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Administrative data

Description of key information

For this endpoint adequate information is provided from a study of the ultimate degradation product. The study was performed according to GLP and the methods applied are fully compliant with OECD TG 422.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
For this endpoint adequate information is provided from a study of the ultimate degradation product.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
2.5 mg/m³
Study duration:
subchronic
Species:
other: rat & guinea pig

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Study Design

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" (adopted 22 March 1996).

Methods

The test material was administered by gavage to three groups each of ten male and ten female Sprague-Dawley Crl:CD® (SO) IGS BR strain rats. for up to fortyfive consecutive days (including a two week maturation phase. pairing. gestation and early lactation for females). at dose levels of 75. 150 and 300 mglkg/day. A control group of ten males and ten females was dosed with vehicle alone (Distilled water). Two recovery groups, each of five males and five females. were treated with the high dose (300 mg/kg/day) or the vehicle alone for forty-two consecutive days and then maintained without treatment for a further fourteen days.

Clinical signs. behavioural assessments. bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated prior to mating and at termination on five selected non-recovery males and females from each dose group. In addition. haematology and blood chemistry were evaluated after the fourteen day treatment free period on all recovery animals. Urinalysis was evaluated on five selected non-recovery males at the end of the treatment period and for all recovery group males at the end of the treatment free period.

Pairing of animals within each non-recovery 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 nonrecovery dose group after the completion of the mating phase, and for five selected parental females from each non-recovery dose group on Day 4 post partum.

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

Recovery animals were treated according to the dose group continuously up to the point of sacrifice of the non-recovery males at which time the treatment was discontinued. After fourteen days without treatment, the recovery males and females were subjected to a gross necropsy examination of selected tissues.

Results

Adult Responses:

Mortality

One non-recovery female treated with 300 mg/kg/day was killed in extremis on Day 37. Two further non-recovery females from this treatment group were found dead on Days 14 and 39 and one 300 mg/kg/day recovery male was also found dead and cannibalised on Day 56. One control female was killed in extremis on Day 37. There were no further unscheduled deaths during the study.

Clinical Signs

Animals of either sex treated with 300 and 150 mg/kg/day and females treated with 75 mg/kg/day showed episodes of increased salivation immediately post or one hour post dosing. Hunched posture and lethargy were evident in one 300 mg/kg/day male on Day 21 and one female from this treatment group also showed increased lachrymation on Day 38. Instances of generalised staining around the mouth, snout and eyes were detected for animals of either sex treated from all treatment groups throughout the study.

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.

Bodyweights

No toxicologically significant effects were detected in bodyweight development.

Food Consumption and Food Efficiency

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

Water Consumptions

Males treated with 300 and 150 mg/kg/day showed a substantial increase in water consumption from initiation during Week 3 until the end of the treatment period. Recovery 300 mg/kg/day animals continued to show an increase in water consumption during the first week of the recovery period. Females treated with 300 mg/kg/day showed an increase in water consumption during gestation. No such effects were detected in females treated with 150 mg/kg/day or animals of either sex treated with 75 mg/kg/day.

Haematology

Males treated with 300 mg/kg/day showed a statistically significant increase in haemoglobin and haematocrit at the Day 42 evaluations. No such effects were detected in females treated with 300 mg/kgl/day or animals of either sex treated with 150 or 75 mg/kg/day.

Blood Chemistry

Males treated with 300 mg/kg/day showed a statistically significant increase in aspartate aminotransferase at both the Day 14 and Day 42 evaluations. Females from this treatment group also showed an increase in aspartate aminotransferase at the Day 4 post parium evaluations. Following fourteen days without treatment, recovery 300 mg/kg/day males continued to show an increase in aspartate aminotransferase. No such effects were detected in animals of either sex treated with 150 or 75 mg/kg/day.

Urinalysis

There were no treatment-related effects on urinalytical values measured.

Reproductive Performance

Mating.There were no treatment-related effects on mating or conception rates for animals of either sex treated with 300, 150 or 75 mg/kg/day.

Fertility.There were no treatment-related effects on conception rates.

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

Litter Responses

Offspring Litter Size and Viability.Of the litters born, litter size at birth and subsequently on Days 1 and 4 post partum were comparable to controls.

Offspring Growth and Development.Offspring bodyweight gain and litter weights at birth and subsequently on Days 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.

Pathology

Necropsy.No treatment-related macroscopic abnormalities were detected for surviving animals of either sex treated with 300 mg/kg/day, animals of either sex treated with 150 or 75 mg/kg/day or surviving recovery animals.

Organ Weights. Males treated with 300 mg/kg/day showed a statistically significant increase in liver weight both absolute and relative to terminal bodyweight. Females from this treatment group also showed a statistically significant increase in relative liver weight. No such effects were detected in animals of either sex treated with 150 or 75 mg/kg/day.

Histopathology

The following treatment-related changes were observed:

Salivary Gland:A higher incidence of lower grades of secretory activity of the submaxillary salivary glands was seen in relation to treatment for animals of either sex treated with 300 mg/kg/day or at 150 mg/kg/day and also for females treated with 75 mg/kg/day. Treatment-related changes in secretory activity of the salivary glands can be regarded as adaptive.
The condition was observed to have regressed among Recovery 300 mg/kg/day males following an additional fourteen days without treatment, but a marginal residual effect on secretion remained for Recovery 300 mg/kg/day females.

Bone Marrow:A higher incidence of higher grades of severity of adipose infiltration of the bone marrow, indicative of reduced cellularity, was seen for males only treated with 300 mg/kg/day. A similar effect was not seen for females or for males from any other treatment level. The condition had regressed among Recovery 300 mg/kg/day males after completion of the recovery period.


Conclusion

The oral administration of the test material to rats by gavage, at dose levels of 75, 150 and 300 mg/kg/day resulted in treatment-related effects in animals of either sex treated at 300 and 150 mg/kg/day and in females treated with 75 mg/kg/day. A 'No Observed Effect Level' (NOEL) for systemic toxicity for females has therefore not been established; however, the 'No Observed Effect Level' (NOEL) for systemic toxicity for males was considered to be 75 mg/kg/day.

The effects detected at 150 mg/kg/day and in 75 mg/kg/day females were confined to adaptive changes in the salivary glands. In the absence of any associated changes these effects were considered not to represent an adverse health effect. The 'No Observed Adverse Effect Level' (NOAEL) was therefore considered to be 150 mg/kg/day.

No treatment-related effects were detected in the reproductive parameters measured. The 'No Observed Effect Level' (NOEL) for reproductive toxicity was considered to be 300 mg/kg/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study for the degradation product was performed according to GLP and the methods applied are fully compliant with OECD TG 422.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
A collection of scientific publications that meet high standards for documentation have been summarized in a WoE approach for the endpoint of Repeated dose toxicity via inhalative route of exposre.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification