Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110 (2010)
Overall assessment factor (AF):
28.44
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
176.32 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-to-route: 2 IGHRC Guidelines April 2006 and ECHA 2012. Ch R.8. p19 In the absence of route-specific information on the starting route a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) is included in the case of oral-to inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption and 100% for inhalation.

Bioavailability differences between human and animal species: 1 No evidence for a difference between species for oral exposure to test substance

Bioavailability differences between test and target substances: 1 Not applicable

Modification for exposure (experiment in animal and human): 2.632 ECHA Ch R.8, 2012: Modification for exposure for workers - 8 h exposure /day = 1/sRV rat (8h)= 1/0.38 m3/kg/d.  Applicable worker = 1/0.38; Applicable general population = 1/1.15

Modification for the respiratory volume: 0.67 ECHA Ch R.8, 2012, p 20: Respiratory volume light activity, standard conditions for worker - 8 hour (sRV human = 6.7 m3/kg/d) with relevant duration of 8 h - respiratory volume / exposure of 10 m3 (wRV). Applicable worker = 6.7/10

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL was derived from a well performed OECD TG 422 study (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
3
Justification:
The AF proposed by ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: ECETOC 3; general population: ECETOC 5). The ECETOC proposal is based on an evaluation of the scientific literature. Therefore, for the evaluation of 3-methylsulfolane the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1.58
Justification:
In accordance with Guidance R.8 a positive result in OECD TG 421/422 may be considered sufficient for the calculation of a DNELfertility and/or a DNELdevelopment; however, an additional assessment factor of 2 to 5, decided on a case-by-case basis, should generally be used to take account of the lower sensitivity of the study, unless there is evidence to support that the lower sensitivity is not relevant for the effect mechanism of the test substance (e.g. specific teratogenic effects that are the result of a known mechanism of action). Based on ECETOC TR 110: the larger group sizes of the OECD TG 416 study design afford a probability of detecting a statistically significant difference, and therefore a NOAEL, that is between √2 and √2.5 lower (1.41- to 1.58-fold) than that of OECD TG 421 and OECD TG 422. ECETOC guidance taking the worst-case AF is followed.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainites
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

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
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.69 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110 (2010)
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to-route: 1 Oral-Dermal; On the assumption that, in general, dermal absorption will not be higher than oral absorption, no factor should be introduced when performing oral-to-dermal extrapolation.

Bioavailability differences between human and animal species: 1. No evidence for a difference between species for oral exposure to the test substance.

Bioavailability differences between test and target substances: 1. Not applicable.

Modification for exposure (experiment in animal and human): 1. Not applicable.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL calculation is a NOAEL, the default assessment factor, as a standard procedure, is 1. ECHA, 2012, Chapter R8
AF for differences in duration of exposure:
6
Justification:
(ii) 6 for duration exposure / Since the dose descriptor is derived from a 28-day study, an additional assessment factor of 6 to take account of extrapolation of subacute data to chronic exposure; subacute to sub-chronic = 3 and sub-chronic to chronic = 2 and subacute to chronic = 6 ; sub-chronic’ usually refers to a 90 day study; ‘sub-acute’ usually refers to a 28 day study; ‘chronic’ usually refers to a 1.5 - 2 year study (for rodents) (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
Extrapolation from Rat to Humans
AF for other interspecies differences:
1
Justification:
Correction for remaining difference i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). [ECHA, 2012, Chapter R8, 32]. ECETOC (TR No. 110 (2010)) supports the inclusion of the factor for allometry, but considers that routine application of the factor of 2.5 is unjustified as a default factor. For interspecies extrapolation for systemic effects of 3-methylsulfolane, both toxicokinetic and toxicodynamic aspects should be considered. Toxicokinetics are covered by the principle of allometric scaling, with a factor of 4 for rats to humans, as the default approach. Allometry is generally accepted in the scientific community when the parent chemical or a stable metabolite is the toxic entity that is metabolically detoxified and when renal excretion is the predominant route of elimination. Therefore, for the derivation for the DNEL for 3-methylsulfolane the factor 2.5 for remaining differences including toxicodynamics is considered unnecessary.
AF for intraspecies differences:
3
Justification:
The AF proposed by ECETOC for intraspecies extrapolation of systemic effects if the Point of Departure is derived from animal studies (worker: ECETOC 3; general population: ECETOC 5). The ECETOC proposal is based on an evaluation of the scientific literature. Therefore, for the evaluation of 3-methylsulfolane the ECETOC TR No. 110 (2010) is followed until the scientific basis for using an alternative approach has been established.
AF for the quality of the whole database:
1
Justification:
Appropriate completeness and adequacy of the database
AF for remaining uncertainties:
1
Justification:
no remaining
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

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
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

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

In accordance with the "Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health" it is not always necessary to derive DNELs for all mentioned populations. Depending on the exposure pattern, only DNELs for the relevant populations will have to be derived. It has to be justified why the selected populations have been considered as relevant (and others as irrelevant).

In the case of 3-Methyl sulfolane the use profile indicates that the product is not used by the general population, and human exposure via the environment is not considered likely (Chapter R.16 Version 3.0 2016 indicates that an exposure assessment of the indirect exposure of humans via the environment is not required for this substance).

In conclusion, as no exposure is foreseen in the general population, it is not considered a relevant population, and consequently no hazard assessment needs to be performed.