Registration Dossier

Administrative data

Description of key information

Acute toxicity - oral: Two reliable studies are available (Klimisch 1). Based on the Calvert study (Vasquez RE, 2012), performed according to OECD guideline 425, the LD50 was estimated to be 550 mg/kg bw.  

Acute toxicity - inhalation: No reliable studies were available for the inhalation route. A supporting K4 study did not observe any mortality or remarkable clinical signs after exposure to saturated vapor for 8 hours. No LD50 could be determined.  

Acute toxicity - dermal: Based on a 24h dermal exposure study on rats (Lemoncelli, 2012), performed according to OECD guideline 402, the LD50 was estimated to be greater than 1000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-03-01 to 2012-03-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 1L708
- Composition of test material, percentage of components: 96% primair amine, 0.08 wt%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, 15 to 30°C
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: 9 to 11 weeks at start of dosing
- Weight at study initiation: 195 to 221 grams
- Fasting period before study: overnight
- Housing: Animals were group housed by sex upon receipt and individually housed during the study. No other species were kept in the same room.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: a minimum of 5 days prior to dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 24°C
- Humidity (%): 20 to 63%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: From: 1 March 2012 To: 30 March 2012
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
at 175mg/kg dose only (low dose)
Details on oral exposure:
Dose preparation:
The proper amount of the test article was measured according to volume since it was a liquid, and was allocated/dosed neat as received from the Sponsor at 2000 and 550 mg/kg with a pH = 7. The stock bottle was inverted several times prior to dispensing. At 175 mg/kg the test article was dissolved in distilled water (175 mg brought to a volume of 5 mL). The resulting clear liquid had a pH equal to 12.
Doses:
175, 550 or 2000 mg/kg body-weight
No. of animals per sex per dose:
A total of 6 females: 175 (1), 550 (3) and 2000 mg/kg (2)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality checks were made at least once daily. Clinical observations were recorded prior to dosing, as well as at 30 minutes, 4 hours post-dose, and daily thereafter through day 15. Body weights were recorded on the day of dosing (day 1), and on days 8 and 15, or upon death. All surviving rats were euthanized by CO2 asphyxiation and necropsied on Day 15.
- Necropsy of survivors performed: yes
Statistics:
The LD50 was calculated test using the AOT425StatPgm developed by Westat May, 2001.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
550 mg/kg bw
Based on:
test mat.
95% CL:
123.9 - 3 930
Mortality:
For the dose of 175 mg/kg, no mortality was observed. One of three animals receiving the test article at 550 mg/kg was found dead and both animals at 2000 mg/kg were found dead. All three deaths occurred by the 30 minute observation time point on day 1.
Clinical signs:
No clinical signs were observed and all surviving animals appeared normal throughout the study.
Body weight:
No biologically significant effect was seen on body weights of the surviving animals on days 8 and 15.
Gross pathology:
Terminal necropsy revealed no visible lesions in the surviving animals at 175 and 550 mg/kg. Necropsy of the animals found dead revealed test article visible in the stomach but no other visible lesions.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the results of this study, the oral LD50 for the test substance in rats was estimated to be 550 mg/kg (95% PL Confidence Interval of 123.9 to 3930 mg/kg). Therefore, the test substance is considered to be classified as category 4 according to the CLP regulation.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Principles of method if other than guideline:
The study was performed to assess the acute toxicity following oral administration of the test substance in Wistar rats.
GLP compliance:
yes (incl. certificate)
Remarks:
Experimental Toxicology and Ecology, BASF AG
Test type:
acute toxic class method
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: ABL. Nr. 85-4113
- Date of production: Nov. 16, 2000
- Analytical purity: 93.9 %

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: guaranteed by the sponsor

OTHER SPECIFICS:
- Name of test material (as cited in study report): Substance-No. 01/0618-1
- Homogeneity: homogeneous by visual inspection
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation: male animals approx. 8-12 weeks; female animals approx. 14-18 weeks
- Weight at study initiation: Animals of comparable weight (+/- 20 %)
- Fasting period before study: Feed was withdrawn from the animals at least 16 hours, water ad libitum
- Housing: single housing
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12 h

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.5 and 2 g/100 ml
- Amount of vehicle (if gavage): 10 ml/kg
- Justification for choice of vehicle: aqueous formulation corresponds to the physiological medium



Doses:
50 , 200 mg/kg
No. of animals per sex per dose:
50 mg/kg bw: 3 males
200 mg/kg bw: 3 males and 3 females were used
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighing was performed at day of application, weekly thereafter and at the end of the study. Recording of signs and symptoms was performed several times on the day of administration and twice each workday and once on Saturdays, Sundays and on public holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, histopathology
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
50 - 200 mg/kg bw
Mortality:
50 mg/kg: no mortality occurred
200 mg/kg: 2/3 female animals died during hour 0
Clinical signs:
200 mg/kg: revealed poor general state, dyspnoea, staggering, piloerection, smeared fur in female animals, male animals displayed no clinical abnormalities
50 mg/kg: No clinical signs and findings were observed
Body weight:
The mean body weights of the 50 mg/kg administration groups and the body weight of the surviving 200 mg/kg group animal increased throughout the study period.
Gross pathology:
Macroscopic pathological abnormalities were not noted, neither in the animals that died, nor in the surviving animals examined at the end of the observation period.

Mortality

 Dose (mg/kg)  No. of Animals  hour 0  14 days
 50 mg/kg  3 male  0/3  0/3
 200 mg/kg  3 male  0/3  0/3
 200 mg/kg  3 female  2/3  2/3
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Under the conditions of this study the median lethal dose of the test substance after oral administration was found to be greater 50 mg/kg and less than 200 mg/kg body weight for male and female rats.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
550 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-05 to 2012-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 1L708
- Purity test date: 21/11/2011

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temp (19-27°C)
- Stability under test conditions: no data

OTHER SPECIFICS:
- Analytical purity: 96% primary amine
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 190-234 g
- Fasting period before study: no data
- Housing: grouped by sex upon receipt; individually housed upon assignment to study
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min 5d prior to dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23°C
- Humidity (%): 24-89%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark

IN-LIFE DATES: From: 31 May 2012 To: 14 June 2012
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: > 10%
- Type of wrap if used: elastic bandage, secured with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped appropriately with gauze and water
- Time after start of exposure: 24h (+/- 0.5h)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg
- Concentration (if solution): 0.978 g/ml
- Constant volume or concentration used: yes

VEHICLE: no vehicle
Duration of exposure:
24h (+/- 0.5h)
Doses:
1000 mg/kg
No. of animals per sex per dose:
5 per sex
Control animals:
yes, concurrent no treatment
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
mortality: once daily
clinical observations: immediately after unwrap + daily thereafter through day 15
weighing on day1, day8, day15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, external body surface, all orifices, thoracic, abdominal and pelvic cavaties and their content.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality observed
Mortality:
No mortality observed
Clinical signs:
7/10: some signs of irritation at the application site starting on day 4, with all irritation resolved by day 14.
No necrosis observed
Body weight:
No effect on body weight observed (weight gain on day 8 and 15)
Gross pathology:
No visible lesions observed in the animals at terminal necropsy
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on the results of the acute dermal toxicity study in rats with the test substance, the estimated LD50 was considered to be greater than 1000 mg/kg bw. Therefore, the substance is considered to be classified as category 4 according to CLP regulation.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1991-04-09 to 1991-05-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
purity not reported
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions: no apparent change in the physical characteristics of the test article during administration

OTHER SPECIFICS:
- Name of test material (as cited in study report): 6398-10-01
- Specific gravity: 0.9812 g/ml
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazeleton Research Products, Denver, Pensylvania
- Age at study initiation: Young adult animals
- Weight at study initiation: 2-3 kg
- Housing: individually in cages
- Diet (e.g. ad libitum): Purina Rabbit Chow H.F. R, ad libitum, checked daily and added or replaced as needed.
- Water (e.g. ad libitum): fresh tap water, ad libitum
- Acclimation period: minimum five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C±3°C
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12hours light, 12hours dark


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: test article directly applied onto intact skin sites of the dorsal area of the trunk (fur was clipped)
- Type of wrap if used: rubber dam and an elastic bandage.
- A square gauze patch was placed on the animals to cover the dose area.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): skin sites were wiped with water and gauze to remove any residual test article
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):400, 800 and 1600 mg/kg
- Constant volume or concentration used: yes

Duration of exposure:
24h
Doses:
400, 800 and 1600 mg/kg
No. of animals per sex per dose:
5M and 5F for each dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: d0, d7, d14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other:decreased activity, abnormal stance, abnormal gait, decreased muscle tone, prostration, diarrhea and dyspnea. Body weight was reported.
Statistics:
Statistics were calculated using Systat by Systat, Inc. Version 4.1, Evanston, II
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
614 mg/kg bw
95% CL:
455 - 828.5
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
561.6 mg/kg bw
95% CL:
401.2 - 786.2
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
862.7 mg/kg bw
95% CL:
563 - 1 321.8
Mortality:
mortality: 1/10 at 400 mg/kg; 8/10 at 800 mg/kg; 10/10 at 1600 mg/kg

Clinical signs:
Clinical signs observed included decreased activity, abnormal stance, abnormal gait, decreased muscle tone, prostration, diarrhea and dyspnea
Body weight:
Statistically significant body weight decreases were detected in the male high dose group on days 7, 14, 21 and 28 when compared to control values. After day 35: a dose-related decrease is seen in males through day 91 (not statistically significant).
No statistically significant differences are observed in the female body weights.
No statistically significant differences detected between recovery control and recovery high dose groups during the 90d treatment and the 28d recovery period.
Gross pathology:
Majority of the gross findings at day 30 (interim), day 90 (terminal), and day 118 (recovery) necropsies were non-specific and low incidence.
Based upon histomorphologic evaluation of the selected tissues, there was no apparent relationship of these gross lesions to test article administration.
At d30 necropsy one high dose male, one mid dose female and two high dose females exhibited multiple scabs and ulcers on treated skin and one high dose female exhibited multiple scabs on treated skin. At d 118 (recovery) necropsy there were no gross lesions detected in the treated or untreated skin sites for either sex.
Other findings:
- Organ weights:
no statistically significant differences in absolute organ weights between the control and treated groups after 30 and 90 days of treatment or 28 days or recovery for either sex. However, a statistically significant decrease in fasted body weight was noted for the high dose males at the day 90 necropsy.
statistically significant increase in the relative brain to body weight and testes to body weight ratios for high dose males on day 90. No other statistically significant differences were evident for either sex after 30 and 90 days of treatment or the 28 day recovery period.

- Histopathology:
Except for dermal irritation at the treatment site in 7 males and 8 females, there were no histomorphologic changes present in tissues evaluated which were related to dermal exposure of the test artical.
The skin irritation seen in the high dose animals was characterized by minimal to slight hyperkeratosis and/or minimal to moderate epidermal hyperplasia. Three of the 7 males and 2 of the 8 females had multifocal areas of moderately - severe acute inflammation of the epidermis of the skin.
Treated skin was ulcerated in 2 males and 2 females, and 3 of these 4 had slight to moderate inflammation of the dermis of the skin.
Clinically, the skin irritation was reversible during the 28d recovery period.

- Potential target organs:

- Other observations:
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Based upon the observations made in the Acute Exposure Dermal Toxicity study in rabbits, the acute dermal LD50, in males and females, was determined to be 614.0 mg/kg (95% CL: 455.0 - 828.5 mg/kg).
Acute dermal LD50, males : 561.6 mg/kg (95% CI: 401. 2 - 786.2 mg/kg).
Acute dermal LD50, females : 862.7 mg/kg (95% CI : 563.0 - 1321.8 mg/kg).
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2002-06-10 to 2002-11-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
The study was performed to assess the acute dermal toxicity of the test substance in Wistar rats.
GLP compliance:
yes (incl. certificate)
Remarks:
Experimental Toxicology and Ecology, BASF AG
Test type:
standard acute method
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Abl. Nr. 85-4113
- Date of production: November 16, 2000

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: was guaranteed by the sponsor

OTHER SPECIFICS:
- Name of test material (as cited in study report): Substance No.: 01/0618-1
- Analytical purity: 93.9 %
- Homogeneity: Homogeneous by visual inspection
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation: male animals approx. 8 - 12 weeks, female animals approx. 14 - 18 weeks
- Weight at study initiation: Animals of comparable weight (+/- 20 %)
- Housing: single housing
- Diet: Kliba-Labordiaet, Provimi Kliba SA, Kaiseraugst, Switzerland, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 40 cm²
- % coverage: 10
- Type of wrap if used: semi-occlusive dressing (the bandage consists of four layers absorbent gauze and Fixomull stretch (adhesive fleece)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm water
- Time after start of exposure: 24 hours




Duration of exposure:
24 hours
Doses:
2000 mg/kg
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 weighing: Weighing was performed at day of application, weekly thereafter and at the end of the study.
- Frequency of observations: Observation of clinical signs was performed several times on the day of administration and once each workday thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
One female animal died 4 hours after administration.
No mortality occurred in the male animals.
Clinical signs:
No systemic clinical observations were noted in the male animals.
Clinical observation of the female animals revealed smeared fur on study day 1.
Body weight:
The mean body weights of the animals increased throughout the study period.
Gross pathology:
No macroscopic pathological abnormalities were noted in the animals examined at the end of the study, except in the skin of the application site of one female animal, where few crust formations were observed. The animal that died did not show any pathological abnormalities either.

The following skin effects were observed at the application site: well defined erythema and scaling (in male animals); very slight, well defined and moderate to severe erythema, very slight and slight edema, scaling, whitish discoloration and eczematous skin change in parts of the application area. Additionally detachment of superficial altered skin layers in the region of eczematous skin changes with scar-like sleek and reddened skin underneath was noted (in female animals). Findings were observed on study day 1 up to study termination on day 14.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute dermal median lethal dose (LD50) of the the test substance after dermal application was found to be greater than 2000 mg/kg body weight in male and female rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
1 000 mg/kg bw

Additional information

The data used in the first draft of the IUCLID dossier for the test substance is of uneven quality and is often conflicting with regard to toxicity testing results for the same mammalian tox endpoints. To clarify the hazard profile for the test substance, follow-up toxicity studies were conducted in 2012 using contemporary OECD study protocols. These follow-up studies were designed with exposure parameters (dosage and/or duration) that are complementary to the UN GHS classification criteria. These studies also used a test sample of the substance which was well-characterized as to chemical identity and the presence of impurities. Due to the high quality of data obtained from these studies, they have been incorporated in the IUCLID dossier as the "key studies" for the CSR and CLP endpoints.

 

Acute toxicity: oral

Calvert Labs (2012) investigated acute oral toxicity (by gavage) of the test substance in females Sprague-Dawley rats. The study was performed according to OECD Guideline 425 (up-and down method). Following doses were applied: 175, 550, 2000 mg/kg. The LD50 was estimated to be 550 mg/kg. For the dose of 175 mg/kg, no mortality was observed. One of three animals receiving the test article at 550 mg/kg was found dead and both animals at 2000 mg/kg were found dead. All three deaths occurred by the 30 minute observation time point on day 1. No clinical signs were observed and all surviving animals appeared normal throughout the study. No biologically significant effect was seen on body weights of the surviving animals on days 8 and 15. Terminal necropsy revealed no visible lesions in the surviving animals at 175 and 550 mg/kg. Necropsy of the animals found dead revealed test article visible in the stomach but no other visible lesions. This study was designated as key study as this high quality study used a test sample of the test substance which was well-characterized as to chemical identity and the presence of impurities.

In the study from BASF AG (2003) according to OECD guideline 423, only 2 doses, administered by oral gavage, were tested in a limited number of rats: 50 mg in 3 male and 200 mg in 3 male and 3 female rats. At 200 mg, 2 out of 3 female rats died immediately. No mortality was observed in the male rats (not at 50 mg, nor at 200 mg). Clinical signs at 200 mg/kg bw revealed poor general state, dyspnoea, staggering, piloerection, smeared fur in female animals. Male animals displayed no clinical abnormalities. No clinical signs were observed at 50 mg/kg bw. Based on this limited number of mortalities observed, it could only be concluded that the LD50 is between 50 and 200 mg/kg bw/d.

Industrial Bio-Test Laboratories, Inc. (1979) investigated acute oral toxicity (by gavage) of the test substance in male and female Crl:COBS CD(SD)BR rats. The study conditions were similar to OECD guideline 401 (fixed dose method). Following doses were applied: 52.67, 79.01, 118.5, 177.8 and 266.7 mg/kg bw. The LD50 was observed to be 116.74 mg/kg bw (95% C.I.: 89.83 - 151.71). Clinical signs as hypoactivity, convulsions, muscular weakness, labored breathing and tremors were observed. From day 0 to day 7 slight body weight decrease was observed in males and females, in contrary from day 7 to day 14 body weight increase was observed.

Acute toxicity: inhalation

Next to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other route (REACH Regulation, column 2 adaptation of Annex VIII).

For the test substance a key study is available for the dermal route of exposure. Therefore, an acute inhalation toxicity study should not be performed.

However, a supporting study (K4) from the Carnegie-Mellon University (1973) is available, where rats were exposed to a saturated vapor for 8 hours. Within this study the authors observed no mortality nor any remarkable clinical signs. These data suggests that the test substance is non-hazardous via the inhalation route.

Acute toxicity: dermal

Lemoncelli A (2012) determined acute dermal toxicity in 10 male / female rats following a GLP study performed according to OECD 402. Only one dose was tested (1000 mg/kg bw). No mortality was observed and 7/10 animals showed reversible skin irritation effects on the site of application. This study was considered as key study. Pharmakon Research International, Inc. (1991) determined acute dermal toxicity in male and female in New Zealand White rabbits following a GLP study in accordance with OECD guideline 402. Doses of 400, 800 and 1600 mg/kg bw were applied. After 24 hours of exposure, an LD50 of 614 mg/kg bw (95% C. I.: 455 - 828.5) was observed. BASF AG (2003) observed an LD50 > 2000 mg/kg bw in male and female Wistar rats after 24 hours of exposure following a GLP study in accordance with OECD guideline 402. .

Justification for classification or non-classification

- Based on the available data and according to the criteria laid down in the CLP Regulation (EC) 1272/2008, the test substance should be classified for acute oral toxicity category 4.

- No reliable acute inhalation studies are available for the test substance. However, a supporting K4 study did not observe any mortality or remarkable clinical signs after exposure to saturated vapor for 8 hours. Therefore, no conclusion can be made on the classification for acute inhalation toxicity for this substance.

- Based on the available data and according to the criteria laid down in the CLP Regulation (EC) 1272/2008, the test substance should be classified as a category 4 acute dermal toxic substance.