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Description of key information

Acute toxicity - oral: The calculated oral LD50 for male and female rats was determined to be 1364 mg/kg (1110 -1675 mg/kg). The substance is considered to be classified as acute oral toxicant category 4 according to CLP regulation.

Acute toxicity - inhalation: According to REACH Annex VIII section 8.5, column 2, the acute toxicity via inhalation route is not required as acute dermal and acute dermal toxicity studies are available with the test substance. Furthermore, as the vapour pressure of the substance is determined to be 12 Pa, the substance is considered not volatile.

Acute toxicity - dermal: The calculated dermal LD50 for the test material was determined to be 5700 mg/kg with 95% confidence limits of 4400 to 7300 mg/kg. The substance is considered not to be an acute dermal toxicant.

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:
1983-10-03 to 1983-10-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Although signs of toxicity and effects in organs for individual animals dosed at 1000 mg/kg were missing from the report, the UK c.a. considers that overall an adequate description of the toxic effects was given. Experimental test were run under GLP conditions.
Qualifier:
according to guideline
Guideline:
other: Annex V
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 5601-22-20, Order # J-174
- Physical state: Light yellow liquid
- Lot/bach No.: Order # J-174
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration
- Other: base factor: Specific gravity = 0.952 g/ml; 1 quart supplied on September 26, 1983; the purity of the test article is the responsibility of the sponsor
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York
- Weight at study initiation: 180-360 g (weight variation in animals or between groups did not exceed +/- 20%)
- Fasting period before study: 18 hours
- Housing: Rats housed in groups, according to sex, or individually in stainless steel 1/2" wire mesh cages.
- Diet (e.g. ad libitum): Wayne Lab BloxR, ad libitum
- Water (e.g. ad libitum): Fresh tap water, fit for human consumption, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: None (Liquid substance used undiluted)
Doses:
800, 1000, 1600, and 2000 mg/kg
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed at approximately 1, 2, 4 and 24 hours after dosing and twice daily for 14 days for pharmacotoxic, CNS effects and mortality. On days 7 and 14, body weights were recorded.
- Necropsy of survivors performed: yes
Statistics:
According to the method of Litchfield and Wilcoxon (1949) JPET 96:99-114
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 364 mg/kg bw
95% CL:
1 110 - 1 675
Sex:
male
Dose descriptor:
LD50
Effect level:
1 693 mg/kg bw
95% CL:
1 433 - 1 999
Sex:
female
Dose descriptor:
LD50
Effect level:
1 007 mg/kg bw
95% CL:
830 - 1 222
Mortality:
Mortality by Sex and Dose:
Male: 800 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 1600 mg/kg bw; Number of animals: 5; Number of deaths: 2
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 4

Female: 800 mg/kg bw; Number of animals: 5; Number of deaths: 1
Female: 1000 mg/kg bw; Number of animals: 5; Number of deaths: 2
Female: 1600 mg/kg bw; Number of animals: 5; Number of deaths: 5
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 4

One out of ten died at the 800 mg/kg level, two out of ten died at the 1000 mg/kg level, seven out of ten died at 1600 mg/kg and eight out of ten died at 2000 mg/kg.
Clinical signs:
Signs of toxicity related to dose levels:
At 1600 mg/kg and 2000 mg/kg, all deaths occurred within 24 hours of dosing apart from one top dose female which died between 72 and 96 hours post exposure. At these doses, toxic signs were primarily decreased activity, piloerection, abnormal stance or gait and in one or two animals red exudate from the nasal area were observed 1-2 hours after exposure. Chromodacryorrhea was noted for one male animal 2-6 days post-exposure at both 1600 mg/kg and 2000 mg/kg. Cyanosis, reduced muscle tone, body drop and hypersensitivity to touch were also noted. Signs of toxicity, apart from deaths, specifically for the 1000 mg/kg dose group were missing from the report. At 800 mg/kg the one female death occurred 24-48 hours post-dosing and toxic signs were confined to decreased activity, piloerection, reduced muscle tone and dyspnea in 20-40% of animals, 24-96 hours post-exposure. Other signs observed include salivation, diarrhea, chromaturia, ptosis, tremors, poor groming and semi-prostration.
Body weight:
No data
Gross pathology:
Effects on organs:
Necropsy of decedents dosed at 1600 and 2000 mg/kg generally showed distended stomachs and intestines with stomach haemorrhages. Discoloured or haemorrhagic intestines were noted in 2/7 and 1/8 decedents at 1600 and 2000 mg/kg respectively and two top dose decedents showed darkened adrenals. Effects in organs specifically for the 1000 mg/kg dose group were missing from the report. No macroscopic effects on organs were observed in surviving animals.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The calculated oral LD50 for male and female rats was determined to be 1364 mg/kg (1110-1675 mg/kg). The calculated oral LD50 for male rats was determined to be 1693 mg/kg (1433-1999 mg/kg). The calculated oral LD50 for female rats was determined to be 1007 mg/kg (830-1222 mg/kg). The substance is considered to be classified as acute oral toxicant category 4 according to the criteria laid down in the CLP Regulation (EC) 1272/2008.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 364 mg/kg bw
Quality of whole database:
Although signs of toxicity and effects in organs for individual animals dosed at 1000 mg/kg were missing from the report, the UK c.a. considers that overall an adequate description of the toxic effects was given. Experimental test were run under GLP conditions.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Clinical signs:
other:
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:
1983-10-05 to 1983-11-01
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well documented scientifically sound acute dermal study similar to OECD guidelines and following GLP. The skin of one male and one female from each dose group was abraded prior to treatment.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Skin of 1 male and 1 female in each group was abraded
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 5601-22-20
- Physical state: Light yellow liquid
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration
- Other: Base factor: Specific gravity = 0.952 g/ml; 1 quart supplied on September 26, 1983; the purity of the test article was the responsibility of the sponsor
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Sgarlat's Rabbitry, Harvey's Lake, PA and Perfection Breeders, Douglassville, PA
- Weight at study initiation: 2 - 3 kg
- Housing: Animals were housed individually in cages sized in accordance with the "Guide for the Care and Use of Laboratory Animals" of the Institute of Laboratory Resources, National Research Council.
- Diet: Wayne Rabbit RationR, ad libitum
- Water: Fresh tap water, suitable for human consumption, ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/-3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: No less than 20% of the dorsal body surface area
- Type of wrap if used: A layer of gauze covering the dosed area; animals were then wrapped with rubber dam and an ace bandage to retard evaporation.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: 24 hours
Duration of exposure:
24 h
Doses:
4000, 5000, 6300, 8000 mg/kg
No. of animals per sex per dose:
2 per sex per dose (16 in total), the skin of one male and one female from each dose group was abraded prior to test substance application.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 30 minutes, 2 and 4 hours after the 24 hour exposure period, and twice daily thereafter for 14 days.
- Necropsy of survivors performed: yes
Statistics:
By the method of Litchfield and Wilcoxon (1949) JPET 96:99-114
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 700 mg/kg bw
95% CL:
4 400 - 7 300
Mortality:
Male: 4000 mg/kg bw; Number of animals: 2; Number of deaths: 0
Male: 5000 mg/kg bw; Number of animals: 2; Number of deaths: 1
Male: 6300 mg/kg bw; Number of animals: 2; Number of deaths: 2
Male: 8000 mg/kg bw; Number of animals: 2; Number of deaths: 1
Female: 4000 mg/kg bw; Number of animals: 2; Number of deaths: 0
Female: 5000 mg/kg bw; Number of animals: 2; Number of deaths: 1
Female: 6300 mg/kg bw; Number of animals: 2; Number of deaths: 1
Female: 8000 mg/kg bw; Number of animals: 2; Number of deaths: 2
Clinical signs:
None of the rabbits died at 4 g/kg, two of four rabbits died at 5 g/kg and three of four died at 6.3 and 8 g/kg. Signs observed included necrosis, severe to moderate erythema and edema of the application sites and surrounding areas, decreased activity, abnormal gait, and abnormal stance. Decreased body tone, body drop, ataxia, ptosis, cyanosis, prostration, tremors and diarrhea were also observed.
Gross pathology:
Necropsy of animals dying on study revealed pale livers with necrotic areas on all lobes. Pale kidneys and hemorrhages of the muscle layers underlying the application sites were also observed.
Terminal necropsy revealed hemorrhages of the muscle layers under the application sites.

No notation regarding effects of abrasion were noted.

Interpretation of results:
GHS criteria not met
Conclusions:
The calculated LD50 for the test material was determined to be 5700 mg/kg with 95% confidence limits of 4400 to 7300 mg/kg. The substance is considered not classified as acute dermal toxicant.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
5 700 mg/kg bw
Quality of whole database:
Well documented scientifically sound acute dermal study similar to OECD guidelines and following GLP. The skin of one male and one female from each dose group was abraded prior to treatment.

Additional information

Acute toxicity - oral:

In a dose range finding study, four fasted animals per dose level, two per sex, were administered the test substance at 1000, 3000, 5000, and 8000 mg/kg, orally by gavage. Signs observed were decreased activity, cyanosis, piloerection, decreased body tone, poor grooming, hypersensitivity, prostration, abnormal stance, arched back, and abnormal gait. None of the rats died at 1000 mg/kg. All of the rats died at 3000, 5000, and 8000 mg/kg dose levels.

In the key acute oral toxicity study, the substance was administered via oral gavage in dose levels 800, 1000, 1600 and 2000 mg/kg in 5 male and 5 female animals per group (Mallory et al., 1983a). The following deaths were observed: at 800 mg/kg 1 out of 10 animals, at 1000 mg/kg 2 out of 10 animals, at 1600 mg/kg 7 out of 10 animals, and at 2000 mg/kg 8 out of 10 animals. Clinical signs were observed at all dose levels. The calculated oral LD50 for male and female rats was determined to be 1364 mg/kg (1110-1675 mg/kg). The calculated oral LD50 for male rats was determined to be 1693 mg/kg (1433-1999 mg/kg). The calculated oral LD50 for female rats was determined to be 1007 mg/kg (830-1222 mg/kg).

Acute toxicity - dermal:

In an acute dermal dose-range finding study, 16 rabbits, eight unabraded and eight abraded rabbits (one male and one female per group) were dermally administered the test substance at 1.6, 3.2, 5.0 and 8.0 g/kg. Signs observed included severe erythema and edema of the application sites and surrounding areas, necrosis, decreased activity, abnormal stance, abnormal gait, decreased body tone, prostration and cyanosis. None of the rabbits died at 1.6, 3.2, or 5.0 g/kg dose levels. Two of two rabbits died at the 8.0 g/kg dose level.

In the key acute dermal toxicity study, performed similar to OECD guideline 402 and following GLP requirements, the test substance was administered dermally (24 hours) to 2 male and 2 female animals per group at dose levels 4000, 5000, 6300 and 8000 mg/kg (Mallory et al., 1983b). The following deaths were observed: at 4000 mg/kg 0 out of 4 animals, at 5000 mg/kg 2 out of 4 animals, at 6300 mg/kg 3 out of 4 animals and at 8000 mg/kg 3 out of 4 animals. Signs observed included necrosis, severe to moderate erythema and edema of the application sites and surrounding areas, decreased activity, abnormal gait, and abnormal stance. Decreased body tone, body drop, ataxia, ptosis, cyanosis, prostration, tremors and diarrhea were also observed. The calculated LD50 for the test material was determined to be 5700 mg/kg with 95% confidence limits of 4400 to 7300 mg/kg.

Acute toxicity - inhalation:

According to REACH Annex VIII section 8.5, column 2, the acute toxicity via inhalation route is not required as acute oral and acute dermal toxicity studies are available with the test substance. Furthermore, as the vapour pressure of the substance is determined to be 12 Pa, the substance is considered not volatile.

Justification for classification or non-classification

Based on the available studies, the test substance should be classified for acute oral toxicity as category 4 (H302) according to EU Regulation 1272/2008.

The substance is considered not to be classified as acute dermal toxicant.

There is no data available to decide on the classification for acute inhalation toxicity.