Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.062 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: Extrapolation from MAK value
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Overall assessment factor (AF):
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL for Long term systemic effects:

The target organ identified in oral repeated dose toxicity studies with DOTE is the thymus. Reduction of thymus weight was observed at very low levels, this is the reason why the substance DOTE is classified as T; R48/25 according to Directive 67/548 and as STOT RE Cat 1 according to GHS for specific organ toxicity.

Based on the available data from recent OECD 414 studies conducted in both rabbits and mice administering DOTE via the oral route, no teratogenic or foetotoxic effects were seen. In other existing studies, no reprotoxic effects were seen at dosages lower than the thymus effects in the repeated dose studies

 

The main critical effect identified was therefore that on the thymus and this was subsequently considered to be the appropriate effect for which to calculate DNELs when using the results of the toxicology studies.

 

For workers, it was considered appropriate to use the recently updated MAK values to derive the no effect level.

 

 

1. WORKERS

 

1.1 Long-term, inhalation, systemic toxicity

 

A MAK-value is available for n-octyltin compounds. MAK-value is "the biggest amount of health-damaging gases and fumes, volatile or floating materials that can still be born without health damage during working hours (8 hours) at the workplace".

 

This MAK value is equal to 0.0098 mg Sn/m3.(following update in 2012)

 

Deutsche Forschungsgemeinschaft - Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area - Report No. 48 2012

 

 

Molecular weight of Sn = 118.7 g/mol

Molecular weight of DOTE = 751.79 g/mol

ð    100% DOTE = 15.8% Sn

 

MAK-value = 0.0098 x 100 / 15.8 = 0.062 mg/m3

 

 Worker DNEL (Inhalation long term, systemic effects)= 0.062 mg/m3

 

 

1.2.Long-term, dermal, systemic toxicity

Occupational exposure to DOTE may also occur by dermal exposure. Although no dermal repeated dose toxicity studies is available a dermal DNEL was derived based on the MAK-value.

 

Step 1) Relevant dose-descriptor          

 

DNEL (inhalation) = 0.062 mg/m3.

 

This value is calculated for workers for a chronic exposure of 8 hours per day, and 5 days per week.

 

 

 

·        Step 2) Modification of starting point:

Calculation of internal dose          = 0.062 x 10* = 0.62 mg/person

                                                          = 0.62 / 70 = 0.0089 mg/kg bw

Calculation of external dose (dermal) = 0.0089 x 100/0.004**= 222.5 mg/kg bw/d

 

* Respiratory volume of workers (10 m3/day)

**Correction for inhalation and dermal absorptions:

-        inhalation: default absorption of 100%

-        dermal: Anin vitroabsorption study though human and rat epidermis was performed (Ward 2003) and indicated very low absorption of tins through rat (0.004%). We consider that dermal absorption is the same in human and in rat.

 

·       

Step 3) Assessment factors

Interspecies and intraspecies : none, because the MAK value is calculated for workers.

 

Exposure duration : none, because the MAK value is calculated for chronic exposure.

 

No assessment factor is required.

 


 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.001 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
400
Modified dose descriptor starting point:
NOAEL
DNEL value:
0.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
N/A
AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Default
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
10
Justification:
Default for General Population
AF for the quality of the whole database:
2
Justification:
DNEL based on older, non-GLP study from large dataset
AF for remaining uncertainties:
1
Justification:
Default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

2. GENERAL POPULATION

 

 

2.3 Long-term, oral, systemic toxicity

 

Of the available long-term studies (All conducted in the rat) the13 week repeated dose toxicity study (performed in 1970 in equivalence to OECD 408) is selected as the starting point for DNEL derivation. Of the available studies this is noted to have been performed using the highest purity of the registered substance, is dosed over the longest duration and also yields the lowest NOAEL with regards to effects on the thymus (the critical target), acting as a precautionary measure with regards to the establishment of the DNEL.

 

 

·        Step 1) Relevant dose-descriptor          

NOAEL, rats=(long term toxicity - effects on the thymus) =10 ppm, equivalent to0.5 mg/kg/day 

 

·        Step 2) Modification of starting point:No

 

·        Step 3) Assessment factors

-Interspecies: 2.5 x 4 (allometric scaling) = 10

-Intraspecies : 10 (general population)

-Exposure duration : 2 (subchronic study)

-Dose response: 1

-Quality of database:2 (the DNELs are based on older, non GLP studies whilst the OECD 414 studies are not yet finalised)

Total safety factor = 400

 

  • Step 4: DNEL derivation:

DNEL Value based on the NOAEL in the 90 day repeated dose toxicity study (Anonymous 1970) :

 

General Pop DNEL (oral, long term, systemic)= 0.5 / 400 = 0.00125 mg/kg bw/d