Registration Dossier

Administrative data

Description of key information

OECD 422: Initial effects on body weights and food intake during the first week of treatment precluded classifying either 75 or 150/100 mg/kg bw/day as a No Observed Effect Level (NOEL) for adult toxicity.  However, as these effects did not persist following the lowering of the high dose level, a dosage of 100 mg/kg bw/day is classified as a No Observed Adverse Effect Level (NOAEL) for adult toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study has been conducted according to OECD Guideline 422 and GLP and is adequately reported. The study has been assigned a reliability 1.

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

14 -Day Range Finding Test:

The oral administration of the test item, Carbohydrazide, to rats for a period of seven consecutive days at 250 mg/kg bw/day resulted in notable treatment-related effects in animals of either sex. Administration of the test item, at 50 and 100 mg/kg bw/day for fourteen consecutive days was much better tolerated. Based on these findings, a high dosage for further investigation of toxicity should probably be greater than 100 mg/kg bw/day but not exceed 150 mg/kg bw/day.

OECD 422:

Treatment at 150 mg/kg bw/day for both sexes was associated with mean body weight loss during the first week of dosing and a concomitant reduction in food consumption compared to control. In view of the extent of body weight loss observed and the length of the treatment period for this study design, the dosage for these animals was lowered to 100 mg/kg bw/day from Day 9. Following this reduction in dosage, no adverse effects on body weight gain or food intake were observed for either sex throughout the remainder of the study.

At 75 mg/kg bw/day, males showed lower body weight gain compared to control and females showed mean body weight loss during the first week of treatment dosing, however no accompanying reduction in food intake was apparent for either sex. Following the first week of treatment, recovery of body weight gain was apparent and no adverse effects on body weight gain or food intake were observed for either sex throughout the remainder of the study.

At 30 mg/kg bw/day body weight gain and food consumption of both sexes appeared unaffected by treatment throughout the study.

While statistically significant differences from control were observed for some haematology and blood chemistry parameters there were no differences in either sex that were considered to be of any toxicological significance.

Macroscopic and microscopic findings for adult animals were generally unremarkable and did not indicate any adverse effect of treatment. There were no statistically significant differences in adult organ weights that, in the absence of any evidence of histopathological change, were considered to be of any toxicological significance.

Within this study, initial effects on body weights and food intake during the first week of treatment preclude classifying either 75 or 100 mg/kg bw/day as a No Observed Effect Level (NOEL) for adult toxicity. However, as the observed body weight and food effects at these dosages did not persist and recovery was evident, following the lowering of the high dose level a dosage of 100 mg/kg bw/day can be classified as a No Observed Adverse Effect Level (NOAEL) for adult toxicity.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The available OECD 422 study is assigned as reliability study 1 and is the only repeat dose toxicity study available.

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

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

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

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

Justification for classification or non-classification

Based on the results of the OECD 422 study and preceding 14-day range finding study, the substance was evaluated as to whether classification for specific target organ toxicity - repeated exposure (STOT-RE) under Regulation EC No. 1272/2008 (CLP) would be applicable.

Based on the CLP criteria, classification as STOT-RE Category 2 may be applicable when significant toxic effects are observed to occur within the following guidance value ranges:

Route of exposure: Oral (rat)

Guidance Value range (dose/concentration): 10 - 100 mg/kg bw/day (based on 90-day repeated exposure)

Guidance Value range (dose/concentration): 30 - 300 mg/kg bw/day (based on 28-day repeated exposure)

The OECD 422 study duration (56 days repeated exposure) falls between the guidance range values for 28 and 90-day studies. It may therefore be considered that for the OECD 422 study the guidance values for 90-day exposure may increased by a factor of 2, giving a guidance range value of 20 - 200 mg/kg bw/day. However, as a worst case assessment the guidance value range of 30 - 300 mg/kg bw/day may be used.

It should be noted however, that these ranges are intended for guidance purposes only, to be used as part of an overall assessment of study results and observed effects.

In a 14-day range finding study at 250 mg/kg bw/day, one female showed adverse clinical condition (lethargy, hunched posture, dehydration and staining around the eyes and mouth) and notable body weight loss on Day 8 of the study and was killed for animal welfare considerations. The remaining animals at this dosage also showed bodyweight loss and low food intake at this time, although no clinical signs were observed. While dosing was extended to fourteen days at lower dosages, animals at 250 mg/kg bw/day were killed on Day 8, as it was considered that this dosage had already been shown to be unsuitable for use in more long term studies.

Therefore, due to the death and significant body weight loss at 250 mg/kg bw/day, it was considered that this dosage would not be tolerated for longer exposure periods. Therefore, testing at 300 mg/kg bw/day (the guidance range value 'cut-off') was not possible in the OECD 422 study.

In the OECD 422 study, the top dose was initially 150 mg/kg bw/day but this had to be reduced to 100 mg/kg bw/day following adverse toxicity, based on body weight and food consumption. However, at the reduced dose of 100 mg/kg bw/day there was no mortality or clinical signs and no significant differences that were considered to be of toxicological significance for haematology, blood chemistry and in organ weights. At necropsy, macroscopic examination of animals did not indicate any adverse effect of treatment and there was no histological evidence of toxicological properties in the organs and tissues examined.

Based on the results from the 14 -day range-finding and OECD 422 studies, and evaluation of observed effects seen in these studies, it is considered that the substance should not currently be classified as STOT-RE Category 2, based on the following reasoning.

The primary observations at 150 mg/kg bw/day in the OECD 422 study were for body weight and food consumption effects, with no effects on gross pathology, specific target organ effects or appreciable clinical symptoms. There is therefore a lack of evidence for specific systemic target organ toxicity having occurred.

The 14 -day range finding study is similar, in that at the high dose (250 mg/kg bw/say), most animals only displayed body weight effects and no clinical signs through day 8.

It is therefore considered that the limitation of the noted effects in the high dose groups (body weight and food consumption), in the absence of any notable specific target organ toxicity effects or clear pathology/histopathology effects or altered functionality, lends the observed effects questionable toxicological significance with regards to classification for STOT-RE.

This is supported by Regulation EC No. 1272/2008 (CLP), section 3.9.2.8. (Effects considered not to support classification for specific target organ toxicity following repeated exposure), which states that effects may be seen in animals that do not justify classification. Such effects include, but are not limited to:

- clinical observations or small changes in bodyweight gain, food consumption or water intake that have toxicological importance but that do, by themselves indicate 'significant' toxicity'.

It is considered the effects on body weight and food consumption observed in the OECD 422 study and 14 -day range finder, fall into this category as discussed above.

Therefore, based on evaluation of all data, the substance will not be classified as STOT-RE Category 2.