[No public or meaningful name is available]

Endpoint summary

Description of key information

Oral:

The acute oral study is performed according to OECD Guideline 425 under GLP. The oral LD50 of the test item when administered to female rats is estimated to be 310.2 mg/kg.

 

Dermal:

The acute dermal study is performed according to OECD Guideline 402 under GLP. The dermal LD50 of the test item was greater than 2000 mg/kg in male and female rats.

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:

From July 14, 2008 to August 29, 2008

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Specific details on test material used for the study:

Test material name in the study: PF-03394197-11

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat (if applicable)
- Source: Charles River Laboratories, Portage, Michigan
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Rationale for use of males (if applicable)
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Female: 184 to 273 g
- Fasting period before study: overnight
- Housing: Individually in stainless steel suspended wire mesh caging
- Historical data:
- Diet (e.g. ad libitum): Block Lab Diet® Certified Rodent Diet #5002, PMI Nutrition International, Inc. Ad libitum, except during designated periods.
- Water (e.g. ad libitum): Automatic watering system, Ad libitum, except during designated periods.
- Acclimation period: 7 to 32 Days
- Microbiological status when known
- Method of randomisation in assigning animals to test and control groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 to 26.1°C
- Humidity (%): 30 to 70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for approximately 12 hours per day.

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual):
The test article, was used as received from the Sponsor, and a correction
factor of 1.344 was applied to correct for the ratio of molecular weight of the salt to the base
of the test article. Dose preparation was performed by mixing the appropriate amount of test
article, with the appropriate amount of vehicle, to achieve the required nominal concentrations for the limit test, 200 mg/mL, and main tests, 17.5 and 55 mg/mL.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: limit dose level of 2000 mg/kg

Doses:

2000, 175, 550, 175, 550, 175, and 550 mg/kg

No. of animals per sex per dose:

1 or 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for morbidity, mortality, injury, and the availability of food and water were conducted twice daily for all animals. Observations for clinical signs were conducted on each surviving animal at 0.5, 2, and 4 hours postdose on the day of dosing, and were continued once daily for no longer than 13 additional days, dependant on survival. Body weights were measured and recorded prior to test article administration on Day 1, and weekly thereafter. Additional body weights were taken for two animals found dead prior to submission to necropsy at dose levels of 2000 mg/kg and 550 mg/kg.
- Necropsy of survivors performed: Necropsy examinations were performed under procedures approved by a veterinary pathologist on all animals found dead, and all surviving animals at the scheduled necropsy. The surviving animals were euthanized by carbon dioxide inhalation, and euthanasia was confirmed by exsanguination via the abdominal vena cava. The animals were examined carefully for external abnormalities including masses. The skin was reflected from a ventral midline incision, and any abnormalities were identified and correlated with antemortem
findings. The abdominal, thoracic, and cranial cavities were examined for abnormalities, and the organs removed, examined, and the tissues and carcasses were discarded.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

310.2 mg/kg bw

Based on:

test mat.

Mortality:

All animals died on Day 2 at 2000 and 550 mg/kg dose level.

Clinical signs:

Impaired limb function, decreased activity, ataxia, slow and difficult breathing, salivation, lacrimation, and partially closed eyelids were observed following the limit dose of 2000 mg/kg, and prior to the animal being found dead. Impaired limb function, decreased activity, ataxia, slow and difficult breathing, prostration, hunched posture, salivation, skin cold to touch, red material around nose, lacrimation, and partially closed eyelids, and decreased feces were all observed in at least one of the three animals dosed at 550 mg/kg. Clinical findings observed following the administration at 550 and 2000 mg/kg were considered to be related to test article administration.

Body weight:

No effect of test article administration was observed on the body weights or body weight gains of the three animals at 175 mg/kg that survived to the scheduled necropsy on Day 15.

Gross pathology:

No test article-related macroscopic observations were made in study animals. Macroscopic observations were usual and/or incidental in rats of this type and age.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 of the test item when administered to female rats is estimated to be 310.2 mg/kg.

Executive summary:

The acute oral study is performed according to OECD Guideline 425 under GLP. The oral LD50 of the test item when administered to female rats is estimated to be 310.2 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

310.2 mg/kg bw

Quality of whole database:

reliable without restrictions

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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:

From July 18, 2008 to August 20, 2008

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

Test material name in the study: PF-03394197-11
Lot Number: PF-01/115802/138A

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat (if applicable)
- Source: Charles River, Portage, Michigan
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Rationale for use of males (if applicable)
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Male: 220 to 225 g Female: 167 to 176 g
- Fasting period before study:
- Housing: Individual, stainless steel suspended wire mesh-type cages
- Historical data:
- Diet (e.g. ad libitum): Block Lab Diet® Certified Rodent Diet #5002, PMI Nutrition International, Inc. Ad libitum.
- Water (e.g. ad libitum): Automatic watering system, Ad libitum.
- Acclimation period: 7 days
- Microbiological status when known
- Method of randomisation in assigning animals to test and control groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (±3) °C
- Humidity (%): 30 to 70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for approximately 12 hours per day. The dark cycle was interrupted intermittently due to study-related activities.

Type of coverage:

occlusive

Vehicle:

other: Mineral oil

Details on dermal exposure:

TEST SITE
- Area of exposure: back of each animal
- % coverage: no less than 10% of the body surface area
- Type of wrap if used: the area was wrapped with gauze and secured with a non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the wrappings were removed and the residual test article was removed using tepid tap 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 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The test animals were observed for clinical signs approximately 0.5, 2, and 4 hours after dosing on Day 1. Thereafter, the animals were observed for clinical signs once daily for 14 days. Observations included, but were not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, respiratory and circulatory effects, autonomic effects such as salivation, nervous system effects including tremors, convulsions, reactivity to handling, and bizarre behavior. Individual body weights were obtained on the day of arrival, just prior to test article administration (Day 1) and
weekly thereafter.
- Necropsy of survivors performed: Complete necropsy examinations were performed under procedures approved by a veterinary pathologist on all animals euthanized at scheduled necropsies. Euthanasia was by carbon dioxide inhalation followed by exsanguination from the abdominal vena cava. The animals were examined carefully for external abnormalities including palpable masses. The skin was reflected from a ventral midline incision, and any subcutaneous masses were identified and correlated with antemortem findings. The abdominal, thoracic, and cranial cavities were examined for abnormalities, and the organs were removed, examined, and the tissues and carcasses were discarded.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived to the scheduled necropsy on Day 15.

Clinical signs:

There were no treatment-related clinical findings. There were clinical findings that may have
been due to the wrapping and the use of Elizabethan collars that included red or brown
material around the eyes and nose and brown skin discoloration of the thoracic region and
sparseness of hair in the abdominal region which were observed very occasionally.

Body weight:

There were no treatment-related changes in body weight gains. The body weight gain of one
female animal (number 3006) was slightly lower than expected; however the body weight
gains of the remaining animals over the two week study period were considered normal.

Gross pathology:

No test article-related macroscopic observations were made in male or female rats.

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 of the test item was greater than 2000 mg/kg in male and female rats.

Executive summary:

The acute dermal study is performed according to OECD Guideline 402 under GLP. The dermal LD50 of the test item was greater than 2000 mg/kg in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

reliable without restrictions

Justification for classification or non-classification

Acute toxicity:
Oral, OECD 425: LD50 is 310.2 mg/kg body weight;

Dermal, OECD 402: LD50 > 2000 mg/kg body weight.
Therefore in accordance with Regulation (EC) No. 1272/2008 (amended by 286/2011) Table 3.1.1 , this substance should be classified for Acute oral Cat 4 and not classified for Acute dermal toxicity.

Specific target organ toxicity-single exposure:
No abnormalities were noted at necropsy in both acute oral and dermal studies.
As there were no effects considered to support classification for Category 1 and 2 observed. Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.8.1 and 3.8.2, this substance should not be classified.