Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 Combined = 1670 mg/kg bw  (similar to OECD 401, rats, K, rel.2);

Acute toxicity: dermal: LD50 Combined = 2900 mg/kg bw (similar to OECD 402, rats, K, rel. 2);

Acute toxicity: inhalation: waiver.

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 December 19, 1978 to March 28, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The study was performed prior to the OECD Test Guideline No. 401 but the protocol is similar to that guidance.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
environmental conditions not reported
Principles of method if other than guideline:
Acute gavage administration to rats.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts.
- Weight at study initiation: 135-219 g (range-finding study); 136-202 g (main study).
- Fasting period before study: Prior to dosing all animals were fasted overnight. After dosing, food was withheld for one hour after which it was available ad libitum.
- Housing: Animals were housed individually in suspended stainless steel cages.
- Diet: Purina Rodent Laboratory Chow®#5001, ad libitum
- Water: Water, ad libitum
- Acclimation period: 7 days
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): Based on a specific gravity of 0.8703 appropriate amounts of test material was admixed with corn oil to achieve required dose levels. Dosing solutions were agitated prior to administration to each animal.
Doses:
Main study: 1000, 1470, 2150, 3160, 4640 mg/kg bw
No. of animals per sex per dose:
5 animals/sex/dose

Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for mortality and signs of toxicity at 1, 3, 6 and 24 h after dosing and daily thereafter for 14 days. Individual body weights were recorded prior to dosing and at time of death or sacrifice on Day 14.
- Necropsy of survivors performed: Yes, all surviving animals were sacrificed using T-61®Euthanasia Solution (National Laboratories Corporation, Somerville, N. J.) on Day 14 and necropsies were performed on all animals at the time of death or sacrifice.
Statistics:
Litchfield and Wilcoxon (1949).
Preliminary study:
Not applicable
Sex:
female
Dose descriptor:
LD50
Effect level:
1 500 mg/kg bw
Based on:
test mat.
95% CL:
940 - 2 450
Remarks on result:
other: 1/5, 3/5, 3/5, 5/5 and 5/5 females died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 800 mg/kg bw
Based on:
test mat.
95% CL:
1 200 - 2 700
Remarks on result:
other: 1/5, 1/5, 3/5, 5/5 and 5/5 males died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 670 mg/kg bw
Based on:
test mat.
95% CL:
970 - 2 900
Remarks on result:
other: 2/10, 4/10, 6/10, 10/10 and 10/10 animals died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively.
Mortality:
2/10 (1 male + 1 female), 4/10 (1 male + 3 females), 6/10 (3 males + 3 females), 10/10 (5 females + 5 males) and 10/10 (5 females + 5 males) animals were died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively.
Clinical signs:
Soft, mucoid feces were frequently observed in animals at all dose levels between 1 h and 4 days after dosing. A roughening of the coat was also observed on Days 2 through 4 in two females dosed with 2150 mg/kg bw and on Day 2 in one female dosed with 3160 mg/kg bw. All surviving animals dosed with 1000, 1470 and 2150 mg/kg bw appeared normal by Day 6 after dosing.
Body weight:
An increase in body weight was noted in all animals surviving to Day 14. Conversely, a decrease in body weight was found in all animals dying prior to Day 14.
Gross pathology:
Gross pathology findings were similar in all of the found-dead animals. No gross tissue alterations attributable to treatment were observed in any of the animals. Presence of the compound was observed in the stomach of all of the found dead animals and the cecum was found to be full of fecal matter. Other frequent observations were a wet, fecal stained anal region and a crust on the nose, mouth and or forepaws. Sacrifice of the animals surviving on Day 14 revealed only mottled lungs which are believed to be an artefact of euthanasia with T-61® Euthanasia Solution.
Other findings:
None

Range-finding study:

- Mortality: Two male animals dosed with 1600 mg/kg bw and four animals (2 males + 2 females) dosed with 5000 mg/kg bw died within 3 days after dosing.

- Clinical signs: All animals were observed to have soft feces antemortem. Except for occasional soft feces, no signs of toxicity were observed in animals dosed with 50, 160 or 500 mg/kg bw.

- Gross pathology: Gross pathology revealed the presence of the compound in the stomach of all of the found dead animals and generally the cecum contained soft stool.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the test conditions, the oral LD50(Combined) is 1670 mg/kg bw, therefore the test material is classified to ‘Category 4’ according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute oral toxicity study, groups of CD® Sprague-Dawley outbred albino rats (5/sex/dose) were administered a single oral (gavage) dose of test material diluted in corn oil at 1000, 1470, 2150, 3160 and 4640 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. A range finding study was conducted at the dose levels of 50, 160, 500, 1600 and 5000 mg/kg bw (2/sex/dose) to determine the dose levels for main study.

In the range-finding study, mortality was observed at 1600 and 5000 mg/kg bw in two males and four animals (2 males + 2 females), respectively. In the main study, 2/10 (1 male + 1 female), 4/10 (1 male + 3 females), 6/10 (3 males + 3 females), 10/10 (5 females + 5 males) and 10/10 (5 females + 5 males) animals were died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively. Soft, mucoid feces were frequently observed in animals at all dose levels between 1 h and 4 days after dosing. A roughening of the coat was also observed on Days 2 through 4 in two females dosed with 2150 mg/kg bw and on Day 2 in one female dosed with 3160 mg/kg bw. All surviving animals dosed with 1000, 1470 and 2150 mg/kg bw appeared normal by Day 6 after dosing. An increase in body weight was noted in all animals surviving to Day 14. Conversely, a decrease in body weight was found in all animals dying prior to Day 14. No gross tissue alterations attributable to treatment were observed in any of the animals.

Oral LD50 Combined = 1670 mg/kg bw (95 % confidence limits of 970-2900 mg/kg bw).

Under the test conditions, the test material is classified to ‘Category 4’ according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 670 mg/kg bw
Quality of whole database:
The key study is non-GLP compliant but of high quality (Klimisch score = 2)

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Reason / purpose:
data waiving: supporting information
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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 December 19, 1978 to April 26, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
This study was performed prior to the OECD test guideline No. 402 but the protocol is similar to that guidance.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
environmental conditions not reported
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts.
- Weight at study initiation: 127-222 g (range-finding study); 140-234 g (main study)
- Housing: Animals were housed individually in suspended stainless steel cages.
- Diet: Purina Rodent Laboratory Chow®#5001, ad libitum
- Water: Water, ad libitum
- Acclimation period: 7 days
Type of coverage:
open
Vehicle:
other: alcohol
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal area

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Any excess test material was wiped off with a cloth dampened with water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 6 mL/mg bw
- Constant volume or concentration used: yes
- Based on a specific gravity of 0.8682, appropriate amounts of test material were admixed with 78-058 alcohol (vehicle) to achieve required dose levels.
Duration of exposure:
24 h
Doses:
1670, 2150, 2780, 3600 and 4640 mg/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for mortality and signs of toxicity at 1, 3 and 24 h after dosing and daily thereafter for 14 days. Individual body weights were recorded prior to dosing and at the time of death or sacrifice on Day 14.
- Necropsy of survivors performed: Yes; all surviving animals were sacrificed using T-61® Euthanasia Solution (National Laboratories Corporation, Somerville, N. J.) on Day 14. Necropsies were performed on all animals at the time of death or sacrifice.
Statistics:
Litchfield and Wilcoxon (1949).
Preliminary study:
Not applicable
Sex:
male
Dose descriptor:
LD50
Effect level:
3 600 - 4 640 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 5/5 males died at 4640 mg/kg bw.
Sex:
female
Dose descriptor:
LD50
Effect level:
2 150 - 2 780 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 3/5, 5/5 and 5/5 females died at 2780, 3600 and 4640 mg/kg bw, respectively.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 900 mg/kg bw
Based on:
test mat.
95% CL:
2 164 - 3 886
Remarks on result:
other: 3/10, 5/10 and 10/10 animals died at 2780, 3600 and 4640 mg/kg bw, respectively.
Mortality:
3/10 (0 male + 3 females), 5/10 (0 male + 5 females) and 10/10 (5 males + 5 females) animals died at 2780, 3600 and 4640 mg/kg bw, respectively. No mortality was observed at 1670 or 2150 mg/kg bw.
Clinical signs:
Soft feces, mucous discharge or morbidity were observed ante mortem in animals receiving 2780, 3600 or 4640 mg/kg bw. Animals in all dosed groups were noted to have crusts around the eyes and/or nose between 1 h post-dosing and Day 3. However, this finding was attributed to the animals being collared during the first 24 h. Desquamation was observed between Days 7 and 14 in animals exposed to 1670, 2150, 2780 and 3600 mg/kg bw. The frequency at which this finding was observed increased with dose level. No dermal irritation was observed in animals treated with 4640 mg/kg bw (all died by Day 4) or vehicle control.
Body weight:
- The mean body weight gain was slightly lower in males at 1670, 2150, 2780 and 3600 mg/kg bw and moderately lower in females at 2150 mg/kg bw when compared to vehicle control. Mean body weight gains for the females receiving 1670 and 2780 mg/kg bw were comparable to the controls.
- The change in mean body weight in males at 4640 mg/kg bw and females at 3600 or 4640 mg/kg bw could not be calculated due to the mortalities in these groups.
Gross pathology:
No gross tissue alterations attributable to treatment were observed in any of the animals. Gross pathology findings were similar in all of the found-dead animals. In all but one of these animals the stomach was filled with food or bile and in all but three the cecum was full. Eleven animals were found to have dark lungs, and nine had dark areas on the liver. These signs were attributed to autolysis. Crust around the eyes and/or nose was also frequently observed. However, no dose-related differences were noted in gross pathology and these findings were not believed to be compound related. Sacrifice of the remaining animals on Day 14 revealed only mottled lungs which is considered to be an artifact of T-61® euthanasia.
Other findings:
None

Range-finding study:

No mortality or signs of compound induced toxicity were observed at 0, 50, 160 or 500 mg/kg bw. At 5000 mg/kg bw, mortality was observed in two females (antemortem: hunched appearance in one of these animals) and one male (antemortem: soft feces) on Day 2 and 3 post-dosing, respectively. The surviving male appeared morbid on Day 3 post-dosing. Necropsy of the found dead animals revealed only red or darkened lungs in the male and in one of the females. Crust was observed around the eyes and/or nose of most of the animals 24 h after dosing and is attributed to the animals being collared during this time.

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the test conditions, the dermal LD50(Combined) is 2900 mg/kg bw, therefore the test substance is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and classified in category 5 according to the GHS.
Executive summary:

In an acute dermal toxicity study, groups of CD® Sprague-Dawley outbred albino rats (5/sex/dose) were given single dermal application of test material diluted in alcohol at 1670, 2150, 2780, 3600 and 4640 mg/kg bw at a constant volume of 6 mL/mg bw. Test material was applied topically to the previously shaven dorsal area of the animal and remained in contact for 24 h. A vehicle control group was treated with undiluted alcohol in the same manner. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

Range finding study was conducted at the dose levels of 50, 160, 500, 1600 and 5000 mg/kg bw (2/sex/dose) to determine the dose levels for main study. In the range-finding study, no mortality or signs of compound induced toxicity were observed at 0, 50, 160 or 500 mg/kg bw.

In the main study, no mortality was observed at 1670 or 2150 mg/kg bw. 3/10 (0 male + 3 females), 5/10 (0 male + 5 females) and 10/10 (5 males + 5 females) animals died at 2780, 3600 and 4640 mg/kg bw, respectively. Soft feces, mucous discharge or morbidity were observed ante mortem in animals receiving 2780, 3600 or 4640 mg/kg bw.

No mortality and no dermal irritation was observed in the vehicle control animals.

Desquamation was observed between Days 7 and 14 in animals exposed to 1670, 2150, 2780 and 3600 mg/kg bw. The mean body weight gain was slightly lower in males at 1670, 2150, 2780 and 3600 mg/kg bw and moderately lower in females at 2150 mg/kg bw when compared to vehicle control. Mean body weight gains for the females receiving 1670 and 2780 mg/kg bw were comparable to the controls. No gross tissue alterations attributable to treatment were observed in any of the animals.

Dermal LD50 Combined = 2900 mg/kg bw (95 % confidence limits of 2164-3886 mg/kg bw).

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and classified in category 5 according to the GHS.

This study is acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 900 mg/kg bw
Quality of whole database:
The key study is of good quality (Klimisch score = 2).

Additional information

Acute toxicity: oral

A key study was available (Borriston 1979, Rel.2). This acute oral toxicity study was performed prior to the OECD test guideline No. 401 but the protocol is similar to that guidance. Groups of CD® Sprague-Dawley outbred albino rats (5/sex/dose) were administered a single oral (gavage) dose of test material diluted in corn oil at 1000, 1470, 2150, 3160 and 4640 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. A range finding study was conducted at the dose levels of 50, 160, 500, 1600 and 5000 mg/kg bw (2/sex/dose) to determine the dose levels for main study.

In the range-finding study, mortality was observed at 1600 and 5000 mg/kg bw in two males and four animals (2 males + 2 females), respectively. In the main study, 2/10 (1 male + 1 female), 4/10 (1 male + 3 females), 6/10 (3 males + 3 females), 10/10 (5 females + 5 males) and 10/10 (5 females + 5 males) animals were died at 1000, 1470, 2150, 3160 and 4640 mg/kg bw, respectively. Soft, mucoid feces were frequently observed in animals at all dose levels between 1 h and 4 days after dosing. A roughening of the coat was also observed on Days 2 through 4 in two females dosed with 2150 mg/kg bw and on Day 2 in one female dosed with 3160 mg/kg bw. All surviving animals dosed with 1000, 1470 and 2150 mg/kg bw appeared normal by Day 6 after dosing. An increase in body weight was noted in all animals surviving to Day 14. Conversely, a decrease in body weight was found in all animals dying prior to Day 14. No gross tissue alterations attributable to treatment were observed in any of the animals.

 

Oral LD50 Combined = 1670 mg/kg bw (95 % confidence limits of 970-2900 mg/kg bw).

 

Acute toxicity: dermal

A key study was available (Borriston 1979, Rel.2). This acute dermal toxicity study was performed prior to OECD test guideline No. 402 but the protocol is similar to that guidance. Groups of CD® Sprague-Dawley outbred albino rats (5/sex/dose) were given single dermal application of test material diluted in alcohol at 1670, 2150, 2780, 3600 and 4640 mg/kg bw at a constant volume of 6 mL/mg bw. Test material was applied topically to the previously shaved dorsal area of the animal and remained in contact for 24 h. A vehicle control group was treated with undiluted alcohol in the same manner. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination. A range finding study was conducted at the dose levels of 50, 160, 500, 1600 and 5000 mg/kg bw (2/sex/dose) to determine the dose levels for main study.

In the range-finding study, no mortality or signs of compound induced toxicity were observed at 0, 50, 160 or 500 mg/kg bw. Mortality was observed in one male and two females at 5000 mg/kg bw.

In the main study, no mortality or mortality was observed at 1670 or 2150 mg/kg bw. 3/10 (0 male + 3 females), 5/10 (0 male + 5 females) and 10/10 (5 males + 5 females) animals died at 2780, 3600 and 4640 mg/kg bw, respectively. Soft feces, mucous discharge or morbidity were observed ante mortem in animals receiving 2780, 3600 or 4640 mg/kg bw. No mortality and no dermal irritation was observed in the vehicle control animals. Desquamation was observed between Days 7 and 14 in animals exposed to 1670, 2150, 2780 and 3600 mg/kg bw. The mean body weight gain was slightly lower in males at 1670, 2150, 2780 and 3600 mg/kg bw and moderately lower in females at 2150 mg/kg bw when compared to vehicle control. Mean body weight gains for the females receiving 1670 and 2780 mg/kg bw were comparable to the controls. No gross tissue alterations attributable to treatment were observed in any of the animals.

 

Dermal LD50 Combined = 2900 mg/kg bw (95 % confidence limits of 2164-3886 mg/kg bw).

This result is confirmed by a second study (Biosearch, 1979). The study was performed prior to the OECD test guideline No. 402 but the protocol is similar to that guidance with the following exceptions: occlusive dressing and abraded skin (worst-case condition) were used and only 3 animals per sex were included. However no mortality was observed during this study. LD50 > 2000 mg/kg bw.

Acute toxicity: inhalation

No data available

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

 

Self classification:

Acute toxicity via Oral route:

Based on the available data, the substance is classified in ‘Category 4’ (H302: Harmful if swallowed") according to the Regulation (EC) No. 1272/2008 as the LD50 is between 300 and 2000 mg/kg bw.

 

Acute toxicity via Dermal route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw but classified in Category 5 according to the GHS as the LD50 is between 2000 and 5000 mg/kg bw/day.

 

Acute toxicity (Inhalation):

No data was available.

 

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no significant health effects were observed immediately or delayed after exposure at the guidance value (oral) for a Category 1 classification (C ≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

 

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the Annex VI of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal) for a Category 1 classification (C ≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw ≥ C > 1000 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity studies.

 

Specific target organ toxicity: single exposure (Inhalation):

No data was available.