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Description of key information

28-day study: The NOEL was determined to be 200 mg/kg/day and the NOAEL to be 1000 mg/kg/day in a 28-day study.
90-day study: A NOEL of 123.1 mg/kg bw/day and a NOAEL of 406.4 mg/kg bw/day have been determined.
Substance not classified as hazardous.

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
406.4 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The two key studies used to assess repeated dose toxicity are discussed below.

28 -day study (OECD Guideline 407):

The oral toxicity of the test material was examined in SD strain male and female rats given daily doses of 8, 40, 200 and 1000 mg/kg for 28 d, followed by the 14-d recovery period.

There were no deaths on account of administration of the test material.

No abnormalities were noted in body weights and food consumption during the dosing period, and hematological examinations, blood chemical examinations, urinalysis and necropsy at the end of the dosing period.

In general conditions, salivation, which noted in both sexes of the 1000 mg/kg group, had slightly toxic effect since it was noted just after dosing and in vehicle control group.

In organ weights, as the dose-related changes, increased absolute and relative liver weights were noted in males of the 1000 mg/kg group. These were considered as the very slightly effect of the test substance since no other related changes were noted. An increase of absolute liver weight in males of the 40 and 200 mg/kg groups were not considered to be effect of the test substance for no changes in relative liver weight.

In the histopathological examinations, cyst formation in the kidney was noted in both sexes of the 1000 mg/kg group at end of the dosing period. But it was not considered as the effect of the test substance because this change was common in this strain and noted in the vehicle control group.

In the recovery test, decreases in mean corpuscular haemoglobin concentration, albumin and A/G ratio and increases inγ-GTP and creatinine were noted in females of the 1000 mg/kg group. These were considered to be unrelated to the test substance since no other changes were associated with them. A decrease in cholinesterase, which was noted in female of the 1000 mg/kg group, was not considered as the effect of the test substance since there was no corresponding changes were noted.

The other statistically significant differences, and changes in general conditions, necropsy and histopathological examinations were not considered related to administration of the test substance since there was no dose relationship and noted in the vehicle control group.

The NOEL for rats in this study was considered to be 200 mg/kg/day since increased relative liver weight was noted in males of the 1000 mg/kg group.

The NOAEL was considered to be 1000 mg/kg bw/day.

90 -day study (OECD Guideline 408):

A 90 -day repeat dose oral toxicity feeding study was performed according to OECD Guideline 408.

The rats were fed for 90 days (7 day a week) and received the following doses:

Group 1: Control group (0 mg/kg bw/day)

Group 2: 20 males at 123.1 mg/kg bw/day and 20 females at 135.7 mg/kg bw/day

Group 3: 20 males at 406.4 mg/kg bw/day and 20 females at 478.5 mg/kg bw/day

Group 4: 20 males at 1261.3 mg/kg bw/day and 20 females at 1479.2 mg/kg bw/day

No mortality and no treatment related clinical signs were noted in any group.

A decreased body weight gain was noted for group 3 males (not significant) and group males and females (statistically significant).

A very slight increase of blood urea nitrogen was noted in group 4 (not significant when compared to controls). This effect was reversible after 4 weeks without treatment.

No histopathological finding was considered to be treatment related.

Considering the weakness of the reactions noted during the study, further histopathological results (which were not available at the time of study completion) were not expected to show further toxicologically significant effects and not to modify the classification of the substance. Only some kidney lesions may be noted, at the highest dose level group.

A NOEL of 123.1 mg/kg bw/day and a NOAEL of 406.4 mg/kg bw/day have been determined from the results of this study.

Supporting data:

The reproduction/developmental toxicity data also provide some supporting information on repeated dose toxicity.

In an OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test) study, a NOEL (No Observed Effect Level) for general toxicity in males and females was considered to be 1000 mg/kg bw/day, the highest dose level tested. Daily administration of the test item was well tolerated in males, females and pups, with no test item-related effects noted on any parameter measured (including mortality, clinical signs, food consumption, body weights, macroscopic/microscopic findings), at any dose level.

In a one generation reproduction study in rats (on a read-across substance), there no mortalities attributed to test substance toxicity, no clinically observable signs of toxicity, no adverse effects on bodyweight, no adverse effects on food and water consumption.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Repeated dose toxicity has been assessed based on two key studies:
- a 28 day repeated dose oral gavage study (OECD 407)
- a 90 day oral feeding study (OECD 408)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Refer to data waiver.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Refer to data waiver.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Refer to data waiver.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Refer to data waiver.

Justification for classification or non-classification

The two key studies have been evaluated with regards to classification for repeated dose toxicity (STOT-RE). Neither the 28 -day study or 90 -day study support classification for STOT-RE.

28 -day study:

The oral toxicity of the test material was examined in SD strain male and female rats given daily doses of 8, 40, 200 and 1000 mg/kg for 28 d, followed by the 14-d recovery period.

In organ weights, as the dose-related changes, increased absolute and relative liver weights were noted in males of the 1000 mg/kg group. These were considered as the very slightly effect of the test substance since no other related changes were noted. An increase of absolute liver weight in males of the 40 and 200 mg/kg groups were not considered to be effect of the test substance for no changes in relative liver weight.

The NOEL for rats in this study was considered to be 200 mg/kg/day since increased relative liver weight was noted in males of the 1000 mg/kg group. The NOAEL for rats in this study was considered to be 1000 mg/kg/day.

No significant/adverse toxic effects were therefore observed within the classification guidance value ranges for a 28 -day study in the CLP regulation for specific target organ toxicity-repeated exposure (Category 2) i.e. no significant/adverse toxic effects were seen at or below a dose of 300 mg/kg bw/day.

In addition, the CLP regulation states that certain effects are considered not to support classification for specific target organ toxicity following repeated exposure. These effects include changes in organ weights with no evidence of organ dysfunction. There was no evidence of liver dysfunction in the study and no elevated liver weight in males in the 1000 mg/kg group after the 14 -day recover period.

Therefore, it is considered that no classification is required for STOT-RE based on the results of this study.

90 -day study:

A NOEL of 123.1 mg/kg bw/day and a NOAEL of 406.4 mg/kg bw/day have been determined from the results of this study.

No significant/adverse toxic effects were therefore observed within the classification guidance value ranges for a 90-day study in the CLP regulation for specific target organ toxicity-repeated exposure (Category 2) i.e. no significant/adverse toxic effects were seen at or below a dose of 100 mg/kg bw/day.

The small effects that were seen in the study, decreased body weight gain and slight increase of blood urea nitrogen (not statistically significant), at the high dose levels are effects considered not to support classification.

Therefore, it is considered that no classification is required for STOT-RE based on the results of this study.