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Description of key information

Key Study: Beyrouty (1997): 90 dayLOAEL (rats) = 25 ppm (equivalent to 1.6 and 2.2 mg/kg/day for males and females, respectively) Reduced food (males only) and water intake and neuropathological lesions. Vacuolisation of white matter in the brain and spinal cord was also observed for animals in the 25 ppm group.
Main supporting study: Appel (2000): 90 day NOAEL (rats) = 0.98 mg/kg day bw (males) and 0.98 mg/kg day bw (females) Neurotoxicity
This result is applicable to cover the REACH endpoints 8.6.1 and 8.6.2.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
1.6 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two reliable 90-day studies were available for this endpoint. Both identified neurotoxicity as the key effect. In addition, two shorter high quality studies were also available as supporting information along with two studies summarised in limited detail which could not be evaluated fully for reliability and another study which was assigned a reliability score of 3 due to the nature of the composition of the test material. The overall quality of the database was therefore considered to be high.

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

ORAL

Two reliable 90-day studies were available to address this endpoint. Beyrouty (1997a) is a well reported 90 day study performed to GLP. It was selected as the key study on account of higher purity of the test material and because effects were seen at lower dosage levels than in the Appel (2000) study. In Beyrouty (1997a), rats were treated for up to 13 weeks with a methyltin chloride mixture containing 90% dimethyltin dichloride at concentrations of 25, 75 or 200 ppm. The study resulted in several deaths, reduced body weight, decreased food and water intake, blood biochemical changes, behavioural effects such as aggressiveness and neuropathological lesions at 200 ppm (equivalent to 15.5 and 19.4 mg/kg/day for males and females, respectively). For the 75 ppm group (equivalent to 5.2 and 6.7 mg/kg/day for males and females, respectively), one male died, body weights were reduced (males only), food and water intake were decreased, and behavioural changes (such as reduced motor activity for females) and neuropathological lesions were noted. At 25 ppm (equivalent to 1.6 and 2.2 mg/kg/day for males and females, respectively), no mortality occurred and treatment-related findings were limited to reduced food (males only) and water intake and neuropathological lesions. The no observed effect level was considered to be below 25 ppm.

The other reliable 90-day study selected was Appel (2000). This study gives NOAEL values of 0.98 mg/kg bw/day for male rats and 1.02 mg/kg day/bw for female rats. After about one month of treatment, neurotoxic effects of the test substance became evident at the highest dose-level. Three high-dose females died and a large number of high-dose animals of both sexes started to develop signs of neurotoxicity, including tremors and convulsions. On account hereof, all animals of the main and satellite high-dose groups were sacrificed after approximately one month of treatment. High-dose (200 ppm) males and females showed slight growth retardation, which was associated with decreased food intake during the first week and with slightly lower food conversion efficiency in weeks three and four. Body weight, food consumption or food conversion efficiency were not affected by the test substance at the lower dose levels. Neurobehavioural and motor activity testing showed clear treatment-related neurotoxic effects in animals of the 200 ppm group in week 4 of the study. In week 1 of the study these effects were not yet observed, which is in accordance with the onset of the neurological clinical signs in the 200 ppm group after about 4 weeks. No toxicologically relevant effects were observed in any of the other dose-groups, at any of the other time-points investigated. Ophthalmoscopy, haematology, clinical chemistry, urinalysis or absolute and relative organ weights did not reveal any treatment-related changes after dietary exposure to concentrations up to 15 ppm for 13 weeks. These parameters were not measured for animals of the 200 ppm group, because of the premature termination of this group. Microscopic examinations (general pathology) demonstrated clear treatment-related changes in the kidneys, thymus and brain of animals of the 200 ppm group. The effect on the thymus was not considered a direct toxic effect, but an effect caused by stress. The effects on the kidneys and brain were considered toxicologically relevant. None of the effects was present in the next lower dose-group treated with 15 ppm. Microscopic examinations (neuropathology) demonstrated treatment-related pathological changes in several parts of the brain (neuronal death) of animals of the 200 ppm group. No significant treatment-related changes were observed in the peripheral nervous system. The effects occurred in both sexes, but were most pronounced in female rats.

On the basis of the neurotoxic effects observed in the high-dose group the No-Observed-Adverse-Effect Level in the present study was placed at 15 ppm. This level was equivalent to 0.98 (males) and 1.02 (females) mg of MMTTC/DMTDC (33.5/66.5) per kg body weight per day.

The other available supporting 90 day studies also showed that neurological effects were the target "organ" for dimethyltin dichloride, with similarly low NOAEL levels but were not selected as key studies because insufficient information meant that these studies could be allocated a sufficiently high enough reliability score. None of the available shorter term studies showed such significant effects.

INHALATION

An adaptation to the standard data requirements has been provided to fulfil this data requirement, as it is not considered to be the most appropriate route of exposure, and since a more appropriate study is available, testing for this endpoint was omitted.

DERMAL

An adaptation to the standard data requirements has been provided to fulfil this data requirement, as it is not considered to be the most appropriate route of exposure, and since a more appropriate study is available, testing for this endpoint was omitted.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two reliable 90-day studies were available for this endpoint. Beyrouty (1997a) was selected as the key study on account of higher purity of the test material and because effects were seen at lower dosage levels compared to the Appel (2000) study.

Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: behaviour; neurologic: brain (multiple sections)

Justification for classification or non-classification

In accordance with the criteria outlined in Regulation (EC) No. 1272/2008 (CLP), the substance meets the following criteria for classification for repeat-dose toxicity:

STOT Rep. Exp 1. with the association hazard phrase H372 'Causes damage to organs' (affected organs - nervous system; route of exposure - oral)

In accordance with the criteria outlined in Directive 64/548/EEC (Dangerous Substances Directive), the substance meets the following criteria for classification for repeat-dose toxicity:

Toxic with the associated risk phrase R48 'Danger of serious damage to health by prolonged exposure'.