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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Repeated Dose Toxicity study : Oral:

The No Observed Adverse Effect Level (NOAEL) of the test chemical in the rat via oral route of exposure is considered to be 7300 mg/kg body weight in male and 8300 mg/kg body weight in female animals.

Repeated dose Inhalation toxicity

The short term inhalation study need not be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the thorough and rigorous exposure. The estimated vapour pressure of test chemical at 25 deg C was observed to be at 1.67E-021 Pa. Hence, this endpoint was considered for waiver.

 

Repeated dose Dermal toxicity

The short term inhalation study need not be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the thorough and rigorous exposure.The acute dermal LD50 of the test chemical can be considered to be >2000 mg/kgbw. Hence, this endpoint was considered for waiver.

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:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from publication
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Toxicity of test chemical was assessed in HaM/ICR (CD-1) mice in life time study.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
other: HaM/ICR (CD-1)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 50 days old
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: Five mice were housed in each polycarbonate box cage. Heat-treated wood chips served as the bedding material.
- Diet (e.g. ad libitum): Purina Laboratory Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21°C
- Humidity (%): 40-60%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle

IN-LIFE DATES: From: To:
Route of administration:
oral: feed
Details on route of administration:
Purina Laboratory Chow
Vehicle:
other: Purina Laboratory Chow
Details on oral exposure:
Fresh diets were prepared and presented weekly. The test material was incorporated into the basal diet using a Patterson- Kelley twin shell blender, and assays were performed to determine the homogeneity and stability of test chemical in the prepared diets.
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
1 wk prior to breeding, throughout a 2- or 3-wk breeding period, and during the gestation and lactation periods. When the last litter reached 21 days of age, weanling mice were randomly selected to populate the F1 phase.
Remarks:
Males: 0.37, 1.39 or 5.19% (0, 507, 1877, 7422 mg/kg bw/day)
Remarks:
Females: 0.37, 1.39 or 5.19% (0, 577, 2043, 8304 mg/kg bw/day)
No. of animals per sex per dose:
50 mice/sex/group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (wk 0-10) and every 4 wk thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (wk 0-10) biweekly (wk 11-26) and every 4 wk thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):Yes
- Time schedule for examinations: weekly (wk 0-10) and every 4 wk thereafter

FOOD EFFICIENCY: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood collected from the tail vein during the study, and from the
abdominal aorta at termination at wk 13, 26, 52 and termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 mice/sex/group
- Parameters checked: haematocrit, haemoglobin, erythrocyte count, and total and differential leucocyte counts.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood collected from the tail vein during the study, and from the
abdominal aorta at termination at wk 52 and at termination
- Animals fasted: No data
- How many animals: 5 mice/sex/group
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, fasting glucose, total protein, serum calcium and total bilirubin.

URINALYSIS: Yes
- Time schedule for collection of urine: Urine samples were obtained by housing mice overnight in metabolism cages (5/cage) at wk 52 and at termination.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: specific gravity, pH, glucose, ketones, total protein, bilirubin and sediment.

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Sacrifice and pathology:
Sacrifice and pathology
GROSS PATHOLOGY: Yes
Gross autopsies were conducted on all mice that died spontaneously, were killed in a moribund condition, or were killed at termination. Mice were killed by exsanguination under sodium pentobarbital. Absolute and relative organ weights were determined for the heart, liver, spleen, kidneys, testes with epididymides, thyroid and adrenal glands.

HISTOPATHOLOGY: Yes
Mice killed at 42 wk for histopathological evaluation and complete histology was conducted on all mice from all groups
Statistics:
Gain in group mean body weight and total food consumption, group mean body weight at termination, and absolute and relative organ weights were analysed by the methods of Bartlett (1937), Scheffe (1953) and Snedecor and Cochran (1967a). Survival data were analysed by the methods of Sachs (1959) and Snedecor and Cochran (1967b).
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no compound-related effects on survival.
Localized alopecia, laboured respiration, coloured hair coat, lacrimation and thinness were noted in similar incidences among control and treated mice.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no consistent statistically significant compound-related effects on mean body weights or survival.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption decreased among the mid- and high-dose males for wk 50-104. There were no consistent statistically significant compound-related effects on mean food consumption.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Few of the haematological parameters differed significantly between control and treated mice, and none of the differences was compound related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Few of the Clinical chemistry parameters differed significantly between control and treated mice, and none of the differences was compound related.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Few of the Urinanalysis parameters differed significantly between control and treated mice, and none of the differences was compound related.
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant compound related gross changes, including changes in organ weights, were noted in mice that died on test or were killed during the study or at termination.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No significant compound related gross changes, including changes in organ weights, were noted in mice that died on test or were killed during the study or at termination.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The mean thyroid weights in the high-dose males and females were 0.0133 and 0.0099 g, respectively, compared with 0.00879 and 0.0078 g in controls (P < 0.05). The respective thyroid/body-weight ratios were 3.51 and 3.23 compared with 2.26 and 2.36 in controls (P ~< 0.05). The significance of these findings
is unclear; there was no histopathology, they were apparently not dose-dependent but were observed at the highest level only and appear to be species-specific. The appearance of lymphocytic lymphoma occurred in study A earlier among treated groups than among controls. Lymphomas were observed in one low-dose male, one mid-dose female and two males and females from the high-dose group between wk 31 and 37. Lymphomas were not observed among controls until wk 85 and 70 for males and females, respectively
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
7 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: No adverse effect observed
Dose descriptor:
NOAEL
Effect level:
8 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: No adverse effect observed
Critical effects observed:
no
System:
other: not specified
Organ:
not specified
Conclusions:
The NOAEL value of test chemical to Male and female HaM/ICR (CD-1) mice in life time study was observed at dose concentration of 7300 and 8300 mg/kg bw/day respectively.
Executive summary:

Toxicity of test chemical was assessed in HaM/ICR (CD-1) mice in life time study. 50 CD1 mice per sex per dose group were fed test chemical in diet at dose concentration of Males: 0.37, 1.39 or 5.19% (0, 507, 1877, 7422 mg/kg bw/day), Females: 0.37, 1.39 or 5.19% (0, 577, 2043, 8304 mg/kg bw/day), for1 wk prior to breeding, throughout a 2- or 3-wk breeding period, and during the gestation and lactation periods. When the last litter reached 21 days of age, weanling mice were randomly selected to populate the F1 phase. No significant compound related adverse effect were observed on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry,gross and histopathology. Hence no-observable-adverse effect level in these studies was 5.19%; approximately 7300 and 8300 mg/kg body weight/day for male and female mice, respectively.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
7 300 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Data is Klimish 2 and from publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Data waiving:
other justification
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
Endpoint conclusion
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
other justification
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
Endpoint conclusion
Quality of whole database:
Waiver

Additional information

Repeated dose Oral toxicity:

Various studies have been reviewed to determine the toxicity of the test chemical when dosed repeatedly via oral route to living organisms. These include in vivo experimental studies performed on rats and mice:

Toxicity of test chemical was assessed in HaM/ICR (CD-1) mice in life time study. 50 CD1 mice per sex per dose group were fed test chemical in diet at dose concentration of Males: 0.37, 1.39 or 5.19% (0, 507, 1877, 7422 mg/kg bw/day), Females: 0.37, 1.39 or 5.19% (0, 577, 2043, 8304 mg/kg bw/day), for1 wk prior to breeding, throughout a 2- or 3-wk breeding period, and during the gestation and lactation periods. When the last litter reached 21 days of age, weanling mice were randomly selected to populate the F1 phase. No significant compound related adverse effect were observed on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry,gross and histopathology. Hence no-observable-adverse effect level in these studies was 5.19%; approximately 7300 and 8300 mg/kg body weight/day for male and female mice, respectively.

In another study, Toxicity of test chemical was assessed in CD-1 outbreed mice in life time study. 50 CD1 mice per sex per dose group were fed test chemical in diet at dose concentration of Males: 0.37, 1.39 or 5.19% (0, 507, 1877, 7422 mg/kg bw/day), Females: 0.37, 1.39 or 5.19% (0, 577, 2043, 8304 mg/kg bw/day), for1 wk prior to breeding, throughout a 2- or 3-wk breeding period, and during the gestation and lactation periods. When the last litter reached 21 days of age, weanling mice were randomly selected to populate the F1 phase. No significant compound related adverse effects were observed on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, gross and histopathology. Hence no-observable-adverse effect level in these studies was 5.19%; approximately 7300 and 8300 mg/kg body weight/day for male and female mice, respectively.

In a similar study, Toxicity of test chemical was assessed in Sprague Dawley rats in life time study. 30 Sprague Dawley rats per sex per dose group were fed test chemical in diet at dose concentration of Males: 0.37, 1.39 or 5.19% (0, 180, 701,2829 mg/kg bw/day), Females: 0.37, 1.39 or 5.19% (0, 228, 901, 3604 mg/kg bw/day), 1 wk before mating, throughout the 3-wk breeding period, and during the gestation and lactation periods .No significant compound related adverse effect were observed on mortality, clinical signs, body weight (except for a reduction in body weight in high-dose females at the end of the study), food consumption, hematology, clinical chemistry, gross and .The no adverse-effect levels in this study were 5.19% (2829 mg/kg/day) for male rats, and 1.39% (901 mg/kg/day) for female rats.

Based on the available results, the test chemical can be considered to be non-toxic to living organisms when dosed repeatedly via oral route. The No Observed Adverse Effect Level can be considered to be >1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”

Repeated dose Inhalation toxicity

The short term inhalation study need not be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the thorough and rigorous exposure. The estimated vapour pressure of test chemical at 25 deg C was observed to be at 1.67E-021 Pa. Hence, this endpoint was considered for waiver.

 

Repeated dose Dermal toxicity

The short term inhalation study need not be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the thorough and rigorous exposure.The acute dermal LD50 of the test chemical can be considered to be >2000 mg/kgbw. Hence, this endpoint was considered for waiver.

Justification for classification or non-classification

Available studies indicate that the test chemical is likely to be non-toxic when exposed via oral, dermal or inhalation route to various living organisms.

According tocriteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.