Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.32 µg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25 000
Dose descriptor starting point:
T25
Value:
4.48 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
7.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of specific absorption data following oral, dermal or inhalation exposure, the acute toxicity data can be used to establish a factor for the oral-to-inhalation route extrapolation.

The inhalation LC50 in the rat after a 6-hour exposure is approximately 1.7 mg/L (OTS, 1992). Taking into account a rat breathing volume of 0.29 m³/kg bw and assuming 100% absorption the corresponding systemic dose is 490 mg/kg bw. In comparison, oral LD50 values ranging between 100 and 350 mg/kg bw have been reported for the rat (OTS, 1992; MAK, 1985; Druckrey et al., 1970), indicating that inhalation absorption will not be higher than oral absorption. Thus, the factor of 1 for oral-to-inhalation extrapolation is justified.

Taking into account the T25 (oral, workplace) of 4.48 mg/kg bw/d, the 8-h standard respiratory volume of 0.38 m³/kg bw for the rat, the adjustment of the respiratory volume for light activity of 6.7 m³/10 m³ and the oral-to-inhalation route extrapolation factor of 1 the T25 (inhalation, workplace) can be calculated as:

T25 (inhalation, workplace) = 4.48 mg/kg bw/d / 0.38 m³/kg bw x 1 x 6.7 m³/10 m³ = 7.9 mg/m³

 

AF for dose response relationship:
25 000
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, the dose descriptor T25, has an increasing order incorporated uncertainty in its estimate and therefore, there is no separate assessment factor to account for this. Another related issue concerning the dose response that is relevant specifically for non-threshold effects is high to low dose extrapolation. This is covered with a default value for the worker of 25000.
AF for differences in duration of exposure:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for this extrapolation step for non-threshold effects.
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012) no interspecies assessment factor for the inhalation route have to apply.
AF for other interspecies differences:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for non-threshold effects.
AF for intraspecies differences:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for non-threshold effects.
AF for the quality of the whole database:
1
Justification:
ECHA standard value for good/standard quality of the database.
AF for remaining uncertainties:
1
Justification:
No further remaining differences are available.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.1 µg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100 000
Dose descriptor starting point:
T25
Value:
4.48 mg/kg bw/day
Modified dose descriptor starting point:
T25
Value:
9.96 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of specific absorption data following oral, dermal or inhalation exposure, the acute toxicity data can be used to establish a factor for the oral-to-dermal route extrapolation.

The only species where both dermal and oral acute toxicity data are available is the mouse. Whereas the oral LD50 is 400 mg/kg bw (OTS, 1992), the dermal LD50 is > 830 mg/kg bw (830 mg/kg bw caused 15% death; Doak et al., 1972). This data indicates that dermal absorption will be more than 2-fold lower than oral absorption, justifying a factor of 0.5 for oral-to-dermal extrapolation.

Taking into account the T25 (oral, workplace) of 4.48 mg/kg bw/d and the oral-to-dermal route extrapolation factor of 0.5 the T25 (dermal, workplace) can be calculated as:

T25 (dermal, workplace) = 4.48 mg/kg bw/d / 0.5 = 9.96 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, the dose descriptor T25, has an increasing order incorporated uncertainty in its estimate and therefore, there is no separate assessment factor to account for this. Another related issue concerning the dose response that is relevant specifically for non-threshold effects is high to low dose extrapolation. This is covered with a default value for the worker of 25000.
AF for differences in duration of exposure:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for this extrapolation step for non-threshold effects.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default value for the rat.
AF for other interspecies differences:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for non-threshold effects.
AF for intraspecies differences:
1
Justification:
According to ECHA Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, 2012), linearised approach for DMEL calculation, no assessment factor has to be applied for non-threshold effects.
AF for the quality of the whole database:
1
Justification:
ECHA standard value for good/standard quality of the database.
AF for remaining uncertainties:
1
Justification:
No further remaining differences are available.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

1,3-propanesultone is a highly reactive alkylating agent. As its hazard potential is dominated by the carcinogenic potency, the establishment of DNELs is not needed and only DMELs are relevant.

Acute /short-term exposure – systemic and local effects

Due to its carcinogenic potency 1,3-propanesultone is manufactured and used under rigorous risk management measures which prevent the occurrence of peak exposures. Therefore, the derivation of acute/short term DMELs for local and systemic effects is not needed. This is in agreement with the “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, 2012).

Long term exposure - systemic and local effects

A dermal T25 value of 9.96 mg/kg bw/d has been established for 1,3-propanesultone. Taking into account an interspecies assessment factor of 4 for rat-to-human extrapolation and the high-to-low-dose extrapolation factor of 25000 the DMEL can be calculated as follows:

DMEL(long term dermal exposure, systemic effects) = 9.96 mg/kg bw/d / 4 / 25000 = 0.0001 mg/kg bw/d or 0.1 µg/kg bw/d.

For inhalation exposure a T25 value of 7.9 mg/m³ has been derived. As for the inhalation route no interspecies assessment factors applies, only the high-to-low-dose extrapolation factor of 25000 has to be taken into account to calculate the DMEL:

DMEL(long term inhalation exposure, systemic effects) = 7.9 mg/m³ / 25000 = 0.00032 mg/m³ or 0.32 µg/m³

In the chronic skin painting study in mice (Doak et al., 1976) the incidence of local and systemic tumors were similar, i.e. 59% of the treated mice developed local tumors and 51% systemic tumors. Therefore, the local effects are covered by the DMEL established for long term exposure - systemic effects and a derivation of a DMEL for long term exposure - local effects is not needed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population