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Description of key information

Oral: LD50= >5000 mg/kg bw, male and female rat, EPA OPP 81-1, Glaza 1995a
Dermal: LD50= >2000 mg/kg bw, male/female rat, EPA OPP 81-2, Glaza 1995c
Inhalation: LC50= >5.1 mg/L bw. male/female rat, EPA OPP 81-3, Bennick 1995

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:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to guideline; under GLP conditions
Qualifier:
according to guideline
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl :CD®(SD)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier.
- Age at study initiation: not reported
- Weight at study initiation: 208 to 232 g
- Fasting period before study: 17-20 hours prior to test material administration.
- Housing: the animals were separated by sex and group housed in screen-bottom stainless steel cages. (During the range-finding study, the animals were individually housed.)
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except during fasting)
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 50 +/- 20%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark

IN-LIFE DATES: From: To: 1995-07-06 to 1995-07-26
Route of administration:
oral: gavage
Vehicle:
other: MC/T 80 [0.5% methylcellulose (w/v) and 0.1% Tween 80 (v/v)] to a concentration of 0.25 g/ml.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.25 g/ml
- Amount of vehicle (if gavage): 20 ml/kg
- Justification for choice of vehicle: not reported
- Lot/batch no. (if required): not reported
- Purity: MC/T 80 [0.5% methylcellulose (w/v) and 0.1% Tween 80 (v/v)]

MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Starting dose selected based on the results of the range-finding test.
Doses:
Range-finding study: 500, 1000, 3000 and 5000 mg/kg of body weight.
Main test: 5000 mg/kg body weight.
No. of animals per sex per dose:
Range-finding study: 2
Main study: 10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks for the definitive study animals were conducted at approximately 1, 2.5, and 4 hours after test or control material administration. Additional clinical observations and twice a day mortality checks (morning and afternoon) were conducted daily thereafter for 14 days. Body weights for both range-finding and definitive study animals were determined before test or control material administration (Day 0), at Day 7 and at termination of the in-life phase (Day 14).
- Necropsy of survivors performed: yes
Statistics:
No statistical analyses were performed.
Preliminary study:
No mortalities were observed in the range-finding study and all animals exhibited the normal body weight gain.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities were observed.
Clinical signs:
All test animals appeared normal throughout the test period.
Body weight:
All animals exhibited normal body weight gain throughout the study.
Gross pathology:
There were no test material-related lesions observed at necropsy.
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: US EPA pesticides
Conclusions:
The acute oral median lethal dose (LD50) of the test material in male and female Crl :CD®(SD)BR strain of rat was estimated to be greater than 5000 mg/kg body weight.
Executive summary:

The study was performed to assess the acute oral toxicity of the test material in the Crl :CD®(SD)BR strain of rat. The study was performed to GLP and the method was designed to meet the requirements of EPA guideline 81-1. The test material was administered orally, after overnight fasting, once only by gavage, as a suspension in MC/T 80 [0.5% methylcellulose (w/v) and 0.1% Tween 80 (v/v)]. The test material concentration in the vehicle was 0.25 g/mL and the administered volume of suspension was 20 mL/kg body weight. Following a preliminary test in which an animal of each sex was dosed with the test material at 500, 1000, 3000 and 5000 mg/kg body weight, there was no mortality or signs of systemic toxicity. For the main test, 10 male and 10 female test animals were dosed at 0 and 5000 mg/kg body weight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy after an observation period of 14 days.

There were no deaths and no signs of systemic toxicity were observed. Animals showed expected gains in bodyweight during the study. No test-related abnormalities were noted at necropsy. The acute oral median lethal dose (LD50) of the test material in the male and female Crl:CD (SD) BR strain rat was estimated to be greater than 5000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information as a whole meets the tonnage driven data requirements of REACH and all studies are of a reliability score 1.

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:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to guideline; under GLP conditions
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
GLP compliance:
yes
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
- Source: Recognised supplier
- Age at study initiation: young adult (quantitative value not reported)
- Weight at study initiation: Males (259-330 g); Females (209-231 g)
- Fasting period before study: not applicable
- Housing: Housed individually, in suspended stainless steel cages with wire bottom.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum (except during exposure period).
- Water (e.g. ad libitum): Municipal water supply from automatic water system, available ad libitum except during the exposure period
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 +/- 5
- Humidity (%): 30-80
- Air changes (per hr): 10-12
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: To: 1995-08-23 to 1995-06-09
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: A 500 L nose-only stainless steel, dynamic flow inhalation chamber was utilized in this experiment, one for the test group and another for the control group. The body of the chamber has 25 ports in 5 rows. Polycarbonate cones are inserted into 10 designated individual ports. The test material is introduced through the opening in the top of the chamber. The bottom section has a corresponding air outlet and a drain valve for cleaning the chamber. The individual polycarbonate cones (tubes) are tapered at one end to fit the shape of the animal's head and the back portion is sealed with a poly carbonate cap. The cones containing the animals fit tightly into the ports, and are sealed with "0" rings.
- Exposure chamber volume: 500 L
- Method of holding animals in test chamber: test animals which were individually housed in polycarbonate exposure tubes were inserted into a 500 L stainless steel nose-only inhalation chamber for the specified exposure period.
- Source and rate of air: filtered air; 17.2 air changes per hour.
- Method of conditioning air: ot reported
- System of generating particulates/aerosols: aerosol was generated by a Venturi Aspirator which aspirated the test material from a motorized revolving disc delivery system coupled to the aspirator, then elutriated the resulting aerosol through a baffling chamber. The concentrated aerosol was then diluted with filtered air and drawn into the exposure chamber. Air flow into the test chamber was maintained through the use of a calibrated critical orifice at a rate 17.2 air changes per hour. Air flow into the control chamber was maintained at a rate of 17.6 air changes per hour.
- Method of particle size determination: Particle size was determined using an Andersen cascade impactor.
- Treatment of exhaust air: The bottom section of the exposure chamber has a corresponding air outlet and a drain valve for cleaning the chamber.
- Temperature, humidity, in air chamber: 72 degrees F, 93% humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of test material in the exposure atmosphere (taken from the breathing zone of the animals) was determined analytically once per hour, and nominally at the end of the exposure. The analytical determination was made using a BAUSCH & LOMB SPECTRONIC 2000 Spectrophotometer.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): not applicable
- Concentration of test material in vehicle (if applicable): not applicable
- Justification of choice of vehicle: not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5.10 mg/L
No. of animals per sex per dose:
5 per sex per dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and signs of pharmacologic and/or toxicologic effects were made frequently on the day of exposure and at least once daily thereafter for 14 days. Individual body weights were recorded just prior to the inhalation exposure and on Days 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
In order to calculate a mean exposure, the Mean Value Theorem of Calculus was used to properly weight the concentration, since the concentrations could not be measured continuously. This method weights concentrations based on the time span of each concentration. A concentration can be calculated for each minute, which better represents the exposure concentration received by each animal.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There was no mortality in test or control animals during the study.
Clinical signs:
other: Prominent in-life observations included piloerection in all animals of both test and control groups, as well as ptosis in one test male.
Body weight:
Body weight gain in test animals was largely unaffected by the administration of the test material. Three females lost weight during the first week; however, two control females also lost weight during the first week. All except one control female gained weight during the second week.
Gross pathology:
The gross necropsy conducted on each animal at termination of the study revealed no observable abnormalities in test or control groups.
Other findings:
- Organ weights: not examined
- Histopathology: not examined
- Potential target organs: not examined
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: US EPA pesticides
Conclusions:
The acute inhalation median lethal dose (LC50) of the test material in male and female Sprague-Dawley strain of rat was determined to be greater than 5.1 mg/L.
Executive summary:

The study was performed to assess the acute inhalation toxicity of the test material in the Sprague-Dawley strain of rat. The study was performed to GLP and the method was designed to meet the requirements of EPA guideline 81-3. Five males and five females were exposed for four hours in a nose-only inhalation system to an aerosol generated from the undiluted test material (fine powder) at a level of 5.10 mg/L. A negative control using an additional five males and five females was run concurrently. There was no mortality during the study.

Clinical signs included piloerection in both sexes of test and control animals, and ptosis in one test male. There was no meaningful effect on body weight gain, and all animals were asymptomatic by Day 3. The gross necropsy revealed no observable abnormalities in any of the animals on test. The acute inhalation LC50 for the test material is greater than 5.10 mg/L.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information as a whole meets the tonnage driven data requirements of REACH and all studies are of a reliability score 1.

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:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to guideline; under GLP conditions.
Qualifier:
according to guideline
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl :CO®(SD)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: not reported.
- Weight at study initiation: 214 - 247 g
- Fasting period before study: not applicable
- Housing: Test animals were individually housed in screen-bottom stainless steel cages.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: At least 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 50 +/- 20
- Air changes (per hr): not reported.
- Photoperiod: 12 h light / 12 hour dark

IN-LIFE DATES: From: To: 1995-06-07 to 1995-20-07
Type of coverage:
occlusive
Vehicle:
other: distilled water, to moisten only
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area
- % coverage: Approximately 20% of total body surface
- Type of wrap if used: The area of application was covered with a 2-in. x 4-in. gauze patch secured with paper tape and overwrapped with Saran Wrap® and Elastoplast® tape to provide an occlusive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test sites were washed using tap water and disposable paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): the solid test material was moistened with distilled water.
- Constant volume or concentration used: not applicable
- For solids, paste formed: no

VEHICLE
- Amount(s) applied (volume or weight with unit): distilled water, for moistening test material only.
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable
Duration of exposure:
24 hours
Doses:
0 and 2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality checks were conducted at approximately 1, 2.5, and 4 hours after test or control material administration. Additional clinical observations (including dermal effects) and twice a day mortality checks (morning and afternoon) were conducted daily thereafter for 14 days. Body weights were determined before test or control material application (Day 0), at Day 7, and at termination of the in-life phase (Day 14).
- Necropsy of survivors performed: yes
Statistics:
No statistical analyses were performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
All animals treated at 0 mg/kg appeared normal throughout the study with the exception of two male and two female animals. Clinical signs observed in these animals included red-stained face, wet and/or yellow-stained urogenital area, and soft stool. These four animals returned to a normal appearance by Day 3 after treatment. All animals treated at 2,000 mg/kg appeared normal throughout the study with the exception of two female animals. Clinical signs observed in these two animals included red-stained face and/or yellow-stained urogenital area. Both animals returned to a normal appearance by Day 3 after treatment. No dermal irritation was observed in either group of animals.
Body weight:
All animals exhibited normal body weight gain throughout the study.
Gross pathology:
No test material-related lesions were observed at necropsy.
Other findings:
At necropsy, the mandibular lymph node in one male given 2,000 mg/kg had multiple pinpoint red foci. This was considered an incidental finding and
unrelated to the test material.
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Criteria used for interpretation of results: US EPA pesticides
Conclusions:
The acute dermal median lethal dose (LD50) of the test material in male and female Crl :CO®(SD)BR rats was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

The study was performed to assess the acute dermal toxicity of the test material in the Crl :CO®(SD)BR strain rat. The study was performed to GLP and the method was designed to meet the requirements of the EPA Guideline 81 -2.10 test animals (5 males and 5 females) were given a single, 24 -hour, semi-occluded dermal application of the test material (slightly moistened using distilled water) to intact skin at a dose of 2000 mg/kg body weight. Bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

No signs of dermal irritation were noted. Animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy. Clinical signs were observed in 2 control males, 2 control females and 2 test females; these included: red-stained face, wet and/or yellow-stained urogenital area, and soft stool. These four animals returned to a normal appearance by Day 3 after treatment. The acute dermal median lethal dose (LD50) of the test material in male and female Crl :CO®(SD)BR rats was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information as a whole meets the tonnage driven data requirements of REACH and all studies are of a reliability score 1.

Additional information

Acute oral

EPA OPP 81-1, Glaza 1995a: The acute oral toxicity of the substance was evaluated in male and female Crl :CD®(SD)BR rats in a GLP study designed to meet the requirements of EPA guideline 81 -1. The substance was administered by gavage as a suspension in MC/T 80 [0.5% methylcellulose (w/v) and 0.1% Tween 80 (v/v)]. There were no deaths or signs of systemic toxicity. There were no other remarkable findings. The acute oral LD50 was estimated to be > 5000 mg/kg bw.

EPA OPP 81-1, Glaza 1995b: The acute oral toxicity of the substance was evaluated in male and female Crl :CD®-l(ICR)BR strain of mouse in a GLP study designed to meet the requirements of EPA guideline 81 -1. The substance was administered by gavage as a suspension in MC/T 80 [0.5% methylcellulose (w/v) and 0.1% Tween 80 (v/v)]. There were no deaths or signs of systemic toxicity. There were no other remarkable findings. The acute oral LD50 was estimated to be > 5000 mg/kg bw.

 

Acute dermal

EPA OPP 81-2, Glaza 1995c: The acute dermal toxicity of the substance was evaluated in male and female Crl:CD (SD) BR rats in a GLP study designed to meet the requirements of EPA guideline 81 -2. The substance was administered as a single, 24-hour, occluded dermal application to intact skin. In 2 male control, 2 female control and 2 female test animals clinical signs observed included a red-stained face, wet and/or yellow-stained urogenital area, and soft stool. There were no other remarkable findings. The acute dermal LD50 was estimated to be > 2000 mg/kg bw.

 

Acute inhalation

EPA OPP 81-3, Bennick 1995: The acute inhalation toxicity of the substance was evaluated in male and female Sprague-Dawley strain of rat in a GLP study designed to meet the requirements of EPA guideline 81 -3. Five males and five females were exposed for four hours in a nose-only inhalation system to an aerosol generated from the undiluted test material (fine powder) at a level of 5.10 mg/L. A negative control using an additional five males and five females was run concurrently. There was no mortality during the study. Clinical signs included piloerection in both sexes of test and control animals, and ptosis in one test male. There was no meaningful effect on body weight gain, and all animals were asymptomatic by Day 3. The gross necropsy revealed no observable abnormalities in any of the animals on test. The acute inhalation LC50 for the test material is greater than 5.10 mg/L.


Justification for selection of acute toxicity – oral endpoint
Robust study summary selected has lowest dose descriptor relevant for this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
Robust study summary selected has lowest dose descriptor relevant for this endpoint.

Justification for selection of acute toxicity – dermal endpoint
Robust study summary selected has lowest dose descriptor relevant for this endpoint.

Justification for classification or non-classification

The substance does not meet classification criteria under EU Directive 67/548/EEC for acute toxicity.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity.

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