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Administrative data

Description of key information

Oral: Equivalent or similar to OECD Guideline 420. Rat LD50 = 7902 mg/kg males; 9939 mg/kg females. CNS depression. Reliability = 2
Inhalation: OECD Guideline 403. Rat 4-hour LC50 ≥24100 ppm (≥95552 mg/m3). Diminished or lack of response to an alerting stimulus. Reliability = 1
Dermal: Equivalent or similar to OECD 402. Rabbit LD50 >5000 mg/kg. Reliability = 1

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Data taken from accepted publication with limited details on methods and results. This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
yes
Remarks:
dose levels not reported
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley derived CD, Charles River
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 22-30 days
- Weight at study initiation: Male and female rats, weighing 113 ± 5 g and 102 ± 2 g, respectively
- Fasting period before study: fasted overnight (water but no feed, 16 hours) before dosing
- Housing: stainless steel wire-bottomed suspended cages
- Diet: Purina Rodent Chow No. 5001, ad libitum
- Water: ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24°C
- Humidity (%): 40-60%
- Photoperiod (hrs dark / hrs light): 12-hour light-dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 450-850 mg/mL

MAXIMUM DOSE VOLUME APPLIED: volume of solution administered was 10 mL/kg
Doses:
not reported
No. of animals per sex per dose:
five dosage groups consisting of 10 rats per sex per group
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Hourly observations were made during the first 9 hours after administration, followed by twice daily (at least 5 hours apart) observations for the next 14 days.
- Necropsy of survivors performed: yes
Statistics:
The LD50 was determined by the method of Litchfield and Wilcoxon.
Sex:
male
Dose descriptor:
LD50
Effect level:
7 902 mg/kg bw
Based on:
test mat.
95% CL:
6 805 - 9 175
Remarks on result:
other: Dose-dependent central nervous system depression, ataxia, and depressed respiration observed at all doses
Sex:
female
Dose descriptor:
LD50
Effect level:
9 939 mg/kg bw
Based on:
test mat.
95% CL:
6 494 - 15 213
Remarks on result:
other: Dose-dependent central nervous system depression, ataxia, and depressed respiration observed at all doses
Mortality:
All deaths occurred within 30 hours after dosing.
Clinical signs:
Central nervous system depression, ataxia, and depressed respiration were observed at all doses; the severity was dose dependent.
Gross pathology:
Gross necropsy findings of all rats that died were essentially negative. No consistent compound-related gross pathological findings were observed at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
LD50 Male Rats = 7902 mg/kg
LD50 Female Rats = 9939 mg/kg
Executive summary:

To determine the LD50 in rats, the test item was administered by gavage to male and female Sprague-Dawley derived Charles River rats. Male and female rats were divided into five dosage groups consisting of 10 rats per sex per group. After administration, hourly observations were made during the first 9 hours then followed by twice daily (at least 5 hours apart) observations for the next 14 days. All deaths occurred within 30 hours after dosing. Central nervous system depression, ataxia, and depressed respiration were observed at all doses; the severity was dose dependent. Gross necropsy findings of all rats that died were essentially negative. No consistent compound-related gross pathological findings were observed at necropsy. The LD50s for male and female rats were 7902 and 9939 mg/kg, respectively.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
7 902 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
Qualifier:
according to guideline
Guideline:
other: MAFF Japan 59 NohSan No. 4200 Testing Guidelines for Toxicity Studies (1985)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Crl:CD®(SD)IGS BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 8 or 9 weeks old
- Weight at study initiation: Males - 233 to 348 grams; Females - 184 to 235 grams
- Housing: Rats were housed either singly or in pairs (sexes separate) in suspended, stainless steel, wire-mesh cages.
- Diet: PMI Nutrition International, Inc. Certified Rodent LabDiet® 5002, ad libitum
- Water: tap water from United Water Delaware, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): targeted to be within a temperature range of 23 ± 1°C
- Humidity (%): 50 ± 10%
- Photoperiod: 12-hour light/12-hour dark cycle
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: Houseline nitrogen and air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass (NYU style)
- Exposure chamber volume: 150 L
- Method of holding animals in test chamber: rats were placed within wire-mesh cages and exposed whole-body inside the exposure chamber
- Source and rate of air: 37 L/min
- System of generating vapour: Chamber atmospheres were generated by flash evaporation of liquid test substance in nitrogen (N2 flow = 3 L/min). For each exposure, the subject test substance was metered into a heated (90-171°C), glass mixing flask with a Cole Palmer Masterflex® Console Drive pump. Houseline nitrogen was introduced to the heated mixing flask to carry the vapour into the exposure chamber. Houseline air was introduced before the exposure chamber to dilute the atmosphere generated at the flask.
- Temperature and humidity in air chamber: 22 to 26°C and 32 to 55%, respectively

TEST ATMOSPHERE
- Brief description of analytical method used: Chamber atmosphere samples were directly injected into a Hewlett Packard model 6890 Plus Series Gas Chromatograph equipped with a flame ionization detector for analysis at approximately 15-minute intervals during each exposure. Vapour samples were drawn by vacuum pump from representative areas of the chamber where rats were exposed. All samples were chromatographed isothermally at 100°C on a Restek RTX-200 column.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Houseline nitrogen and air
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0, 12300, 22500, 28100 and 34100 ppm
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: Rats were observed for mortality and response to alerting stimuli during the exposure and observed for mortality and clinical signs of toxicity immediately after they were removed from the chambers following exposure. During a 14-day postexposure period, all surviving rats were observed each day for mortality, and were weighed and observed daily for clinical signs of toxicity.
- Necropsy of survivors performed: yes
- All rats were given a complete gross pathological examination of their internal organs including observation of the nasal passages. Representative samples of the liver, kidney, lung, and heart were saved at necropsy. All tissues were processed, embedded in paraffin, cut at a nominal thickness of 5 micrometers, stained with hematoxylin and eosin (H&E) and examined microscopically.
Statistics:
Probit Analysis
Sex:
male/female
Dose descriptor:
LC50
Effect level:
24 100 ppm
Based on:
test mat.
95% CL:
19 200 - 26 900
Exp. duration:
4 h
Remarks on result:
other: Diminished or a lack of response to an alerting stimulus observed during exposure at all doses
Sex:
male/female
Dose descriptor:
other: NOEL
Effect level:
34 100 ppm
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: for gross and microscopic pathology; highest concentration tested
Mortality:
See Table in Results below. All deaths occurred during exposures. In calculating the LC50, the male and female rat lethality data was combined because there was no apparent sex difference in the lethality response to the tested compound.
Clinical signs:
other: During exposure, rats were prostrate, many had their eyes open, and exhibited a diminished or a lack of response to an alerting stimulus. After the 12300 ppm exposure, rats appeared to recover and resume a normal appearance within about thirty minutes af
Body weight:
Rats that survived the 22500 ppm exposure showed slight weight loss for one day followed by a normal weight-gain rate. Rats exposed to 28100 ppm showed slight to severe weight loss for one day.
Gross pathology:
There were no test substance-related gross observations.

VAPOUR

CONCENTRATION

MORTALITY

(# deaths/# exposed)

ppm

MALES

FEMALES

Control

0/5

0/5

12300

0/5

0/5

22500

1/5

3/5

28100

3/5

4/5

34100

5/5

5/5

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
LC50 = 24100 ppm
Executive summary:

Groups of 5 male and 5 female Crl:CD®(SD)IGS BR rats were exposed whole-body to the test item for a single 4-hour exposure period. A control group was treated similarly except for exposure to the test substance. The test atmosphere was generated by flash evaporating the liquid test substance in nitrogen. The concentration was determined by gas chromatographic analysis.  During a 14-day recovery period, rats were weighed and observed for clinical signs of toxicity. All rats underwent gross pathologic examination immediately after death or at the end of the recovery period and the liver, kidney, heart, and lung were evaluated histologically. In calculating the LC50, the male and female rat lethality data was combined because there was no apparent sex difference in the lethality response to the test compound. The LC50 for the test item was 24100 ppm. All deaths occurred during exposures. During each exposure, the rats were prostrate, many had their eyes open, and showed a diminished or lack of response to an alerting stimulus.
After the 12300 ppm exposure, rats appeared to recover and resume a normal appearance within about thirty minutes after the end of the exposure. There were no effects on rat body weights at this concentration. Rats that survived the 22500 ppm exposure showed lethargy and irregular respiration immediately after exposure and showed slight weight loss for one day followed by a normal weight-gain rate. Rats exposed to 28100 ppm of showed weakness immediately after exposure and slight to severe weight loss for one day. There were no test substance-related gross or microscopic observations for the test substance.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
95 552 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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
dosed with 5000 mg/kg bodyweight
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
- Age at study initiation: Young adult
- Weight at study initiation: 3115 to 3312 grams
- Housing: housed singly in suspended, stainless steel, wire-mesh cages
- Diet: Purina Certified Rabbit Chow® #5322 ad libitum
- Water: ad libitum
- Acclimation period: approximately 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 2°C
- Humidity (%): 50% ± 10%.
- Photoperiod: 12-hour light/12-hour dark cycle
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 190 square centimeters
- Type of wrap if used: After application of the test material, sterile gauze pads were applied to the treated site. The rabbits were then wrapped with successive layers of plastic film, stretch gauze bandage and elastic adhesive bandage.

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

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
Male - 2
Female - 3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: Observations for clinical signs were made approximately 24 hours after dosing and then daily thereafter for 14 days (excluding weekends). Observations for mortalities were made daily throughout the study.
- Frequency of weighing: weighed on days 1, 7 and 14 following treatment
- Necropsy of survivors performed: no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality
Mortality:
None
Clinical signs:
The test item produced mild or moderate erythema and no to mild oedema in the treated rabbits by approximately 24 hours. The dermal irritation in the rabbits became more severe during the study. At day 7, mild to severe erythema with slight to severe oedema, necrosis, fissuring of the skin and raw areas was observed. At day 8, the dermal irritation in 1 rabbit began to resolve. However, at study termination (day 14), mild to severe erythema with no to severe oedema, necrosis, fissuring of the skin, raw areas and epidermal scaling was still evident in the treated rabbits.
Body weight:
Body weight losses of up to 3% of initial body weight were observed in 3 rabbits at 1 day following treatment.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
LD50 > 5000 mg/kg
Executive summary:

A single dose of the test item was applied to the clipped, intact skin of 2 male and 3 female New Zealand White rabbits at a dosage of 5000 mg/kg of body weight. The application site was occluded for 24 hours. The rabbits were observed for 14 days following application. No rabbits died during the study.

The test item produced mild or moderate erythema and no to mild oedema in the treated rabbits by approximately 24 hours. The dermal irritation in the rabbits became more severe during the study; by day 7 mild to severe erythema with slight to severe oedema, necrosis, fissuring of the skin and raw areas was observed. At study termination, mild to severe erythema with no to severe oedema, necrosis, fissuring of the skin, raw areas and epidermal scaling was still evident in the treated rabbits. Body weight losses of up to 3% of initial body weight were observed in 3 rabbits at 1 day following treatment. Under the conditions of this test, the skin absorption LD50 was greater than 5000 mg/kg of body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

The test substance has low acute oral and inhalation toxicity in the rat and low acute dermal toxicity in the rabbit. The oral LD50 in rats was 7902 mg/kg for males and 9939 mg/kg for females. The dermal LD50 in rabbits was >5000 mg/kg, and the inhalation 4-hour LC50 in rats was 24100 ppm ( 95552 mg/m3). CNS depression was observed in the oral study and a diminished or lack of response to an alerting stimulus was observed in the inhalation study. Additionally, no gross or microscopic lesions were observed in the liver, heart, kidney, or lung in the inhalation study. The no-observed-adverse-effect-concentration for gross and microscopic pathology was determined to be 34100 ppm.


Justification for selection of acute toxicity – oral endpoint
Equivalent or similar to OECD Guideline

Justification for selection of acute toxicity – inhalation endpoint
OECD Guideline, GLP study

Justification for selection of acute toxicity – dermal endpoint
OECD Guideline, GLP study

Justification for classification or non-classification

Based on an acute oral LD50 in rats of 7902 mg/kg for males and 9939 mg/kg for females, a dermal LD50 in rabbits of >5000 mg/kg, and an inhalation 4-hour LC50 in rats of 24100 ppm (95552 mg/m3), no classification is required for acute oral, dermal, or inhalation endpoints according to the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. While the study data for acute inhalation does not warrant a classification, the stricter classification of Acute Tox. 4 (H332: Harmful if inhaled) according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 ATP02 and Xn; R20 (Harmful by inhalation) according to EU Directive 67/548/EEC will be adhered to.