Dibutyltin dilaurate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

0.77 mg/m³

Explanation for the modification of the dose descriptor starting point:

0.62 x 1/0.38 x 6.7/10 x 0.5 [50% oral abs rat / 100% inhalation abs hum]); = 0.77 mg/m³

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default subchronic - chronic

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Default

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

5

Justification:

ECHA Default workers

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.059 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Value:

0.593 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.732 mg/m³

Explanation for the modification of the dose descriptor starting point:

according to ECHA Guidance

AF for dose response relationship:

1

Justification:

default factor

AF for interspecies differences (allometric scaling):

2.5

Justification:

default factor rat - human

AF for other interspecies differences:

5

Justification:

default factor worker

AF for intraspecies differences:

1

Justification:

default factor inhalation

AF for the quality of the whole database:

1

Justification:

default factor

AF for remaining uncertainties:

1

Justification:

default factor

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:

DNEL (Derived No Effect Level)

Value:

0.43 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

43.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

0.62 x 50 [oral abs rat 50/dermal abs hum 1] * 7/5 [experimental exposure conditions]

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default for 90 days study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

5

Justification:

ECHA Default for workers

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.08 mg/kg bw/day

Most sensitive endpoint:

immunotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Value:

1

AF for dose response relationship:

1

Justification:

ECHA Default

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default rat

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

5

Justification:

ECHA Default worker

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

For the organotins as a group, SCPFC/EFSA (2004) have concluded a group NOAEL for organotins at 0.025 mg/kg bw based on immunological changes in a chronic study of tributyltin oxide (TBTO). SCPFC/EFSA comment: "Short term experiments however demonstrate that TBT-induced thymus atrophy and hepatotoxicity is preferentially generated by its metabolite DBT with a lower activity of TBT itself. From this it is concluded that DBT is at least as potent as TBT. In addition in comparative toxicity studies investigating the structure activity relationship regarding thymus toxicity in the rat, DBT were the most potent compounds producing dose-related thymus atrophy in similar extents". It therefore follows that a robust study of DBT is entirely appropriate for DNEL setting. SCPFC/EFSA identified no NOAEL, but a LEL for DBT-Cl, at 2.5 mg/kg bw/day based on a 2-week study; these data remain consistent with data used to derive DNELs in this CSR. An in vitro study simulating gastric condition indicate that DBT-Cl is an appropriate anchor compound when exposure occurs by the oral route, because the substance quickly hydrolised to DBT-Cl. A critical study, not included in the SCPFC/EFSA review, is the OECD 421 study with DBT-Cl (Waalkens-Berendsen, 2003) with a NOAEL at 0.3 mg/kg bw/day for thymus effects in female rats following dietary exposure. The thymus effects are critical toassessment of organotin toxicity; this study evaluates the critical effect in an appropriate study design. The OECD 421 NOAEL is supported by results of a teratogenicity study in rats (Osterburg 1993), and by studies of immune function showing an absence of effect at doses up to 2.5 mg/kg bw/day in adult rats and in pups exposed in utero and throughout lactation (DeWitt 2005, 2006) also not included in the EFSA/SPCFC review. As proposed classification for Annex I inclusion included Xn; R22, acute systemic DNELs have been derived on the basis of the maternal NOAEL of 1 mg/kg bw/day, obtained in a teratogenicity study in rats (Osterburg 1993) in which thymus weight was included among the evaluated parameters. These data for DBT-Cl are more robust (longer duration, more informative dose levels, more modern and GLP-compliant) than the data on which EFSA/SPCFC conclusions are based, and considered sufficiently robust that they can be used for the substance in preference to the SPCFC/EFSA group NOAEL for organotins. The NOAEL of the OECD 421 study by Waalkens et al (2003) is supported by the results of a subchronic study, and is therefore considered as a subchronic (not subacute) NOAEL for purposes of assessment factors used for deriving chronic DNELs. Consequences of exceeding the DNEL: The DNELs calculated in this CSR compare to published occupational hygiene limits for the organotins, expressed at OEL, TLV or STELs, at 0.2 mg/m3 (for very short term exposures equivalent to “acute” in this CSR) or 0.1 mg/m3 for longer-term exposures. Exceedance of DNELs by as much as 10-fold would remain within acceptable limits in most jurisdictions. At higher concentrations, workplace complaints of irritancy to the respiratory tract have been reported. Irritancy to the respiratory system is likely to be the most sensitive endpoint for the organotins, and likely to occur at levels below those at risk of causing systemic toxicities (e.g. immunotoxicity). Since affected workers are likely to adopt behaviour to reduce unpleasant irritancy, e.g. to remove themselves from the workplace, minor exceedances of the DNEL are unlikely to be cause for significant concern.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.005 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

0.23 mg/m³

Explanation for the modification of the dose descriptor starting point:

0.23 mg/m3 (0.62 * 1/1.35 x 0.5 [rat oral abs 50%/human inhalation abs 100%/]); Most sensitive endpoint: NOAEL 0.3 mg/kg bw/day (oral) thymus effects, OECD 421 rat Correction factor DBTC to DBTL = 0.48 (different content of DBT)

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default subchronic -chronic

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Default

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general population

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.04 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

0.37 mg/m³

Explanation for the modification of the dose descriptor starting point:

Corrected dose descriptor: 0.37 mg/m3 (1 * 1/1.15 x 0.5 [rat oral abs 50%/human inhalation abs 100%]); Most sensitive endpoint: 1 mg/kg bw/day NOAEL for maternal toxicity (thymus weight) obtained in a teratogenicity study in rats (Osterburg, I., 1993) Correction factor DBTC to DBTL = 0.48 (different content of DBT)

AF for dose response relationship:

1

Justification:

ECHA Default

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Default

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general popuplation

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

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:

DNEL (Derived No Effect Level)

Value:

0.16 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

31 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

0.62 x 50 [oral abs rat 50/dermal abs hum 1] = 31 mg/kg DBTL bw/day

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default subchronic - chronic

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default rat

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general population

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

immunotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Corrected dose descriptor: 50 mg/kg bw (1 mg/kg bw/day x 50 [Oral abs rat 50%/ dermal abs human 1%; Most sensitve endpoint: 1 mg/kg bw/day NOAEL for maternal toxicity (thymus weight) obtained in a teratogenicity study in rats (Osterburg, I., 1993) Correction factor DBTC to DBTL = 0.48 (different content of DBT

AF for dose response relationship:

1

Justification:

ECHA Default

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default rat

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general population

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

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:

0.003 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):

200

Modified dose descriptor starting point:

NOAEL

Value:

0.62 mg/kg bw/day

AF for dose response relationship:

1

Justification:

ECHA Default

AF for differences in duration of exposure:

2

Justification:

ECHA Default subchronic - chronic

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default rat

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general population

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

2.08 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Most sensitive endpoint: 1 mg/kg bw/day NOAEL for maternal toxicity (thymus weight) obtained in a teratogenicity study in rats (Osterburg, I., 1993) Correction factor DBTC to DBTL = 0.48 (different content of DBT)

AF for dose response relationship:

1

Justification:

ECHA Default

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Default rat

AF for other interspecies differences:

2.5

Justification:

ECHA Default

AF for intraspecies differences:

10

Justification:

ECHA Default general population

AF for the quality of the whole database:

1

Justification:

ECHA Default

AF for remaining uncertainties:

1

Justification:

ECHA Default

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The same toxicological endpoints chosen for setting the DNELs for workers have been used for setting DNELs for the general population. The increased assessment factor for interspecies sensitivity is considered sufficiently protective. Furthermore the same correction factor from DBTC to DBTL has been used.