Registration Dossier

Administrative data

Description of key information

Repeated oral toxicity: NOAEL was considered to be 500 mg/kg bw when male and female Sprague-Dawley rats were treated with test chemical orally by gavage for 28 days. Hence the test chemical is not likely to classify as repeated dose oral toxic as per the criteria mentioned in CLP regulation.

Repeated dose inhalation toxicity:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapor pressure of the test substance, which is reported as 4.60E-15 mm Hg at 25 C. Thus, exposure to inhalable dust, mist and vapor of the chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dose dermal toxicity:

In accordance with column 2 of Annex IX, this end point was considered for waiver since the acute toxicity by the dermal route has already been provided in section 7.2.3 (as part of the Annex VIII information requirements).

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary source
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
28 days repeated dose oral toxicity study of test chemical in rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
not specified
Route of administration:
oral: gavage
Details on route of administration:
not specified
Vehicle:
water
Remarks:
distilled
Details on oral exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total: 1000 mg/kg day: 10 male, 10 female
250 mg/kg day: 10 male, 10 female
500 mg/kg day: 10 male, 10 female
1000 mg/kg day: 10 male, 10 female
Recovery groups
0 mg/kg day: 5 male, 5 female
1000 mg/kg day: 5 male, 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:- Cage side observations checked in table [No.?] were included. Mortality were observed
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: No data
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time
-weighted averages from the consumption and body weight gain data: Yes / No / No data

FOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time
-weighted averages from the consumption and body weight gain data: Yes / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: No data
- Dose groups that were examined: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals:
- Parameters checked in table [No.?] were examined. No data
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data
URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER:
Absolute and relative organ weights were weighted.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
not specified
Statistics:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
When treated with 1000 mg/kg bw, Symptoms of local irritation of the gastrointestinal tract (head protrusion at the beginning of week 3, salivation at the beginning of week 4) were observed through the end of the study.
Mortality:
no mortality observed
Description (incidence):
No effect on survival of treated rats were observed.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No effect on Opthalmoscopic examination of treated rats were observed.
Haematological findings:
no effects observed
Description (incidence and severity):
No effect on Haematology examination of treated rats were observed.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effect on Clinical chemistry of treated rats were observed.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No effect on absolute and relative organ weights of treated rats were observed.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 1000 mg/kg bw, edema of the mucosa of the forestomach were observed in treated rats, which disappeared in rats of the recovery group 28 days after termination of treatment.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
When treated with 1000 mg/kg bw, acanthosis of the mucosa, inflammatory edema of the submucosa and multiple ulcerations in treated rats. The recovery animals showed complete and regular regeneration of the forestomach mucosa.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
clinical signs
gross pathology
haematology
histopathology: non-neoplastic
mortality
ophthalmological examination
organ weights and organ / body weight ratios
Remarks on result:
other: No effect observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Conclusions:
NOAEL was considered to be 500 mg/kg bw when male and female Sprague-Dawley rats were treated with test chemical orally by gavage for 28 days.
Executive summary:

In 28 days repeated dose oral toxicity study, male and female Sprague-Dawley rats were treated with test chemical in the contraction of 0, 250, 500 or 1000 mg/kg-day orally by gavage for 28 days. Symptoms of local irritation of the gastrointestinal tract (head protrusion at the beginning of week 3, salivation at the beginning of week 4) were observed through the end of the study at 1000 mg/kg bw. No effect on survival, hematological evaluations, clinical chemistry, ophthalmic examinations and absolute and relative organ weights of treated rats were observed in treated rats. In addition,edema of the mucosa of the forestomach were observed in treated rats at 1000 mg/kg bw, which disappeared in rats of the recovery group 28 days after termination of treatment. Acanthosis of the mucosa, inflammatory edema of the submucosa and multiple ulcerations in treated rats at 1000 mg/kg bw. The recovery animals showed complete and regular regeneration of the forestomach mucosa. Therefore, NOAEL was considered to be 500 mg/kg bw when male and female Sprague-Dawley rats were treated with test chemical orally by gavage for 28 days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimisch 4 and from secondary source

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Remarks:
Repeated dose inhalation toxicity
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose oral toxicity:

Data available for test chemical was reviewed to determine the repeated dose oral toxicity of test chemical. The studies are as mentioned below:

In 28 days repeated dose oral toxicity study, male and female Sprague-Dawley rats were treated with test chemical in the contraction of 0, 250, 500 or 1000 mg/kg-day orally by gavage for 28 days. Symptoms of local irritation of the gastrointestinal tract (head protrusion at the beginning of week 3, salivation at the beginning of week 4) were observed through the end of the study at 1000 mg/kg bw. No effect on survival, hematological evaluations, clinical chemistry, ophthalmic examinations and absolute and relative organ weights of treated rats were observed in treated rats. In addition, edema of the mucosa of the forestomach were observed in treated rats at 1000 mg/kg bw, which disappeared in rats of the recovery group 28 days after termination of treatment. Acanthosis of the mucosa, inflammatory edema of the submucosa and multiple ulcerations in treated rats at 1000 mg/kg bw. The recovery animals showed complete and regular regeneration of the forestomach mucosa. Therefore, NOAEL was considered to be 500 mg/kg bw when male and female Sprague-Dawley rats were treated with test chemical orally by gavage for 28 days.

A supporting repeated dose toxicity study was performed in rats to determine the toxic nature of the test chemical. Ten male and 10 female rats were used during the 28 days study. The test substance was administered in olive oil, at doses of 750, 250 and 70 mg/kg body weight per day for 14 days. After 14 days the dose in the 750 mg/kg body weight test group was increased to 1500 mg/kg body weight per day. Recovery groups consisting of five males and five females per dose level were used to determine the reversibility of possible compound related findings. The compatibility of the test substance was evaluated after 28 days of treatment. None of the rats died. Body weight gain and total increase in body weight did not differ from control values and no significant compound-related gross pathology or tissue damage was noted. Biochemical parameters did not show any signs of irregulations. Slight alterations of phosphate in the highest group were noted and regarded as dose /compound -related but not as a critical effect. Gonads were examined histologically. At the highest feasible dose, 750 mg/kg, daily for 28 days, no lethal dose was attained indicating that the test chemical is not toxic in nature.

 

In 90 days repeated dose oral toxicity study, male and female Sprague-Dawley rats were treated with test chemical in the contraction of 0, 250, 500 or 1000 mg/kg-day orally by gavage for 28 days. No effect on survival, clinical observations, body weight gain, food consumption, ophthalmic observations, hematologic evaluations, blood chemistry, urinalysis and organ weights were observed in treated rats. In addition, stomach ulceration at the fundus and cardiac regions and forestomach gastritis in six male and three female rats at 1000 mg/kg-day and in two males and two females at 500 mg/kg-day in treated rats. Therefore, NOAEL was considered to be 250 mg/kg bw when male and female Sprague-Dawley rats were treated with test chemical orally by gavage for 90 days.

Based on the data available, the test chemical does not exhibit repeated dose oral toxicity. Hence the test chemical is not likely to classify as repeated dose oral toxic as per the criteria mentioned in CLP regulation

Repeated dose inhalation toxicity:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapor pressure of the test substance, which is reported as 4.60E-15 mm Hg at 25 C. Thus, exposure to inhalable dust, mist and vapor of the chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dose dermal toxicity:

In accordance with column 2 of Annex IX, this end point was considered for waiver since the acute toxicity by the dermal route has already been provided in section 7.2.3 (as part of the Annex VIII information requirements).

Justification for classification or non-classification

Based on the data available, the test chemical does not exhibit repeated dose oral, dermal and inhalation toxicity. Hence the test chemical is not likely to classify as repeated dose oral toxic as per the criteria mentioned in CLP regulation.