 1, 2, 3, 4 and 6 hours post treatment and once each day for 14 days thereafter. Body weight was measured on Day -1 and just before treatment and weekly after. All surviving animals were examined macroscopically at the end of the study.

Test substance caused mortalities at 2000 mg/kg bw (2/2) and at 550 mg/kg bw (1/3). No deaths occurred in any animals treated at 175 mg/kg bw. Clinical signs including decreased activity, prone position, incoordination, lateral position and hunched back were observed in both animals treated at 2000 mg/kg bw. Additionally, one animal dosed at 2000 mg/kg showed decreased body temperature and noisy respiration. Clinical signs were also observed in animals treated at 550 mg/kg bw. These included decreased activity (3/3), incoordination (3/3), hunched back (2/3), piloerection (2/3), lateral position (2/3) and decreased body temperature (2/3). No clinical signs were observed in the animal dosed at 175 mg/kg. Body weight and body weight changes of the surviving animals during the study showed no indication of a treatment-related effect. No treatment related macroscopic findings were observed in this study.

Under the conditions of this study, the acute oral median lethal dose (LD50) of the test substance was calculated to be 550 mg/kg bw in female RjHan:WI rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

550 mg/kg bw

Quality of whole database:

GLP compliant OECD TG 425 study

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:

18 Nov 1987 to 9 Dec 1987

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:

1981

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Species:

rat

Strain:

other: Tif:RAI f (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Sex: male and female
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 194-232 g
- Housing: 5/sex in Macrolon type 4 cages
- Diet: Rat food ad libitum (except during exposure)
- Water: Water ad libitum (except during exposure)
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±2 °C
- Humidity: 55 ± 10 %
- Air changes (per hr): Not reported
- Photoperiod: 12 hours light/12 hours dark

IN-LIFE DATES: 10 Nov 1987 to 9 Dec 1987

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: ethanol

Mass median aerodynamic diameter (MMAD):

> 2.3 - < 2.6 µm

Geometric standard deviation (GSD):

> 2 - < 2.2

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
All exposures were conducted in a stainless steel, nose-only exposure system. The chamber was designed to ensure a rapid equilibration and a uniform exposure of all animals in the system. The flow in any individual aerosol delivery tube was standardized to 2 L/min (velocity 1.25 m/s).
For the inhalation period, the rats were placed in Macrolon animal holders positioned radially around the exposure chamber, so that only the snouts and nostrils of the animals were exposed to the aerosol. The chamber was maintained at an exactly balanced pressure to prevent leakage of the test atmosphere from the system, as well as dilution with outside air. The exhaust air was decontaminated by subsequent passage through a Pall HDC absolute filter.
The aerosol was generated in two pneumatic nebulizers arranged in parallel. Both units had a small aspirating reservoir (1-2 mL) and an attached bulk fluid container (to keep solvent evaporation to a minimum). The nebulizers were operated at 6 and 6 L/min (input pressure 76 and 58 kPa), and the aerosol was diluted with filtered humidified air to yield a total flow of 32 L/min. Coarse particles were removed from the aerosol by means of a glass cyclone. The throughput of the test material/vehicle mixture was determined by weighing the nebulizer, reservoir, and cyclone, before and after aerosol generation.

TEST ATMOSPHERE
Brief description of analytical method and equipment used: The aerosol concentration in the chamber (in the breathing zone of the animals), was determined gravimetrically 5 times during the exposure period. Particle size analysis was conducted with an APS-33 Aerodynamic Particle sizer, equipped with appropriate dilution systems to avoid coincidence counts. The number distribution in the 48 size classes was converted to a mass distribution, based on the bulk density of the test substance, which was determined separately.
Samples taken from breathing zone: yes

VEHICLE
Composition of vehicle: absolute ethanol
Concentration of test material in vehicle: 30% w/w solution

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5836 ± 186 mg/m3

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During exposure they were observed at 1, 2 and 4 hours, as well as 2 hours after exposure and then daily throughout the study. Body weights were measured on Day 1 (prior to exposure), 7 and 14.
- Necropsy of survivors performed: yes, particular attention was given to the respiratory tract.
- Clinical signs: yes

Statistics:

Inhalation LC50 values (including their 95 % confidence limits) for a 4-hour treatment and a subsequent 14-day observation period could not be calculated, because no mortalities were elicited by the test substance at concentrations up to 5836 +/- 186 mg/m3, and thus only a limit test and not a full study was considered necessary.
The body weights of the treated animals and the controls were compared by analysis of variance.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5 836 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths during the exposure or observation periods.

Clinical signs:

other: Signs of systemic toxicity (ruffled fur, dyspnea, abnormal body positions and reduced activity) were seen in control and, to a greater severity, in test animals. All animals had fully recovered by day 9 of the study.

Body weight:

All animals gained body weight during the study. The males exposed to the test article experienced a significantly lower body weight gain compared to controls.

Gross pathology:

There were no macroscopic abnormalities at the examination post mortem.

Table 1. Mortality / animals treated

Exposure concentration mg/m^3.	Mortality (Number dead / total)
	Males	Females	Combined
5836±186	0/5	0/5	0/10

Table 2. Intergroup comparison of mean body weight (g)

Exposure group	Males			Females
	Day 0 #	Day 7	Day 14	Day 0 #	Day 7	Day 14
Control	223	258	301	206	218	236
Test substance	219	242*	284	206	212	233

# Pre-exposure

*statistically significant difference from control

 

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute inhalation toxicity study performed in compliance with GLP and following a OECD 403 guideline the LC50 of the test substance after a 4 hour nose-only exposure was greater than 5836 mg/m3 in male and female rats.

Executive summary:

In an acute inhalation toxicity study performed in compliance with GLP and following a OECD 403 guideline, a group of five male and five female young adult Tif:RAI f (SPF) rats were exposed by nose-only inhalation route to an aerosol of test substance in absolute ethanol (as a 30% w/w solution) for 4 hours to a concentration of 5836 ± 186 mg/m³. Animals were observed for 14 days. Body weights were measured on days 1 (prior to exposure), 7 and 14. Clinical signs were recorded during the exposure at 1, 2 and 4 hours, 2 hours after exposure and then daily throughout the study. All animals were examined macroscopically at the end of the study. A control group of equal size was exposed to an inhalation of absolute ethanol GR (as a 30% w/w solution) under the same conditions as the test substance animals, within one week of the test substance study exposure. Test atmospheres were analyzed for aerosol concentration and particle size distribution.

There were no deaths. Signs of systemic toxicity (ruffled fur, dyspnea, abnormal body positions and reduced activity) were seen in control and, to a greater severity, in test animals. All animals had fully recovered by day 9 of the study. All animals gained body weight during the study. The males exposed to the test article experienced a significantly lower body weight gain compared to controls. There were no macroscopic abnormalities at the examination post-mortem.

The acute inhalation LC₅₀ of test substance after a 4-hour nose-only exposure was greater than 5836 mg/m³ in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5 836 mg/m³ air

Quality of whole database:

GLP compliant OECD TG 403 study

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:

31 Aug 2010 to 14 Sep 2010

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:

February 24, 1987

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

August 1998

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

30 May, 2008

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

RjHan:(WI)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult rats
- Weight at study initiation: Between 208 g and 247 g
- Housing: individual caging, type II polypropylene/polycarbonate; odents are housed with deep wood sawdust bedding to allow digging and other normal rodent activities
- Diet: complete feed for rats and mice, ad libitum
- Water: tap water from municipal supply, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.4 - 24.1
- Humidity (%): 35 - 93
- Air changes: 15-20 air exchanges per hour
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m

IN-LIFE DATES: 31 Augt 2010 to 14 Sep 2010

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10
- Type of wrap: gauze pads kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi-occlusive plastic wrap.

REMOVAL OF TEST SUBSTANCE
- Washing: washing using body temperature water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 5000 mg/kg body weight

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical examination performed on the day of treatment, at 1 and 5 hours after the application of the test item, and once each day for 14 days thereafter; body weight of all animals was recorded on Day 0 (beginning of the experiment) and on Days 7 and 14
- Necropsy of survivors performed: yes
- Clinical signs including body weight: Observations included the skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particular attention was directed to the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Postmortem examniations: All animals were subjected to gross macroscopic examination. All animals were anaesthetised and exsanguinated. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. Any gross macroscopic findings were recorded.

Key result

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Mortality:

None

Clinical signs:

other: No adverse clinical signs were observed after treatment with the test item or during the 14 day observation period

Gross pathology:

Enlargement of the thymus was noted in 5/10 animals treated. No other findings were observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of the test substancei n an acute dermal toxicity study performed in compliance with GLP and following the OECD 402 guideline, after single dermal administration was found to be greater than 5000 mg/kg bw in male and female RjHan:(WI) Wistar rats.

Executive summary:

In an acute dermal toxicity study performed in compliance with GLP and following the OECD 402 guideline, a group of five male and five female, young adult, RjHan:(WI) Wistar rats was exposed by a single semi-occlusive dermal application of 5000 mg/kg of test substance for 24 hours to approximately 10% of the total body surface. Animals were observed for 14 days. Body weight was measured on Day 0 (before treatment) and on Days 7 and 14. A clinical examination was performed on the day of treatment, at 1 and 5 hours after the application of the test item, and once each day for 14 days thereafter. All animals were examined macroscopically at the end of the study. 

There were no deaths. There were no clinical signs or effect on body weight. Enlargement of the thymus was noted in 5/10 animals treated. No other findings were observed at necropsy.  The acute dermal LD50 of the test substance was greater than 5000 mg/kg bw in male and female RjHan:(WI) Wistar rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Quality of whole database:

GLP compliant OECD TG 402 study

Additional information

All available data was assessed and the studies representing the worst-case effects were included as key or weight-of-evidence studies. Other studies are included as supporting information. Dosing with the test substance in rats, mice, rabbits and hamsters results in slight acute toxicity by the oral route of exposure. The test substance was not acutely toxic via the dermal and inhalation route of exposure. The key studies are considered to be worst-case and were selected for the CSA. 

 

Acute Toxicity: Oral

In the key study (Tavazsi 2010) performed in compliance with GLP and following the OECD TG 425 guideline a single oral (gavage) dose was administered followed by a 14 day observation period. The animals were fasted overnight prior to treatment. Animals were weighed before dosing and food was returned 3 hours after dosing. Single animals were dosed sequentially at no less than 24 hour intervals. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Limit test was not performed. The starting dose of the main test was 2000 mg/kg. Surviving animals were observed individually after dosing at 30 minutes, 1, 2, 3, 4 and 6 hours post treatment and once each day for 14 days thereafter. Body weight was measured on Day -1 and just before treatment and weekly after. All surviving animals were examined macroscopically at the end of the study.

 

Test substance caused mortalities at 2000 mg/kg bw (2/2) and at 550 mg/kg bw (1/3). No deaths occurred in any animals treated at 175 mg/kg bw. Clinical signs including decreased activity, prone position, incoordination, lateral position and hunched back were observed in both animals treated at 2000 mg/kg bw. Additionally, one animal dosed at 2000 mg/kg showed decreased body temperature and noisy respiration. Clinical signs were also observed in animals treated at 550 mg/kg bw. These included decreased activity (3/3), incoordination (3/3), hunched back (2/3), piloerection (2/3), lateral position (2/3) and decreased body temperature (2/3). No clinical signs were observed in the animal dosed at 175 mg/kg. Body weight and body weight changes of the surviving animals during the study showed no indication of a treatment-related effect. No treatment related macroscopic findings were observed in this study.

Under the conditions of this study, the acute oral median lethal dose (LD50) of the test substance was calculated to be 550 mg/kg bw in female RjHan:WI rats.

 

Four supporting studies are available for this endpoint which support the findings of the key study, all of which were similar to OECD TG 401 and did not follow GLP. In the first supporting study (Bathe & Sachsse 1978), the test substance was administered to male and female rats as a single dose of 500, 1000, 3000 and 4000 mg/kg bw. The LD50 value in rats was 1517 mg/kg (958-2291 mg/kg). In the second supporting study (Sachsse & Ullmann 1978), male and female rabbits were administered a single dose of 600, 1000, 2150 and 3590 mg/kg bw. The LD50 value in rabbits of both sexes over a period of 14 days was 1344 mg/kg (1062-1710 mg/kg). In the third supporting study (Bathe & Sachsse 1979a), the test substance was administered to male and female Chinese Hamsters as a single dose of 1000, 3000, 4500 and 6000 mg/kg and the LD50 of the test substance was 3006 mg/kg (2152-3943 mg/kg). In the final supporting study (Bathe & Sachsse 1979b), the test substance was administered to male and female mice as a single dose of 800, 1500, 2500, 3000 mg/kg bw. The LD50 of the test substance was 1490 mg/kg (1138-1875 mg/kg). 

 

 

Acute Toxicity: Inhalation

In the key acute inhalation toxicity study (Hartmann 1988) performed in compliance with GLP and following a OECD TG 403 guideline, a group of five male and five female young adult Tif:RAI f (SPF) rats were exposed by nose- only inhalation route to an aerosol of test substance in absolute ethanol (as a 30% w/w solution) for 4 hours to a concentration of 5836 ± 186 mg/m3. Animals were observed for 14 days. Body weights were measured on days 1 (prior to exposure), 7 and 14. Clinical signs were recorded during the exposure at 1, 2 and 4 hours, 2 hours after exposure and then daily throughout the study. All animals were examined macroscopically at the end of the study. A control group of equal size was exposed to an inhalation of absolute ethanol GR (as a 30% w/w solution) under the same conditions as the test substance animals, within one week of the test substance study exposure. Test atmospheres were analyzed for aerosol concentration and particle size distribution.

There were no deaths. Signs of systemic toxicity (ruffled fur, dyspnea, abnormal body positions and reduced activity) were seen in control and, to a greater severity, in test animals. All animals had fully recovered by day 9 of the study. All animals gained body weight during the study. The males exposed to the test article experienced a significantly lower body weight gain compared to controls. There were no macroscopic abnormalities at the examination post-mortem.

The acute inhalation LC50 of test substance after a 4-hour nose-only exposure was greater than 5836 mg/m3 in male and female rats.

 

Acute Toxicity: Dermal

In the key dermal toxicity study (Zelenak 2010) performed in compliance with GLP and following the OECD TG 402 guideline, a group of five male and five female, young adult, RjHan:(WI) Wistar rats was exposed by a single semi-occlusive dermal application of 5000 mg/kg of test substance for 24 hours to approximately 10% of the total body surface. Animals were observed for 14 days. Body weight was measured on Day 0 (before treatment) and on Days 7 and 14. A clinical examination was performed on the day of treatment, at 1 and 5 hours after the application of the test item, and once each day for 14 days thereafter. All animals were examined macroscopically at the end of the study.

 

There were no deaths. There were no clinical signs or effect on body weight. Enlargement of the thymus was noted in 5/10 animals treated. No other findings were observed at necropsy. The acute dermal LD50 of the test substance was greater than 5000 mg/kg bw in male and female RjHan:(WI) Wistar rats.

 

Two supporting studies are available for this endpoint which support the findings of the key study, all of which were similar to OECD TG 402 and did not follow GLP. In the first supporting study (Bathe & Sachsse 1979), the test substance was administered to male and female rats as a single dermal dose of either 3000 or 4000 mg/kg bw. The LD50 of the test substance in rats of both sexes over a period of 14 days was > 4000 mg/kg. In the second supporting study (Ullmann & Sachsse 1979), the test substance was administered to male and female rats as a single dermal dose of either 2000 or 6000 mg/kg bw. The acute dermal LD50 of the test substance in rabbits of both sexes over a period of 14 days was > 6000 mg/kg.

Justification for classification or non-classification

Based on the results of the acute oral toxicity studies, the test substance is classified as an acute toxicant category 4, H302: Harmful if swallowed, in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008. The test substance does not have to be classified for acute dermal or inhalation toxicity in accordance with CLP.