Registration Dossier

Administrative data

Description of key information

ORAL

The LD50 for the test material was determined to be >2000 mg/kg bw according to a study performed in line with EPA OPPTS 870.1100.

DERMAL

The LD50 for the test material was determined to be >2000 mg/kg bw according to a study performed in line with OECD Guideline 402, EU Method B.3 and EPA FIFRA 81-2.

INHALATION

The LC50 for the test material was determined to be >250 mg/m³ (maximum attainable concentration) according to a study performed in line with EPA Guideline OPP 81-3 and in part with EU Method B.2.

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:
22 April 1999 to 23 June 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Boyertown, PA, USA
- Weight at study initiation: 206-275 g (male); 200-237 g (female)
- Fasting period before study: 16-20 hours prior to dosing
- Housing: suspended wire cages
- Diet (e.g. ad libitum): Purina Rat Chow (Diet #5012) ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DOSAGE PREPARATION
10 g of test material was added to 40 mL of corn oil
Doses:
2000 mg/kg
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 1, 2 and 4 hours postdose and once daily for 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: body weights were recorded immediately pretest, at death and at termination in the survivors
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Nine out of ten animals survived. One male was sacrificed on day 2 due to moribund condition.
Clinical signs:
Physical signs in the surviving animals included: lethargy, chromorhinorrhoea, ataxia, sagging eyelids, soiling of the anogenitial area, diarrhoea, red staining of the nose/mouth area, wetness of the anogenital area and localised alopecia. Similar symptoms were noted in the animal that was sacrificed.
Body weight:
Body weight changes in surviving animals were normal.
Gross pathology:
Necroposy of the survivors was normal in 2/9 animals. Kidney abnormalities were noted in 7/9 survivors. Necropsy of the sacrificed animal revealed abnormalities of the intestines, as well as red staining of the nose/mouth area.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the test, the LD50 of the test material was >2000 mg/kg.
Executive summary:

In a GLP compliant acute oral toxicity study conducted in line with standardised guideline EPA OPPTS 870.1100, the acute oral toxicity of the test material was determined. Under the conditions of the test, the LD50 of the test material in rats was determined to be >2000 mg/kg bw and so the substance is considered to be unclassified for this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

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:
16 August 1984 to 02 May 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
yes
Remarks:
(only two test concentrations)
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: stainless steel wire mesh cages
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: 6-8 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25 °C
- Humidity: 48-77 %
- Air changes: 26 times per hour
- Photoperiod: 12 hours light / 12 hours dark
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: 40 L
- System of generating particulates/aerosols: Rehma type 504104 nebulizer
- Method of particle size determination: measured using a Marple personal cascade impactor, model 296. Samples were taken through the inlet adaptor at nose level at 1.5 L/min at 105 and 165 minutes after the start of exposure. Directly after sampling, the filters were extracted with methanol and the test material measured spectrophotometrically.
- Temperature, humidity, pressure in air chamber: 23.4-23.8 °C; 60.1-65.0 %

TEST ATMOSPHERE
- Brief description of analytical method used: samples of test atmosphere were taken through a 6cm plastic tube at 2 L/min for 2 minutes. After sampling, filters and the silica were extracted with dichloromethane and amounts of test material measured spectrophotometrically.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.11-2.57 µm (105 minutes); 2.00-2.61 µm (165 minutes) / 2.89-3.13 (105 minutes); 2.90-3.14 (165 minutes)
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
240 min
Concentrations:
0, 540 and 700 mg/m^3 (nominal)
133-233 mg/m^3 (lowest dose) - 250-326 mg/m^3 (highest dose)
No. of animals per sex per dose:
Five
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: during exposure, respiratory frequencies if two males and two females were recorded; At 1.5, 18, 24 and 48 hours after exposure each animal was checked for toxic symptoms and then observed daily
- Necropsy of survivors performed: yes
- Other examinations performed: organ weights (lungs and trachea) and organ histopathology
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 250 mg/m³ air (analytical)
Based on:
test mat.
Remarks on result:
other: maximum attainable concentration (limit dose)
Mortality:
No deaths were reported during the study.
Clinical signs:
A temporarily decreased reactivity and locomotor activity of the rats suggested a slight effect on the nervous system when compared to controls.
Body weight:
No effects were observed.
Gross pathology:
All animals appeared normal. No macro- or microscopic abnormalities were detected which could be attributed to the test material.
Other findings:
- Organ weights: no changes in lung weights were observed.
- Histopathology: minor changes, not attributable to the test material, were observed.
- Other observations: respiratory frequencies were depressed in the test groups when compared to the controls.
Interpretation of results:
other: Not classified in accordance with EU Criteria
Conclusions:
Under the conditions of the test, the LC50 of the test material was >250 mg/m³. A decreased respiratory frequency, observed during the exposure period, indicates an irritating action of the test material on the respiratory system. Further observations at 1.5 hours after exposure suggest a slight depression of the test material on the behaviour of the treated animals.
Executive summary:

In a GLP compliant acute inhalation study conducted in line with standardised guidelines EPA OPP 81-3 and partly in line with EU Method B.2, the acute inhalation toxicity of the test material was determined.

Under the conditions of the test the LC50 of the test material in rats was determined to be >250 mg/m3. A decreased respiratory frequency, observed during the exposure period, indicates an irritating action of the test material on the respiratory system. Further observations at 1.5 hours after exposure suggest a slight depression of the test material on the behaviour of the treated animals.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
250 mg/m³

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:
8 December 1993 to 19 May 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: four months old
- Weight at study initiation: 2.68-2.90 kg (male); 2.84-3.09 (female)
- Housing: individually in suspended stainless steel cages
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature: 15-23 ºC
- Humidity: 40-70 %
- Air changes: at least 10
- Photoperiod: 12 hours light/12 hours dark
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 12 cm x 14 cm
- % coverage: approximately 10 %
- Type of wrap if used: unmedicated gauze patch; occluded with aluminium foil

REMOVAL OF TEST SUBSTANCE
- Washing (if done): gently wiped with wet tissues
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: three separate observations were made during the first hour after administration and two further recordings were made during day 1. From day 2 onwards, the animals were inspected at least twice daily and recordings of systemic signs made once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: body weights were recorded on the day before dosing and days 1, 8 and 15.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two female rabbits were found dead on day 5
Clinical signs:
Ante mortem signs comprised under-activity, pallor, cold to touch, pigmented straining of the snout and closed eyes. One surviving female rabbit showed pallor on day 4. The other surviving animals showed no systemic or local sign of reaction to treatment.
Body weight:
The surviving animals achieved expected body weight gains.
Gross pathology:
Necropsy of the deceased animals revealed blood staining around the mouth and nares of both animals, dark tracheal contents and dark areas on the left lung lobe of one animal and dark fluid in the thorax and abdomen of the other animal. The latter animal also had a thickened dermal application site with dark encrustations.

Necropsy of the surviving animals revealed no significant internal macroscopic lesion, although one animal had multiple dark areas in the musculature below the application site.
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the test, the LD50 of the test material was >2000 mg/kg.
Executive summary:

In a GLP compliant acute dermal toxicity study conducted in line with standardised guidelines OECD 402, EU Method B.3 and EPA FIFRA Guideline 81-2, the acute dermal toxicity of the test material was determined.

Under the conditions of the test, the LD50 of the test material was determined to be >2000 mg/kg bw and so the substance is considered to be unclassified for this endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

The test material was of low acute toxicity by the oral and dermal routes of exposure. The acute oral LD50 in the rat was >2000 mg/kg and 4460 mg/kg in two studies and the acute dermal LD50 in the rabbit was >2000 mg/kg. The key study for acute oral toxicity (Graver, 1999) was chosen as it was performed to GLP and in line with standardised guidelines and so the value of >2000 mg/kg was used for risk assessment.

In two 4 hour duration inhalation studies with rats, the LC50 was >5 mg/L and >250 mg/m3. The key study for acute inhalation toxicity (Janseen and Rooy, 1986) was chosen as it was performed to GLP and in line with standardised guidelines and so the value of >250 mg/m3 was used for risk assessment.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity.

However, the substance has a European harmonised classification under Regulation 1272/2008 of GHS07 and H312 (Harmful in contact with the skin).