Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
22.5
Dose descriptor starting point:
other: LOAEL fom 2-EHA (100 mg/kg bw/day) adjusted for weight fraction in tin bis (2-ethylhexanoate) (then 140 mg/kg bw/day)
DNEL value:
140 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
178 mg/m³
Explanation for the modification of the dose descriptor starting point:

140 mg/kg/d tin bis (2 -ethylhexanoate) is the LOAEL in oral gavage developmental toxicity study. 

No allometric scaling factor for species is necessary (Ch. R8. p.32) 

Correction factor for oral to inhalation based on pharmacokinetic study is 0.72 . 

Using formula for calculating a human DNEL from a rat oral NOAEL (Ch. R8, p.27) 

Corrected LOAEC= Oral LOAEL X 1/ 0.38 m3/kg/d X Abs orl-rat/Abs. inh-hum X 6.7 m3/ 10 m3

Corrected LOAEC= 140 mg/kg/d X   1/0.38 m3/kg/d X 0.72 X 0.67=178 mg/m3

AF for dose response relationship:
3
Justification:
No NOAEL could be identified in the key study
AF for differences in duration of exposure:
1
Justification:
Critical window in prenatal development was covered
AF for interspecies differences (allometric scaling):
1
Justification:
inhalation endpoint
AF for other interspecies differences:
2.5
Justification:
ECHA Guidance
AF for intraspecies differences:
3
Justification:
Derived from the Hattis 1999 and Renwick & Lazarus databases, as explained in the ECETOC TR 110.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

The Point of Departure is a LOAEL of 100 mg/kg/d determined in a prenatal development toxicity test of EHA in rats (Pennanen, 1992), where skeletal and visceral malformations were observed in all treatment groups with a dose-dependent increase. Those effects were considered treatment-related and adverse. 

 

Adjusting the LOAEL for the weight fraction of EHA in tin bis(2 -ethylhexanoate) (0.71) yields a LOAEL for tin bis(2 -ethylhexanoate) = 140 mg/kg/d [that is, 140 mg/kg tin bis(2 -ethylhexanoate) represents 100 mg/kg ethylhexanoic acid and 40 mg/kg tin]. The dose of tin obtained from exposure to 140 mg/kg/d tin bis(2 -ethylhexanoate) (40 mg/kg/d) is far below the lowest NOAEL identified for stannous chloride (312 mg/kg/d = 196 mg/kg tin per weight fraction of 0.63).

Development of a long-term inhalation DNEL for Worker

140 mg/kg/d is the LOAEL in oral gavage developmental toxicity study.

 

No allometric scaling factor for species is necessary (Ch. R8. p.32)

 

Correction factor for oral to inhalation based on pharmacokinetic study is 0.72 based.

 

Using formula for calculating a human DNEC from a rat oral LOAEL (Ch. R8, p.27)

 

Corrected LOAEC= Oral LOAEL X 1/ 0.38 m3/kg/d X Abs orl-rat/Abs. inh-hum X 6.7 m3/ 10 m3

Corrected LOAEC= 140 mg/kg/d X   1/0.38 m3/kg/d X 0.72 X 0.67 =178 mg/m3

 

Combined interspecies and intraspecies assessment factor of 3 x 2.5 = 7.5

 

Duration AF = 1 since the critical window in prenatal development was covered

Dose-Response AF= 3

 

In accordance with ECHA Guidance R8, a Dose-Response Assessment Factor of 3 is the default AF to extrapolate from the Lowest Observed Adverse Effect Level /Concentration (LOAEL/LOAEC) to a No Adverse Effect Leve/Concentrationl (NAEL/NAEC). Benchmark Dose Modelling of the findings in the Pennanen (1992) study resulted in a BMDL of 35 mg/kg, based on the most sensitive endpoint (skeletal malformations on a litter base), which justifies the use of the default AF 3.

 

Quality of Data Base AF = 1 since all data endpoints are satisfied or waived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.8 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
other: LOAEL fom 2-EHA (100 mg/kg bw/day) adjusted for weight fraction in tin bis (2-ethylhexanoate) (then 140 mg/kg bw/day)
DNEL value:
140 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
178 mg/m³
Explanation for the modification of the dose descriptor starting point:

The Point of Departure is a LOAEL of 100 mg/kg/d determined in a prenatal development toxicity test of EHA in rats (Pennanen, 1992), where skeletal and visceral malformations were observed in all treatment groups with a dose-dependent increase. Those effects were considered treatment-related and adverse. 

 

Adjusting the LOAEL for the weight fraction of EHA in tin bis(2 -ethylhexanoate) (0.71) yields a LOAEL for tin bis(2 -ethylhexanoate) = 140 mg/kg/d [that is, 140 mg/kg tin bis(2 -ethylhexanoate) represents 100 mg/kg ethylhexanoic acid and 40 mg/kg tin]. The dose of tin obtained from exposure to 140 mg/kg/d tin bis(2 -ethylhexanoate) (40 mg/kg/d) is far below the lowest NOAEL identified for stannous chloride (312 mg/kg/d = 196 mg/kg tin per weight fraction of 0.63).

 

Development of a long-term inhalation DNEL for the General Population

140 mg/kg/d is the LOAEL in an oral gavage developmental toxicity study. 

No allometric scaling factor for species is necessary (Ch. R8. p.32) 

Correction factor for oral to inhalation based on pharmacokinetic study is 0.72. 

Using formula for calculating a human DNEL from a rat oral LOAEL (Ch. R8, p.27) 

Corrected LOAEC= Oral LOAEL X 1/ 0.38 m3/kg/d X Abs orl-rat/Abs. inh-hum X 6.7 m3/ 10 m3

Corrected LOAEC= 140 mg/kg/d X   1/0.38 m3/kg/d X 0.72 X 0.67 =178 mg/m3)

AF for dose response relationship:
3
Justification:
see worker
AF for differences in duration of exposure:
1
Justification:
see worker
AF for interspecies differences (allometric scaling):
1
Justification:
see worker
AF for other interspecies differences:
2.5
Justification:
see worker
AF for intraspecies differences:
5
Justification:
ECETOC TG 110
AF for the quality of the whole database:
1
Justification:
see worker
AF for remaining uncertainties:
1
Justification:
see worker
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 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):
150
Dose descriptor starting point:
other: LOAEL fom 2-EHA (100 mg/kg bw/day) adjusted for weight fraction in tin bis (2-ethylhexanoate) (then 140 mg/kg bw/day)
DNEL value:
140 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Explanation for the modification of the dose descriptor starting point:

see worker

AF for dose response relationship:
3
Justification:
see worker
AF for differences in duration of exposure:
1
Justification:
see worker
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
see worker
AF for intraspecies differences:
5
Justification:
see worker
AF for the quality of the whole database:
1
Justification:
database sufficient
AF for remaining uncertainties:
1
Justification:
none
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

The Point of Departure is a LOAEL of 100 mg/kg/d as determined in a prenatal development toxicity test of EHA in rats (Pennanen, 1992), where skeletal and visceral malformations were observed in all treatment groups with a dose-dependent increase. Those effects were considered treatment-related and adverse. Adjusting the LOAEL for the weight fraction of EHA in tin bis (2 -ethylhexanoate) (0.71) yields a NOAEL for tin bis (2 -ethylhexanoate) = 140 mg/kg/d [that is, 140 mg/kg tin bis(2 -ethylhexanoate) represents 100 mg/kg ethylhexanoic acid and 40 mg/kg tin]. The dose of tin obtained from exposure to 140 mg/kg/d tin bis(2 -ethylhexanoate) (40 mg/kg/d) is far below the lowest NOAEL identified for stannous chloride (312 mg/kg/d = 196 mg/kg tin per weight fraction of 0.63).

Development of a long-term inhalation DNEL for the General Population

140 mg/kg/d is the LOAEL in an oral gavage prenatal development toxicity study.

 

No allometric scaling factor for species is necessary (Ch. R8. p.32)

 

Correction factor for oral to inhalation based on pharmacokinetic study is 0.72.

 

Using formula for calculating a human DNEL from a rat oral LOAEL (Ch. R8, p.27)

 

Corrected LOAEC = Oral LOAEL X 1/ 0.38 m3/kg/d X Abs orl-rat/Abs. inh-hum X 6.7 m3/ 10 m3

Corrected LOAEC= 140 mg/kg/d X   1/0.38 m3/kg/d X 0.72 X 0.67 =178 mg/m3

 

Combined interspecies and intraspecies assessment factor of 12.5 (Interspecies AF: 2.5 = 10 in accordance with ECHA Guidance, 5 for general population in accordance with ECETOC TG 110)

 

Duration AF = 1 since the critical window of fetal development was covered

Dose-Response AF=3 default (and in accordance with estimated BMDL), since no clear NOAEL was achieved

Quality of Data Base AF = 1 since all data endpoints are satisfied or waived.

Development of a long-term oral DNEL for the General Population

 

140 mg/kg/d is NOAEL in oral gavage reproductive toxicity study.

 

Allometric scaling is necessary for oral rat to oral human exposure. SF = 4

Corrected NOAEL =35 mg/kg/d

 

No absorption correction factor is needed for oral rat to oral human exposure.

 

Combined interspecies and intraspecies assessment factor of 12.5 (see above)

 

Duration AF = 1 since the critical window of fetal development was covered

Dose-Response AF=3 default (and in accordance with estimated BMDL), since no clear NOAEL was achieved

Quality of Data Base AF = 1 since all data endpoints are satisfied or waived.