Registration Dossier

Administrative data

Description of key information

oral: not classified as STOT RE, Key study, (OECD 407, Kr. 1)
inhalation: no data
dermal: no data

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

In a subacute oral toxicity exposure study, performed similarly to OECD guideline No. 407 and in compliance with the GLP, P#620 (purity > 99%) diluted in an 0.5% CMC-Na aqueous solution with 0.5% Tween 80 was administered by gavage to male and female Crj: CD(SD) rats (6/sex/conditions) for 28 days at three dose levels. A recovery period was set for rats of the control and high-dose groups. Control rats were given the vehicle alone. An eight-day preliminary study was performed at the doses of 0 and 1000 mg/kg bw/d, and a slight increase of the liver weight was observed, but no death was found. Based on these results, the high-dose was set at 1000 mg/kg bw, and the medium and lose doses were set at 140 and 20 mg/kg bw/d, respectively.

Clinical signs were observed each day whereas body-weight was measured once a week. Before the scheduled sacrifice, urine were collected and further analyzed. At the end of the treatment period (for all groups) or after the recovery period (for the control and high-dose group), the animals were sacrificed and further observed for hematology, blood chemistry, gross macroscopy, organ weight and histopathology.

P#620 induced increase in platelet counts in males of the high-dose group, and decrease in hemoglobin concentration, MCHC, prothrombin time, and an increase in the rate of lymphoid cells in females of the high-dose group but these effects were considered as not adverse. The test substance induced also absolute and relative increase of liver weight accompanied with brownish change of the liver and hypertrophy of hepatocytes in the high-dose groups of both sexes.

It is however well known that these changes occur as an induction of the microsomal drug metabolizing enzyme systems caused by the treatment of several compounds, and are considered to be cellular adaptation phenomena. Furthermore, these changes had tendency to recover after withdrawal. Moreover, bile pigments in hepatocyte and connective tissues, bile plugs in interlobular bile duct and cholangitis (lymphocytic infiltration) were observed in the high-dose males. Furthermore, the increase of ɣ-GTP in the high-dose group of both sexes was likely related to an induction in the liver. Furthermore, the increase of ɣ-GTP in the high-dose group of both sexes was likely related to an induction in the liver. Hence, the adaptation response to the treatment with Amber core was very important at the highest dose (1000 mg/kg bw/d) in the 28-day repeated oral dose toxicity study as described in this dossier (see § 7.5.1). Moreover, the observation of cholangitis (inflammatory effect) associated to cholestasis in both sexes at the highest dose of Amber core in the sub-acute repeated oral toxicity study showed that the substance induced adverse systemic toxicity.

Therefore, even if this effect had tendency to recover after withdrawal (2-week recovery period), the highest dose of 1000 mg/kg bw/d was considered as a LOAEL .

Hyaline droplets of the renal tubular epithelium and basophilic changes were observed in the mid and high-dose male group. This lesion is known to be spontaneous in male rats only and is not observed in other species. Therefore, this effect is specific to male rat, and is not relevant for the risk assessment in human. Therefore, a NOAEL of 140 mg/kg bw/d can be considered based only on the excess of salivation in both sexes. Finally the 20 mg/kg bw/d is considered as a NOEL.

In conclusion, under the test conditions, the highest dose (1000 mg/kg bw/d) is considered as a LOAELin a worst-case taking into account liver adverse systemic effects of the substance. P#620 is not classified for damage to organs through prolonged oral dose repeated exposure according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for repeated dose toxicty endpoint.

Justification for classification or non-classification

Harmonized classification:

The test item has no harmonized classification for human health according to the Regulation (EC) No. 1272/2008 including the ATP2 draft.

Self-classification:

Based on the available data, no self-classification is proposed regarding the specific target organ toxicity after oral dose repeated exposure.

There were no data concerning the dermal and inhalation route.