Registration Dossier

The oral administration of test material to rats for a period of forty-two days for males and up to fifty-four days for females (including two weeks pre-mating, gestation and early lactation period) at dose levels of up to 1000 mg/kg/day, and no treatment-related effects in the reproductive parameters were observed. All treated and control females showed comparable number of litters at termination on Day 5 post partum and no treatment-related effects were observed for offspring growth or development. Therefore, a NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

other: 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

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

See "Details on results (parental animals)"

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

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.

Test Substance Intake (Parental Animals): No data available.

Reproductive Function: Estrous Cycle (Parental Animals): No data available.

Reproductive Function: Sperm Measures (Parental Animals): No data available.

Reproductive Performance (Parental Animals):
Mating. There were no treatment-related effects on mating or conception rates. One female treated with 350 mg/kg/day was non pregnant.
Gestation. There were no differences in gestation lengths. The distribution for treated females was comparable to controls.

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

Gross Pathology.
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 - 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.

Key result

Dose descriptor:

NOEC

Remarks:

reproduction toxicity

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed up to the limit concentration

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Litter Size and Viability. Of the litters born, litter size at birth and subsequently on Day 1 and 4 post partum were comparable to controls.
Offspring Growth and Development. Offspring bodyweight gain and litter weights at birth and subsequently on Day 1 and 4 post partum were comparable to controls.
Litter observations. No clinically observable signs of toxicity were detected for offspring from all treatment groups.

Key result

Dose descriptor:

NOAEL

Generation:

F1

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 up to the limit concentration

Key result

Reproductive 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. No treatment-related effects were observed for reproduction, therefore, a NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.

Executive summary:

Introduction.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” .

Methods.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.

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 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.

Reproductive Performance

Mating.There were no treatment-related effects on mating or conception rates.

One female treated with 350 mg/kg/day was non pregnant.

Gestation.There were no differences in gestation lengths. The distribution for treated females was comparable to controls.

Litter Size and Viability.Of the litters born, litter size at birth and subsequently on Day 1 and 4post partumwere comparable to controls.

Offspring Growth and Development.Offspring bodyweight gain and litter weights at birth and subsequently on Day 1 and 4post partumwere comparable to controls.

Litter observations.No clinically observable signs of toxicity were detected for offspring from all treatment groups.

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.

Conclusion.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. No treatment-related effects were observed for reproduction, therefore, a NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

Quality of whole database:

Key study

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Short description of key information:
OECD 422:
The test material was orally administered 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. No treatment-related effects in the reproductive parameters were observed, and a NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.

OECD 422:
The test material was orally administered 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. No treatment-related effects in the reproductive parameters were observed, and a NOEL for reproductive/developmental toxicity was considered to be 1000 mg/kg/day.

Reference

Endpoint:

developmental toxicity

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

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality.
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.

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.

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.
No toxicologically significant effects were detected

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

Histopathology - non-neoplastic.
The following treatment-related effects were detected:
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.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal systemic toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Offspring Growth and Development. Offspring bodyweight gain and litter weights at birth and subsequently on Day 1 and 4 post partum were comparable to controls.

Litter observations. No clinically observable signs of toxicity were detected for offspring from all treatment groups.

Key result

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects observed

Abnormalities:

not specified

Developmental effects observed:

not specified

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 and reproductive/developmental toxicity was considered to be 1000 mg/kg/day.
No treatment-related effects were observed for reproduction, therefore, a NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.