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Administrative data

Description of key information

Repeated dose toxicity, oral: NOAEL = 300 mg/kg bw/day (OECD 408, GLP).

Repeated dose toxicity, dermal: no data

Repeated dose toxicity, inhalation: no data

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is suitable for risk assessment purposes.

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

1- Repeated dose toxicity: oral

Two studies were available for this endpoint and the 90 day study(Cole 1993 and Parr 2014) is considered as the key study (Parr 2014).

The Parr study was following the 408 OECD guideline and groups of ten male and ten female Sprague-Dawley rats were orally (gavage) administered the vehicle (sodium phosphate buffer 0.5M pH7.2 in drinking water) or the test item, ITC288 (batch No. B288P22E1) at dose-levels of 100, 300 and 1000 mg/kg/day (active ingredient), under the constant dosage volume of 5 mL/kg, daily for 13 weeks.

Evaluations of animals included a daily observations, weekly detailed clinical observation, weekly body weight and food consumption recording, ophthalmological examinations (pre-dose and in Week 13), monitoring of estrous cycle (Weeks 12 and 13), hematology and blood biochemistry (Week 13). At necropsy, spermogram, organ weight, macro- and microscopic examinations were performed.

There were no mortalities during the study. ITC288-related clinical observations were noted at 1000 mg/kg/day only, and consisted of ptyalism (18/20) and abnormal growth of teeth in most males (7/10) and a few females (3/10). There were no test item related changes during the functional observation battery. There was a dose-related decrease in body weights and body weight gains in males at all doses which reached statistical significance at 1000 mg/kg/day. There was a trend to reduced food consumption in males at all doses correlating with reduced body weights and body weight gains in males only. There were no changes in ophthalmology during the study. There were no changes in estrus cycles that considered to be related to treatment. Changes in hematology parameters were observed in males at 1000 mg/kg/day, and were limited to increased absolute number of white blood cells and neutrophils. There were no ITC288-related changes in biochemistry parameters. Seminology was not considered affected by the treatment with ITC288 at any dose-level.

At necropsy, test item-related lower mean body weights were noted in males treated at 1000 mg/kg/day. Macroscopic test item-related abnormal growth or irregular color of lower incisor teeth was observed in some males and females treated at 1000 mg/kg/day. These findings correlated with adverse ameloblast disorganization and atrophy associated with degeneration/necrosis of these cells. The adjacent enamel was altered. In the mesenteric lymph nodes from males and females treated at 300 or 1000 mg/kg/day, non adverse infiltrate of macrophages was seen.

In conclusion, the administration of ITC288 at 100, 300 and 1000 mg/kg/day (active ingredient) for 13 weeks to male and female Sprague-Dawley rats was well tolerated and resulted in no mortalities. Adverse changes were observed at 1000 mg/kg/day only and consisted in decreased body weights and body weight gains associated with reduced food consumption in males only. In both gender, there were increased absolute number of white blood cells and neutrophils, and gross and microscopic findings in teeth. As such, the Non Observable Adverse Effect Level (NOAEL) was 300 mg/kg/day.

This Cole study was performed according to the OECD test guideline No. 407 and in compliance with GLP (Kr: 1). ITC 288 was administered by gavage to Sprague-Dawley CD rats, at dose levels of 150, 400 and 1000 mg/kg/day (5 animals/sex/dose). A control group of five males and five females was dosed with vehicle alone (distilled water). No satellite groups were used. Clinical signs (immediately, one and five hours after dosing), bodyweight (on days 0, 7, 14, 21 and 28), food and water consumptions were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study. All animals were subjected to a gross necropsy examination and a limited histopathological evaluation of tissues was performed (Adrenals, Spleen, Heart, Kidneys, Liver and Testes). Urinalysis was not performed in this study. There were no treatment-related deaths. High dose females showed signs of pilo-erection, increased salivation and red/brown staining of the fur from day 23 onwards. High dose males and the remaining dose groups showed no clinically observable signs of toxicity throughout the study period. No adverse effects on bodyweight gain were noted. Food and water consumption in test animals were comparable with that seen in controls. No treatment-related effects on haematology were detected. Plasma alkaline phosphatase levels were elevated in high dose animals of either sex but there were no other changes that could be considered toxicologically significant. At necropsy, no treatment-related macroscopic abnormalities were detected. No treatment-related effects were effected on organ weights or histopathology. Under the conditions of this test, oral administration of ITC 288 to rats for a period of 28 consecutive days, at dose levels of up to 1000 mg/kg/day, resulted in a slight effects at the top dose level. These effects were confined to a slight change in physical conditions and an increase in plasma alkaline phosphatase levels, which, cannot be regarded as significant effects on the health of the animals. No such effects were detected in the 400 or 150 mg/kg/day dose groups. A NOAEL >= 1000 mg/kg/day were identified.

As a general conclution, the retained Non Observable Adverse Effect Level (NOAEL) is 300 mg/kg/day based on the Parr 2014 study.

2- Repeated dose toxicity: inhalation

No data was available.

3- Repeated dose toxicity: dermal

No data was available.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Their is one study which is fully compliant with GLP and OECD guidelines.

Justification for classification or non-classification

1- Repeated dose toxicity: oral

As NOAEL/oral/rat = 300 mg/kg/day (OECD 408, Kr:1) based in

increased absolute number of white blood cells and neutrophils for both sexes and diminution of body weights and gross and microscopic findings in males teeth at the highest tested dose ( 1000 mg/kg/bw), no classification is required according to the EU legislation (Directive 67/548/EEC and CLP regulation (1272/2008))

2- Repeated dose toxicity: inhalation

No classification is possible due to lack of data.

3- Repeated dose toxicity: dermal

No classification is possible due to lack of data.