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Administrative data

Description of key information

The oral toxicity of the test item is > 2000 mg/kg/bw since 3 out of 10 animals died at this dose level (SafePharm, 1992).

As the test item is considered to be corrosive to skin (Skin Corr. 1C) a dermal LD50 study according to a current guideline has not been performed.

As part of a 14-day repeated dermal study rats were exposed to the test item at 1000 mg/kg/bw 6 hours per day for 4 days.

No animal died but this dosage level was terminated for humane reasons due to the severity of the skin effects.

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:
1992-01-07 to 1992-02-25
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
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 (UK) Limited,
- Strain:Sprague-Dawley Cr1:CD (SD)
- Sex. male and female
- Age: approximately five to eight weeks old
- Weight at study initiation: Males:126 - 148 g, females:120 - 142 g
- Housing:group-housed, up to 5 animals of the same sex and dose group/cage
- Diet: Rat and Mouse Expanded Diet No. 1, Special Diet, Services Limited, Witham, Essex, U.K.)K,
ad libitum, with the exception of an overnight fast immediately before dosing and for approximately two hours after dosing,
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 22 °C
- Humidity (%): 52 - 63 %
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours daily
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
For the purpose of the study the test material was used as supplied. The specific gravit was determined by Safepharm Laboratories Limited and used to calculate the appropriate dose volumes for the required dose levels.

ADMINISTRATION:
- Doses: 1333, 2000, and 3000 mg/kg bw
- Doses per time period: single dose by gavage
- Volume administered or concentration: 1.38-3.10 ml/kg bw
Doses:
1333, 2000, and 3000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Post dose observation period: 14 days

EXAMINATIONS:
- clinical signs and mortality: 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days
- body weight: day 0, 7 and 14 (or at death)
- macroscopy
Statistics:
STATISTICAL METHOD: - Thompson, 1947
Preliminary study:
see table above
Animals treated with 2000 mg/kg were found dead one day after dosing. Common signs of systemic toxicity noted were hunched posture, lethargy and ptosis with additional signs of decreased
respiratory rate.
Based on this information, dose levels of 1333, 2000 and 3000 mg/kg bodyweight were selected for the main study.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 169 mg/kg bw
Based on:
test mat.
95% CL:
> 1 916 - < 2 455
Mortality:
- Number of deaths at each dose (time of death): at 1333, 2000 and 3000 mg/kg: 0, 1 male (day 4)/2 females (day 1), 10 (day 1)
Clinical signs:
- At 1333 mg/kg hunched posture;
- at 2000 mg/kg lethargy and/or hunched posture and decreased respiratory rate and labored breathing in the male that died. All animals were recovered by day 3;
- at 3000 mg/kg lethargy, comatosis, ptosis, ataxia, and hunched posture, decreased respiratory rate and red/brown stains around the snout in one male
Body weight:
- body weight decreased in animals that died and at 2000 mg/kg
Gross pathology:
NECROPSY FINDINGS:
- At 1333 mg/kg large amounts of white foci scattered over nog-glandular epithelium of stomach;
- At 2000 mg/kg (in animals that died) and 3000 mg/kg hemorrhagic and red stained lungs, dark or patchy pallored liver, dark colored kidneys, hemorrhagic gastrous mucosa and non-glandular stomach epithelium, gaseous distension or severe hemorrhage of small and large intestine; surviving animals at 2000 mg/kg displayed foci on stomach epithelium.
Other findings:
no other findings

LD50:
Combined sexes 2169 (1916-2455) mg/kg bw
Males: 2259 (1920-2656) mg/kg bw
Females: 2083 (1707-2540) mg/kg bw

Conclusions:
The oral LD50 for test item in rats was 2169 mg/kg body weight. Test item is practically non-toxic following a single oral exposure.
Executive summary:

The study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley strain rat. The method used followed the recommendations of the OECD Guidelines for Testing of Chemicals (1987) No. 401 "Acute Oral Toxicity" referenced as Method B1 i n Commission Directive 84/449/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 83/467/EEC).

The test system was chosen because the rat has been shown to be a suitable model for this type of study and is recommended in the test method. The results of the study are believed to be of value in predicting the likely toxicity of the test material to man.

 

Groups of ten Sprague-Dawley rats (five male and five female) were orally administered undiluted test item at dose levels of 1333, 2000 and 3000 mg/kg body weight. 

Surviving animals were observed daily post-dose for 14 days. 

All animals in the low dose group survived. Three out of ten animals in the mid-dose group died. All animals in the high-dose group died. 

All surviving animals appeared normal within three days or less of dosing, gained weight, and the only findings seen at necropsy in the survivors were abnormalities of the non-glandular stomach epithelium. 

Since this material is corrosive, the stomach findings were not unusual. 

The oral LD50 for test item in rats was 2169 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 169 mg/kg bw
Quality of whole database:
The study is a guideline study with Klimisch score 1 (reliable without restriction).

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 the substance is classified as corrosive to the skin
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:
1983-09-22 to 1983-10-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
14-day repeat dermal test
GLP compliance:
yes
Test type:
other: 14-day repeat dermal test
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain:Sprague-Dawley
- Sex. male
- Age: adult
- Weight at study initiation: Males: 400 - 450 g
- Housing: single
- Diet: ad libitum, Rat and Mouse Expanded Diet No. 1, Special Diet, Services Limited, Witham, Essex, U.K.)K,
- Water (e.g. ad libitum): tap water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3 °C
- Humidity (%): 50 - 80 %
- Photoperiod (hrs dark / hrs light): 12 hours daily
Type of coverage:
semiocclusive
Details on dermal exposure:
- The hair was shaved from the back and flanks of all animals approximately 24 hr before first treatment.
- Each day for 14 days each animal was subject to the following procedure.
Animal weighed and weight recorded.
Animals condition and behaviour observed.
The appropriate volume of test-article was dispensed onto a predetermined quarter of the shaved area.
Care was taken to avoid application of test-article to skin which had visible damage from a previous treatment.
Control animals received no treatment.
The treated area was covered with a gauze patch, held in place by non-irritant adhesive tape
After 6 hr the rat was released from the restraining cage and the dressings removed.
The treated area was washed gently with tap-water to remove any remaining test-article.
Duration of exposure:
6 hours
Doses:
4
No. of animals per sex per dose:
8
Control animals:
yes
Details on study design:
The rat was observed and any abnormalities of behaviour or condition not noted at the morning examination were recorded.

Assessment of degree of irritation
The degree of irritation present in the treated skin was scored numerically
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
> 1 mL/kg bw
Based on:
test mat.
Remarks on result:
other: No animals died but skin effects were so severe that treatment was stopped after 4 days. More prolonged treatment with test item was not possible.
Mortality:
No deaths occurred during the study.
Clinical signs:
There were no visible signs of systemic toxicity during the study
At a dose of 1.0 ml/kg/day the test-article produced a very severe skin response consisting of extensive eschar formation and ulceration. This response was so severe that treatment was discontinued after 4 days, both to avoid unnecessary suffering and because there was insufficient unaltered skin to which treatment could be applied.
Body weight:
The rats given the 1.0 ml/kg/day dose of test item lost an average of 60 g during the four-day treatment compared with a slight (4 g) gain by the controls. The treated rats gained weight when dosing was stopped and although the gain over the 14-day period of the study was less than the control the gain over the last ten days was higher than control.
Gross pathology:
At post-mortem examination no difference was seen between treated and control animals in the appearance of any of the tissues apart from the treated areas of skin.

No deaths occurred during the study, however at a dose of 1.0 ml/kg/day the test-article produced a very severe skin response consisting of extensive eschar formation and ulceration. This response was so severe that treatment was discontinued after 4 days, both to avoid unnecessary suffering and because there was insufficient unaltered skin to which treatment could be applied.

There were no visible signs of systemic toxicity during the study and, within the limits of a gross examination, no organ damage was seen at autopsy. The rats given the 1.0 ml/kg/day dose of test item lost an average of 60 g during the four-day treatment

compared with a slight (4 g) gain by the controls. The treated rats gained weight when dosing was stopped and although the gain over the 14-day period of the study was less than the control the gain over the last ten days was higher than control.

These changes of weight gain possibly reflect a toxic change but might be due to a reduced food intake resulting from the discomfort caused by the severe irritation. Without more detailed data it is not possible to separate these two possibilities.

Conclusions:
The dermal LD50 is > 1 ml/kg in rats.
Executive summary:

The test material is corrosive and with the exception of local effects at the site of administration the test material doesn't appear to cause systemic effects when applied dermally to the skin of rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

The oral toxicity of the test item is > 2000 mg/kg/bw since 3 out of 10 animals died at this dose level. The test material is corrosive so a guideline dermal LD50 study has not been performed. As part of a 14-day test rats were dermally exposed to the test item at 1000 mg/kg/bw 6 hours per day for 4 days. No animals died and no systemic dermal effects occured, however, this dosage level was terminated for humane reasons due to the severity of the local skin effects.

Justification for classification or non-classification

Based on the results of the acute oral and dermal toxicity studies in rats and according to the criteria of EC Regulation 1272/2008 and subsequent regulations on classification, labelling and packaging of substances and mixtures, the test item has not to be classified.