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Description of key information

Oral administration of the test item to rats for a period of forty-two days for males and up to fifty-four days for females at dose levels of up to 1000 mg/kg/day resulted in treatment-related effects in males treated with 1000 and 350 mg/kg/day. No toxicologically significant effects were detected in females from any treatment groups. No clinically observable signs of toxicity were observed during the daily clinical observations and no toxicologically significant effects were observed during the weekly open field arena observations, the haematological parameters, or the blood chemical parameters. The effects detected in this study were considered not to represent an adverse health effect, therefore a NOAEL and a suitable high dose level for use on a twenty-eight day study was considered to be 1000 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
see "Details on results"
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see "Details on results"
Histopathological findings: neoplastic:
no effects observed
Details on results:
Mortality.
One male treated with 350 mg/kg/day was found dead on Day 35. One female
from this treatment group was also terminated early due to an unscheduled mating on Day 18.
There were no further unscheduled deaths during the study.

Clinical Signs.
No clinical signs of toxicity were detected.

Bodyweights.
No adverse effects on bodyweight development were detected.

Food Consumption and Food Efficiency.
No adverse effects on food consumption or food efficiency were detected.

Water Consumptions. No significant intergroup differences were detected.
No intergroup differences were detected.

Ophthalmoscopic Examination
Not examined.

Haematology.
No toxicologically significant effects were detected in the haematological parameters measured.

Blood Chemistry.
No toxicologically significant effects were detected in the blood chemical parameters measured.

Urinalysis.
Not examined.

Behavioural Assessment.
There were no treatment-related changes in the behavioural parameters measured.

Functional Performance Tests.
There were no treatment-related changes in functional performance.

Sensory Reactivity Assessments.
There were no treatment-related changes in sensory reactivity.

Necropsy.
The male treated with 350 mg/kg/day that was found dead on Day 35 had reddened lungs and fluid in the thoracic cavity.

Organ Weights.
No toxicologically significant effects were detected in the organ weights measured.

Histopathology - non-neoplastic.
The following treatment-related effects were detected:
LIVER: Centrilobular hepatocyte enlargement was seen in relation to treatment for males only treated with 1000 mg/kg/day.
Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature.
KIDNEY: A higher incidence of globular accumulations of eosinophilic material was observed in the tubular epithelium of males treated with 1000 or 350 mg/kg/day. A slightly higher incidence of the condition was also seen for males treated with 50 mg/kg/day compared with the control group, but this condition is seen occasionally as a spontaneous change and an effect of treatment at the low dose was not convincing. This finding is consistent with the presence of hydrocarbon nephropathy, which results from the excessive accumulation of α2-microglobulin in renal proximal tubular epithelial cells. α2-Microglobulin is found only in the proximal tubular epithelium of adult male rats.


HISTOPATHOLOGY: NEOPLASTIC (if applicable) Not applicable.
HISTORICAL CONTROL DATA (if applicable) Not applicable.
OTHER FINDINGS
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Critical effects observed:
no
Conclusions:
The oral administration of test material to rats by gavage, at dose levels of 1000, 350 and 50 mg/kg/day, resulted in treatment-related effects at 1000 and 350 mg/kg/day. These effects were considered not to represent an adverse effect of treatment, hence the NOAEL for systemic toxicity was considered to be 1000 mg/kg/day.
Executive summary:

The study was designed to investigate the systemic toxicity and potential adverse effects of the test material on reproduction (including offspring development) and complies with the recommendations of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test” .

 

The test material was administered by gavage to three groups each of ten male and ten female Wistar Han™:HsdRccHan™:WIST strain rats, for up to fifty-four consecutive days (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 50, 350 and 1000 mg/kg/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).

Clinical signs, behavioural assessments, bodyweight development, food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated prior to mating and at termination on five selected males and females from each dose group.

Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation.

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex.

Extensive functional observations were performed on five selected males from each dose group after the completion of the mating phase, and for five selected parental females from each dose group on Day 4post partum.

Males were terminated on Day 43, followed by the termination of all surviving females and offspring on Day 5post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Mortality.

One male treated with 350 mg/kg/day was found dead on Day 35. One female from this treatment group was also terminated early due to an unscheduled mating on Day 18.

There were no further unscheduled deaths during the study.

Clinical Observations.

No clinical signs of toxicity were detected.

Behavioural Assessment.

There were no treatment-related changes in the behavioural parameters measured.

Functional Performance Tests.

There were no treatment-related changes in functional performance.

Sensory Reactivity Assessments.

There were no treatment-related changes in sensory reactivity.

Bodyweight.

No adverse effects on bodyweight development were detected.

Food Consumption.

No adverse effects on food consumption or food efficiency were detected.

Water Consumption.

No intergroup differences were detected.

Haematology.

No toxicologically significant effects were detected in the haematological parameters measured.

Blood Chemistry.

No toxicologically significant effects were detected in the blood

chemical parameters measured.

Organ Weights.

No toxicologically significant effects were detected in the organ weights measured.

Necropsy.

The male treated with 350 mg/kg/day that was found dead on Day 35 had reddened lungs and fluid in the thoracic cavity.

Histopathology.

The following treatment-related effects were detected:

LIVER: Centrilobular hepatocyte enlargement was seen in relation to treatment for males only treated with 1000 mg/kg/day.

Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature.

KIDNEY: A higher incidence of globular accumulations of eosinophilic material was observed in the tubular epithelium of males treated with 1000 or 350 mg/kg/day. A slightly higher incidence of the condition was also seen for males treated with

50 mg/kg/day compared with the control group, but this condition is seen occasionally as a spontaneous change and an effect of treatment at the low dose was not convincing.

This finding is consistent with the presence of hydrocarbon nephropathy, which results from the excessive accumulation ofα2-microglobulin in renal proximal tubular epithelial cells.α2-Microglobulin is found only in the proximal tubular epithelium of adult male rats.

The oral administration of test material to rats by gavage, at dose levels of 1000, 350 and 50 mg/kg/day, resulted in treatment-related effects at 1000 and 350 mg/kg/day. These effects were considered not to represent an adverse effect of treatment, hence the 'No Observed Adverse Effect Level' (NOAEL) for systemic toxicity was considered to be 1000 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
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:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
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:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral administration of the test item to rats for a period of forty-two days for males and up to fifty-four days for females at dose levels of up to 1000 mg/kg/day resulted in treatment-related effects in males treated with 1000 and 350 mg/kg/day. No toxicologically significant effects were detected in females from any treatment groups. No clinically observable signs of toxicity were observed during the daily clinical observations and no toxicologically significant effects were observed during the weekly open field arena observations, the haematological parameters, or the blood chemical parameters.

 

Macroscopic findings did not reveal any effects considered to be attributable to treatment. Organ weight data however revealed increases in absolute and relative liver and kidney weight for males treated with 1000 and 350 mg/kg/day and microscopic examinations revealed treatment related effects in the liver and kidney for males treated with 1000 mg/kg/day. Centrilobular hepatocyte enlargement was evident however this is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature.

A higher incidence of globular accumulations of eosinophilic material in the tubular epithelium was also detected. Accumulations of globular eosinophilic material in the tubular epithelium is a well documented effect and are peculiar to the male rat, which occurs in response to treatment with certain hydrocarbons. Female rats and other species do not develop “hydrocarbon nephropathy” and for this reason, the effect is not indicative of a hazard to human health.
Centrilobular hepatocyte enlargement was seen in relation to treatment for males only treated with 1000 mg/kg/day. Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and, in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature.

The effects detected in this study were considered not to represent an adverse health effect, therefore a NOAEL and a suitable high dose level for use on a twenty-eight day study was considered to be 1000 mg/kg/day.

Justification for classification or non-classification

There are conclusive and sufficient data for classification of the substance with regard to repeated dose toxicity.

The test item is not classified for this endpoint in accordance with CLP Regulation (EC) No 1272/2008.