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Description of key information

Acute Oral Toxicity: The LD50 is greater than 5000 mg/kg.
Acute Dermal Toxicity: The LD50 is greater than 2000 mg/kg.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Animals were received from Ace Animals, Boyertown, PA.
- Age at study initiation: Approximately four to twelve weeks.
- Weight at study initiation: 220 - 299 grams for male and 224 - 268 grams for females.
- Fasting period before study: 16-20 hours prior to dosing.
- Housing: The animals were housed 5/sex/cage in suspended wire cages.
- Diet (e.g. ad libitum): Fresh Purina Rat Chow was freely avaiable (except during fasting period).
- Water (e.g. ad libitum): Water was freely available at all times.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The animal room was temperatue controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle.

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE:
Corn oil

DOSAGE PREPARATION:
The test article was ground with a mortar and pestle. 15 g was mixed with corn oil to a total volume of 30 ml and dosed from a stir plate. The dose was based on the dry weight of the test article. A single dose was administered orally by syringe and dosing needle.

Doses:
5000 mg/kg bw and 2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 1, 2 and 4 hours post dose and once daily for 14 days for toxicity and pharmacological effects.
The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, on days 3 and 7, at death or at termination in the survivors.
- Necropsy of survivors performed: yes, all animals were examined for gross pathology.
Statistics:
An estimate of the LD50 was made based on the results.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
One male rat from the high dose group (5000 mg/kg) died on day 3 and one from the 2000 mg/kg dose group died on day 2.
Clinical signs:
5000 mg/kg: One male died on day 3 with predeath physical signs of diarrhea, chromodacryorrhea, soiling of the anogenital area, piloerection,
lethargy, flaccid muscle tone, brown staining of the nose/mouth area and wetness of the anogenital area.
Physical signs noted in survivors included diarrhea, soiling of the anogenital area, lethargy, bloated abdomen, piloerection, wetness of body areas, brown staining of the nose/mouth area and localized alopecia.

2000 mg/kg: One male died on day 2 with predeath physical signs of lethargy, dyspnea and soiling of the anogenital area.
Physical signs of diarrhea, soiling of the anogenital area, lethargy, brown staining of the nose/mouth area and wetness of the anogenital area were noted in survivors.
Body weight:
Body weight changes were normal in 7/9 surviving animals in the 5000 mg/kg group. Two males lost weight by day 3 but gained normally by day 7.
Body weight changes were normal in 8/9 survivors dosed at 2000 mg/kg. One female lost weight during the second week of the observation period.
Gross pathology:
Necropsy of the animal that died at the 5000 mg/kg level revealed abnormalities of the thymus, lungs, liver, kidneys, spleen and gastrointestinal tract, as well as soiling and wetness of the anogenital area. Necropsy results of survivors were normal in 2/9 animals dosed at 5000 mg/kg.
Localized alopecia was noted in the remaining seven animals.
All animals dosed at 2000 mg/kg appeared normal at necropsy.
No necropsy was performed on the animal that died at the 2000 mg/kg level since it was cannibalized.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 is greater than 5000 mg/kg.
Executive summary:

Objective:

To determine the potential for toxicity of the test article when administered orally to rats. This study was designed to comply with the standards set forth by:

EC Official Joumal of the European Communities. L 383 A Part B, Method B.l. Acute Oral Toxicity 12/29/92.

OECD Guidelines for Testing of Chemicals, No. 401, Acute Oral Toxicity, adopted 2/24/87.

Method:

Five healthy male and five healthy female Wistar albino rats were dosed orally with the test substance at 5000 mg/kg of body weight. Since test article related mortality occurred at this level, an additional group of five male and five females were dosed at 2000 mg/kg of body weight. The rats were observed 1,2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for mortality. Body weights were recorded immediately pretest, on days 3 and 7, at death or at tennination in the survivors. All animals were examined for gross pathology.

Results:

5000 mg/kg: Nine of ten animals survived the 5000 mg/kg oral dose. One male died on day 3 with predeath physical signs of diarrhea, chromodacryonliea, soiling of the anogenital area, piloerection, lethargy, flaccid muscle tone, brown staining of the nose/mouth area and wetness of the anogenital area. Necropsy revealed abnonnalities of the thymus, lungs, liver, kidneys, spleen and gastrointestinal tract, as well as soiling and wetness of the anogenital area. Physical signs noted in survivors included diarrhea, soiling of the anogenital area, lethargy, bloated abdomen, piloerection, wetness of body areas, brown staining of the nose/mouth area and localized alopecia. Body weight changes were nonnal in 7/9 survivors. Two males lost weight by day 3 but gained normally by day 7. Necropsy results of survivors were normal in 2/9 animals. Localized alopecia was noted in 7/9 animals.

2000 mg/kg: Nine of ten animals survived the 2000 mg/kg oral dose. One male died on day 2 with predeath physical signs of lethargy, dyspnea and soiling of the anogenital area. A necropsy was not performed since the animal was cannibalized. Physical signs of diarrhea, soiling of the anogenital area, lethargy, brown staining of the nose/mouth area and wetness of the anogenital area were noted in survivors. Body weight changes were normal in 8/9 survivors. One female lost weight during the second week of the observation period. Necropsy results of survivors were normal.

Conclusion:

The LD50 is greater than 5000 mg/kg.

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

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:
Experimental start date (1st exposure to test substance): 2nd March 1998. Experimental termination date (last date data collected): 16th March 1998.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
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 OTS 798.1100 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Animals were received from Ace Animals, Boyertown, PA.
- Age at study initiation: Approx 8 to 12 weeks.
- Weight at study initiation: Pretest body weight range was 2.1-2.7 kg for males and 2.0-2.4 kg for females.
- Fasting period before study: None, food was provided daily.
- Housing: Animals were housed 1 per cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times per week.
- Diet (e.g. ad libitum): Fresh Purina Rabbit Chow was provided daily.
- Water (e.g. ad libitum): Water was freely available at all times.
- Acclimation period: At least one week.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Animal room was temperature controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle.

IN-LIFE DATES: From: Day 1 To: Day 14
Type of coverage:
semiocclusive
Vehicle:
other: test artilcel moistened with 1.5 ml of saline.
Details on dermal exposure:
TEST SITE
- Area of exposure: Approximately 24 hours prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair.
- % coverage: The prepared site was approximately 10% of the body surface.
- Type of wrap if used: The test article was applied under a 4 layered surgical gauze patch approximately 10 x 15 cm. The patch and test article were moistened with 1.5 ml of saline to enhance contact of the test article with the dose site. Gentle pressure was applied to the gauze to aid in the
distribution of the test substance over the prepared site. The torso was wrapped with plastic which was secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test article was gently wiped from the treated site prior to dermal observations.
- Time after start of exposure: The test article remained in contact with the skin for 24 hours at which time the wrappings were removed.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): A single dose of the test article was applied to the prepared site at a dose level of 2000 mg/kg.


VEHICLE
The test article was moistened with 1.5 ml of saline to enhance contact of the test article with the dose site.
Duration of exposure:
24 hour contact period.
Doses:
Single dose level of 2000 mg/kg (dose was based on dry weight).
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 animals were observed 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects. The animals were observed twice daily for 14 days for mortality.
Body weights were recorded pretest and on days 3, 7 and 14 or at death.
- Necropsy of survivors performed: yes, all animals were examined for gross pathology.
- Other examinations performed:
The test sites were scored for dermal initation at 30 to 60 minutes post patch removal and again at 24, 48 and 72 hours post patch removal and on days 5, 7, 10 and 14 using the numerical Draize scoring code. The skin was also evaluated for ulceration and necrosis or any evidence of tissue
destruction. Additional signs were described. When there were no further positive scores noted in an animal scoring was discontinued in that animal.

An estimate of the LD50 was made based on the survival of animals during the study.
Preliminary study:
No preliminary study conducted.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities. All animals survived the 2000 mg/kg dermal application.
Clinical signs:
Dermal Observations ( Table 1 in attached background material):
Dermal reactions were absent to well defined on day 1, absent to slight on day 2, absent to well defined on day 3, absent to moderate on days 4 and 5, and absent to well defined on day 7. By days 10 and 14, dermal reactions were absent to slight.

Systemic Observations (Table 2 in attached background material):
There were no abnormal systemic signs noted during the observation period.
Body weight:
Body weight (Table 1 in attached background material):
Body weight changes were normal in 8/10 animals. One male and one female lost weight at some time during the observation period.
Gross pathology:
Necropsy findings (Table 3 in attached background material):
Necropsy results were normal in 7/10 animals. Kidney abnormalities were noted in two males and treated skin abnormalities in one female.

Please refer to attached background material for Tables 1 -3:

Table 1: Body weights, dose volume in grams and dermal observations

Table 2: Systemic observations

Table 3:Necropsy observations

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 is greater than 2000 mg/kg of body weight.
Executive summary:

Objective:

To determine the potential for toxicity of the test article when applied dermally. This study was designed to comply with the standards set forth by EPA Acute Dermal Toxicity 40 CFR 798.1100 and EC Official Journal of the European Communities, L 383 A, Part B, Method B.3. Acute Dermal Toxicity, 12/29/92 and OECD Guidelines for Testing of Chemicals, No. 402, Acute Dermal Toxicity,

adopted 2/24/1987.

Method:

Five healthy male and five healthy female New Zealand White rabbits were dosed dermally with the test substance at 2000 mg/kg of body weight. The test article was kept in contact with the skin for 24 hours. Dermal responses were recorded at 30 - 60 minutes and at 24, 48 and 72 hours post patch removal and again on days 5, 7, 10 and 14. Animals were observed for toxicity and pharmacological effects at 1, 2 and 4 hours post dose and once daily for 14 days. All animals were observed twice a day for mortality. Body weights were recorded pretest, and on days 3, 7 and 14 or at death. All animals were examined for gross pathology.

Summary:

All animals survived the 2000 mg/kg dermal application.

There were no abnormal systemic signs noted during the observation period.

Dermal reactions were absent to well defined on day 1, absent to slight on day 2, absent to well defined on day 3, absent to moderate on days 4 and 5, and absent to well defined on day 7. By days 10 and 14, dermal reactions were absent to slight.

Body weight changes were normal in 8/10 animals. One male and one female lost weight at some time during the observation period.

Necropsy results were normal in 7/10 animals. Kidney abnormalities were noted in two males and treated skin abnormalities in one female.

Conclusion:

The LD50 is greater than 2000 mg/kg of body weight.

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

Additional information

Acute Oral Toxicity:

5000 mg/kg:

Nine of ten animals survived the 5000 mg/kg oral dose. One male died on day 3 with predeath physical signs of diarrhea, chromodacryorrhea, soiling of the anogenital area, piloerection, lethargy, flaccid muscle tone, brown staining of the nose/mouth area and wetness of the anogenital area. Necropsy revealed abnormalities of the thymus, lungs, liver, kidneys, spleen and gastrointestinal tract, as well as soiling and wetness of the anogenital area. Physical signs noted in survivors included diarrhea, soiling of the anogenital area, lethargy, bloated abdomen, piloerection, wetness of body areas, brown staining of the nose/mouth area and localized alopecia. Body weight changes were normal in 7/9 survivors. Two males lost weight by day 3 but gained normally by day 7. Necropsy results of survivors were normal in 2/9 animals. Localized alopecia was noted in 7/9 animals.

2000 mg/kg:

Nine of ten animals survived the 2000 mg/kg oral dose. One male died on day 2 with predeath physical signs of lethargy, dyspnea and soiling of the anogenital area. A necropsy was not performed since the animal was cannibalized. Physical signs of diarrhea, soiling of the anogenital area, lethargy, brown staining of the nose/mouth area and wetness of the anogenital area were noted in survivors. Body weight changes were normal in 8/9 survivors. One female lost weight during the second week of the observation period. Necropsy results of survivors were normal.

Acute Dermal Toxicity:

All animals survived the 2000 mg/kg dermal application.

There were no abnormal systemic signs noted during the observation period.

Dermal reactions were absent to well defined on day 1, absent to slight on day 2, absent to well defined on day 3, absent to moderate on days 4 and 5, and absent to well defined on day 7. By days 10 and 14, dermal reactions were absent to slight.

Body weight changes were normal in 8/10 animals. One male and one female lost weight at some time during the observation period.

Necropsy results were normal in 7/10 animals. Kidney abnormalities were noted in two males and treated skin abnormalities in one female.

Acute Inhalation Toxicity:

Inhalation is not considered an appropriate route of exposure and a study has therefore not been conducted.

Justification for classification or non-classification

The substance does not meet the criteria for classification for the oral and dermal routes based on the LD50 results of >5000 mg/kg bw and >2000 mg/kg bw respectively.