Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Oral (similar to OECD 401): LD50 > 5000 mg/kg bw (limit test, rat)
Inhalation (OECD 403): LC50 > 6.3 mg/L (limit test, rat; 4 h exposure)
Dermal (OECD 402): LD50 > 2000 mg/kg bw (limit test, rabbit)

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
analytical purity of test substance not specified, 1.5 mL/ 100 g bw of non aqueous liquid administered at once
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, New York, USA
- Weight at study initiation: males 112 - 131 g and females 87 -103 g
- Fasting period before study: over night (~ 18 h)
- Housing: Animals were housed five per cage by sex in suspended solid-bottom polycarbonate cages. The cage dimensions were 55.9 x 31.8 x 20.3 cm and were fitted with grommets to fit the external-to-cage watering system.
- Diet: ad libitum (NIH 07 Open Diet, Zeigler Bros., Inc., Gardners, PA, USA)
- Water: tap water, ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean 24, range 20 - 27
- Humidity (%): mean 47, range 32 - 72
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 15 mL/kg bw in 3 doses to a total of 45 mL/kg bw
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 15 mL/kg bw
Doses:
single dose of 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: 5 animals of each sex served as vehicle controls
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed 4x on the day of treatment, and the observations were separated by 1 - 1.5 h. On the 13 remaining days of the study the animals were observed 2x each day (AM and PM), and the observations were separated by at least 4 h.
- Necropsy of survivors performed: yes, external examination including body orifices, and an internal examination of all of the following tissues: Gross lesions; skin; mandibular lymph node; mammary gland; salivary gland; thigh muscle; sciatic nerve; sternebrae, vertebrae or femur including marrow; costochondral junction, rib; thymus; larynx; trachea; lungs and bronchi; heart; thyroid; parathyroids; esophagus; stomach; duodenum; jejunum; mesentery; aorta; ileum; colon; cecum; rectum; mesenteric lymph node; liver; pancreas; spleen; kidneys; adrenals; urinary bladder; seminal vesicles; prostate; testes; ovaries; uterus; nasal cavity; brain; pituitary; spinal cord (if neurologic signs are present); eyes.
- Other examinations performed: All gross observations were recorded by animal on Acute Study Data Sheets. Initial, 7-day, 15-day and final body weights were also recorded for each animal.
Statistics:
- Weight gain was calculated by (14 Day Body Weight - Mean Initial Body Weight)/Mean Initial Body Weight
- No other statistical tests were mentioned
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
Not observed.
Clinical signs:
Not observed.
Body weight:
No abnormalities observed.
Gross pathology:
No abnormalities observed.
Other findings:
- Other observations: The "ruffled coat" and diarrhea noted among vehicle controls was attributable to the large volume of vehicle (corn oil) received by these animals.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

The absence of any adverse reaction relating to treatment like mortality, abnormal clinical signs, depressed growth rate or gross anatomical abnormalities at necropsy indicates that the test substance is non-toxic for F344 rats. According to the criteria laid down in Regulation (EC) No. 1272/2008 the substance does not have to be classified for acute toxicity via the oral route.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Only 4 animals per test group
Principles of method if other than guideline:
Study performed before actual guideline was established.
GLP compliance:
no
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
- Fasting period before study: 16 h immediately prior to oral intubation
- Housing: individually in stock cages
- Diet: standard laboratory diet, ad libitum
- Water: ad libitum
- Acclimation period: 5 days
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50% (w/v) suspension
Doses:
1350, 4556, 15380 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Initial and final body weights, mortalities and reactions, intervals not further specified
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The acute oral media lethal dose (LD50) of the test material was calculated, if possible, using the techniques of Weil, Thompson and Thompson and Weil.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 15 380 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
15 380 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hypoactivity was noted in all animals within 5 minutes post-administration and subsided by the next day.
Body weight:
No effects observed.
Gross pathology:
No gross pathologic alterations.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Dose volume 20 mL/kg bw in non-aqueous vehicle
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Cpb:WU; Wistar random
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: young adult
- Weight at study initiation: males 111 - 137 g, females 92 - 112 g
- Fasting period before study: overnight before and 4 h after dosing
- Housing: groups of 5, males and females separated, in stainless steel cages with grid bottom and front
- Diet: stock diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 1
- Humidity (%): 30 - 70
- Air changes (per hr): about 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25% (w/v) suspension
- Amount of vehicle (if gavage): 20 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: frequently for signs of intoxication during the first 4 post-treatment hours, thereafter once daily; individual body weights were recorded on day 0, 7 and 14
- Necropsy of survivors performed: yes, macroscopic examination
- Other examinations performed: clinical signs, body weight
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
No signs of intoxication were observed.
Body weight:
The individual body weights on days 0, 7 and 14 indicated normal growth.
Gross pathology:
Macroscopic examination of survivors at autopsy did not reveal any treatment-related gross alterations.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

According to the criteria laid down in Regulation (EC) No. 1272/2008 the substance does not have to be classified for acute toxicity via the oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score 2) studies. The information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, Item 1.2, of Regulation (EC) No. 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, Item 8.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
analytical purity of test substance not specified, only 4 days acclimatisation time, particle size of 5.2 µm MMAD in accordance to former guideline
GLP compliance:
yes
Test type:
traditional 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: Harlan Sprague Dawley, Inc.
- Age at study initiation: young adult
- Weight at study initiation: 180 - 300 g
- Housing: All animal housing and care conformed to AAALAC standards and to those published in the "Guide for the CareI and Use of Laboratory Animals," NIH Publication N0. 85-23. The animals were individually housed in suspended stainless steel wire mesh bottom cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Mass median aerodynamic diameter (MMAD):
5.2 µm
Geometric standard deviation (GSD):
1.7
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester type inhalation chamber
- Exposure chamber volume: 270 L
- Method of holding animals in test chamber: The animals were individually housed during the exposure in wire mesh cages without access to food or water.
- Source and rate of air: High pressure external air source, 75 L/min
- System of generating particulates/aerosols: Particle generator (Model FD-100. Unifab Corporation, Kalamazoo. Michigan)
- Method of particle size determination: Particle size analysis was performed once per hour during the exposure using an Anderson 2000 impactor (Model 20-800). Stages one to eight of the impactor, and the final filter stage were fitted with pre-weighed glass fiber filters. A known volume of chamber air (30 L) was drawn through the impactor and the change in weight of each filter was then determined and recorded.
- Treatment of exhaust air: Air treatment system which consisted of a HEPA filter, a charcoal filter and a water scrubber
- Temperature, humidity, pressure in air chamber: The test atmosphere temperature, relative humidity and percent oxygen content, and the air flow rate to the chamber were recorded at approximately 30 min intervals during the exposure. Average temperature, relative humidity, and oxygen content of the test atmosphere were 21°C, 56.8% and 21.0%, respectively.

TEST ATMOSPHERE
The inhalation chamber was maintained at a slightly negative pressure at all times during operation. Air flow rate to the chamber was monitored continuously during the exposure using calibrated Dwyer air flow meters (Dwyer Instruments, Inc.).
- Brief description of analytical method used: The average actual concentration of the test atmosphere was determined by gravimetric sampling. At the time of theoretical chamber equilibration a test atmosphere sample was drawn from the breathing zone of the chamber (5 L) through a pre·weighed glass fiber filter. The change in weight of the filter (mg) was determined and this value was divided by the volume of test atmosphere sampled (5 L) to yield the actual test atmosphere concentration. Additional gravimetric samples were obtained at approximately 30 minute intervals during the exposure. The average actual concentration of the test atmosphere was calculated for the exposure based on the initial and subsequent concentration analyses.
- Samples taken from breathing zone: yes
- MMAD: The mass median aerodynamic diameter of the generated particles was 5.2 µm and the standard geometric deviation was 1.7. Approximately 87% of the particles were less than 10 µm in size.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
by gravimetric sampling
Duration of exposure:
240 min
Concentrations:
The average actual test atmosphere concentration was determined to be 6.3 mg/L. The calculated nominal concentration was 27 mg/L. Thus, the average actual concentration was approximately 23.3% of the calculated nominal test atmosphere concentration.
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 and weighing: Mortality checks were performed twice daily, a minimum of 5 h apart. The animals were observed for outward signs of toxicity 3 times on study day 1 (post exposure) and once daily thereafter for the duration of the study (day 15). Due to the density of the test atmosphere, an accurate observation of the study animals could not be performed during the actual exposure. Individual body weights were determined and recorded on study days 1, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
not determined
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 6.3 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
240 min
Mortality:
1 male, necropsy findings suggest that death was caused by asphyxiation.
Clinical signs:
other: Labored breathing and/or rales, dark material around nose or mouth, decreased activity, urine stain, thrashing (in cage), for details see Table 1 under 'Any other information on results'.
Body weight:
Decreased body weight gain and/or weight loss were observed in both the male and female animals. No net change in mean body weight was observed in the male rats between days 1 and 15. In the female animals, mean body weight was decreased approximately 5% during the period of the study.
Gross pathology:
Necropsy examinations of the surviving animals revealed yellow material in the stomach (4 females), pale lungs (one male) and multifocal dark red foci on the lungs (one male). The significance of the above findings, if any, was not determined in this study.
Other findings:
- Histopathology: No microscopic lesions were observed in the kidneys or liver of any animal.

Table 1: Clinical signs during the 4 day observation period after exposure; because of the death of one male, 4 males and 5 females (9 animals) were examined

 

Incidence of animals exhibiting finding / number of total animals on day

Finding

1

2

3

4

Labored breathing and/or rales

7 / 9

7 / 9

3 / 9

2 / 9

Dark material around nose or mouth

3 / 9

4 / 9

1 / 9

0 / 9

Decreased activity

0 / 9

3 / 9

0 / 9

0 / 9

Urine stain

0 / 9

1 / 9

0 / 9

0 / 9

Thrashing (in cage)

1 / 9

0 / 9

0 / 9

0 / 9

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

Based on the results of this study, the acute inhalation LC50 of the registered substance in rats is estimated to be greater than 6.3 mg/L. According to the criteria laid down in Regulation (EC) No. 1272/2008 the registered substance does not have to be classified for acute toxicity via the inhalation route.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Only 1 h inhalation exposure
Principles of method if other than guideline:
Study performed before actual guideline was established.
GLP compliance:
no
Test type:
traditional 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 Breeding Laboratories, Wilmington, Massachusetts, USA
- Weight at study initiation: 206 - 297 g
- Fasting period before study: not applicable, inhalation exposure
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass exposure chamber
- Exposure chamber volume: 26.5 L
- Method of holding animals in test chamber: not specified
- Source and rate of air: 4 L/min
- Method of conditioning air: Air was dried
- System of generating particulates/aerosols: The test material was sieved through a 60-mesh sieve and placed in a 1000 mL three-neck flask. Dry air was passed through the flask and a metal stir rod, powered by a Fisher Jumbo Stirrer, was used to generate the dust. The resultant dust-laden airstream was passed out of the flask through a glass elbow and was directed, undiluted, into a 26.5 liter glass exposure chamber containing the animals. The exposure lasted for 1 h. The 1000 mL three-neck flask containing the test material and the glass elbow were weighed before and after the exposure. The difference in weight was equal to the amount of material consumed during the exposure. The nominal concentration was calculated by dividing the weight lost by the total flow through the chamber during the exposure.
- Method of particle size determination: sieving through 60-mesh sieve (equivalent to 250 µm) prior to exposure

TEST ATMOSPHERE
- Brief description of analytical method used: Nominal test material concentration in atmosphere determined by calculation on the basis of weight difference.
- Samples taken from breathing zone: no

VEHICLE
- Composition of vehicle (if applicable): dry air
- Concentration of test material in vehicle (if applicable): 58.2 mg/L

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: smaller than 60-mesh (sieved), i.e. smaller than 250 µm
Analytical verification of test atmosphere concentrations:
no
Remarks:
During the exposure, a total of 13.96 g of test material was delivered in a total of 240 liters of air, yielding a nominal exposure concentration of 58.2 mg/L.
Duration of exposure:
1 h
Concentrations:
58.2 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 and weighing: Observations prior to exposure and in 15-minute intervals during the exposure, upon removal from the chamber, hourly for 4 h post-exposure, and daily thereafter for 14 days. Individual body weights were measured on day 0 (prior to exposure) and on days 1, 2, 4, 7 and 14 (terminus).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 58.2 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
1 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 14.55 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Calculated from 1-h value acccording to Haber's law.
Mortality:
No mortality occurred.
Clinical signs:
other: No abnormalities were observed in any of the test animals throughout the exposure period. Upon removal from the exposure chamber the following signs were observed: mucoid nasal discharge (4/10), red nasal discharge (6/10), excessive salivation (4/10), dry
Body weight:
Individual body weights were considered normal for this type of exposure.
Gross pathology:
Necropsy examination revealed lung discolouration in 4/10 animals.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
6 300 mg/m³
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, Item 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
analytical purity of the test substance, humidity and temperature are not specified in the study report
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Gota-Frisco Farms
- Age at study initiation: young adult, not further specified
- Weight at study initiation: 2.0 - 3.0 kg, weight variation did not exceed ± 20% of the group mean of each sex
- Housing: Individually housing in suspended stainless steel wire mesh bottom cages, conform to AAALAC standards and those published in the "Guide for the care and use of laboratory animals" NIH publication No. 85-23
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Minimum of 5 days

ENVIRONMENTAL CONDITIONS

- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: 12 x 20 cm
- % coverage: 10%
- Type of wrap if used: A tubular stockinette sleeve and an adjustable harness were placed around the animal’s trunk. Nonirritating tape was used to secure both the gauze dressing and stockinette sleeve.

REMOVAL OF TEST SUBSTANCE
- Washing: yes, with distilled water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: yes, the dressing was moistened with distilled water at a rate of 1 mL/g of test article to ensure good contact of the test article with the skin.
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:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for pharmacotoxic signs three times on the day of dosing and once daily thereafter for the duration of the study (15 days). Mortality checks were performed twice daily, a minimum of 5 h apart. Individual body weights were determined and recorded on Days 1, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: Histopathology: At study termination (day 15), the heart, kidneys, liver, lungs and stomach were excised from each animal and preserved. After complete fixation, the liver and kidneys from each rabbit were embedded in paraffin, sectioned at 3-5 mm in thickness, stained with hematoxylin and eosin, and then examined microscopically by an SIB Pathologist.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
All animals survived until scheduled sacrifice.
Clinical signs:
No clinical signs of toxicity were noted during the study.
Body weight:
No treatment related body-weight changes were noted during the study.
Gross pathology:
Necropsy examinations revealed the kidneys of two males to have a pitted capsular surface. No other gross abnormalities were noted.
Other findings:
- Histopathology: Microscopic examination of the liver revealed minimal chronic multifocal inflammation in three animals (one male and two females) and minimal acute exudative multifocal inflammation in one animal (male). In three of the ten test animals, chronic multifocal inflammation of the liver and kidneys occurred together.

- Other observations: The occurrence of the above pathological findings cannot be definitely attributed to treatment with the test article as similar lesions are commonly seen at this incidence level in the liver and kidneys of untreated stock laboratory rabbits.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

The registered substance is judged to be nonlethal and nontoxic when administered by the dermal route at 2000 mg/kg bw to New Zealand albino rabbits. The registered substance does not have to be classified for acute toxicity via the dermal route according to the criteria laid down in Regulation (EC) No. 1272/2008.

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 (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, Item 8.5, of Regulation (EC) No. 1907/2006.

Additional information

Acute oral toxicity

There are three studies available for oral toxicity, two limit tests and a study with three doses in the range 1350 to 15380 mg/kg bw. Although all of these study reports are acceptable for assessment, each of them has some minor flaws. The study by EG&G Mason, 1981, was a limit test conducted with 10 animals at a dose of 5000 mg/kg bw, but administered in a high dose volume of 15 mL/kg bw of a non-aqueous vehicle; the study by TNO, 1983, was conducted with 20 animals receiving a dose of 5000 mg/kg bw, but with an even higher dose volume of 20 mL/kg bw of a non-aqueous vehicle. In the study by Industrial BIO-TEST Labs, 1976, three dose levels of 1350, 4556 and 15380 mg/kg bw were administered, but only 4 animals (2 of each sex) were included in the respective groups.

However, there was no mortality observed in any of these studies even up to the highest administered dose of 15380 mg/kg bw, no clinical signs were observed except a slight hypoactivity within 5 min after application described in the study by Industrial BIO-TEST Labs, body weights were not affected, and no apparent gross tissue or organ abnormalities were detected by pathology in any of the animals necropsied 14 days after treatment. Therefore, it is reasonable to conclude that the LD50 is at least greater than 5000 mg/kg bw.

Acute inhalation toxicity

Two studies are available for acute inhalation toxicity. In the key study (Springborn Institute, 1987) 10 animals (5 per sex) were exposed whole body to a fixed gravimetrically determined concentration of 6.3 mg/L for 4 h. The mass median aerodynamic diameter of the generated particles was determined to be 5.2 ± 1.7 µm, which is acceptable considering the technical standards and the requirements of the guideline at the time of the study. No mortality occured during exposure or the 14-day observation period, therefore the LC50 was determined to be greater than 6.3 mg/L. In the supporting study (Biodynamics, 1979) 10 animals were exposed to a nominal exposure concentration of 58.2 mg/L for 1 h only, which was not analytically confirmed. No mortality occurred under the conditions of this study. During exposure, no treatment-related abnormalities were observed, while clear signs of a reversible irritant effect were reported in the post-treatment observation period. According to Haber's Law one could calculate a nominal LC50 > 14.55 mg/L for a 4-h exposure, but as analytical confirmation of the actual concentration is missing, the lack of mortality in this study can only support the view of an LC50 > 6.3 mg/L.

Acute dermal toxicity

There are data for acute dermal toxicity available from a limit test conducted with rabbits (Springborn Institute, 1986). In this study 10 animals (5 per sex) were exposed to a single dose of 2000 mg/kg bw under semiocclusive conditions for 24 h. No mortality occurred, and no clinical signs were observed in the 14-day observation period. Pathological and histopathological findings in the liver and the kidneys were observed in some animals at necropsy which were assumed to be not treatment-related and to be common for untreated stock laboratory rabbits, as well. Therefore, the acute dermal LD50 was assumed to be greater than 2000 mg/kg bw.

Justification for classification or non-classification

The available data on the acute toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.