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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
44.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
220.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

See discussion.

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
88.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
10
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
220.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

See discussion.

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:
5.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
24
Dose descriptor starting point:
NOAEL
DNEL value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See discussion.

Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
48
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
NOAEL
DNEL value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

See discussion.

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: qualitative risk assessment
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: qualitative risk assessment

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General considerations

Dermal and inhalation exposure are the most relevant routes for assessing occupational risk in humans. Based on the physicochemical properties of 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) exposure of workers to significant vapor concentrations is unlikely (vapor pressure 0.000013hPa). Nevertheless inhalation DNELs for systemic effects were derived, though it is recommended to match the DNELs with the maximally feasible saturated air concentrations in case vapour atmospheres are evaluated.

 

Identification of key values

Based on the available toxicological profile for 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) skin sensitization and repeated dose toxicity are the relevant toxicological effects which may occur following dermal (or inhalation) exposure. A specific liver toxicity was identified as the most sensitive systemic effect following repeated oral exposure. For this effect a NOAEL of 125 mg/kg bw/day was identified in a 90 day subacute gavage study with rats (BASF SE, 2016). The substance is neither considered to be genotoxic nor toxic to reproduction. 

 

 

DNEL derivation

Acute/short-term exposure – systemic effects – dermal and inhalation DNEL

According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C & L has been identified. Since for workers the dermal and inhalation exposure are the relevant routes of exposure, formally no acute/short-term exposure DNELs for systemic effects need to be derived. 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) is not classified for acute toxicity on the dermal and inhalation route of exposure.

Nevertheless a genericacute/short-term exposure DNEL was derived based on a ceiling factor of 2, in order to protect from systemic liver toxicity observed in the available oral repeated dose toxicity bioassay. A ceiling factor of 2 is recommended by theGerman Committee on Hazardous Substances for substances for which no relevant kinetic data is existing (DFG, 2011).

 

Acute/short-term and long-term exposure – local effects – dermal and inhalation DNEL

2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) is neither classified for skin irritation nor for eye irritation. Therefore, local irritation does not need to be considered in the derivation of DNELs. Though 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO) was skin sensitizing in a mouse induction assay (LLNA, BASF SE, 2012). In accordance to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008) a qualitative approach was applied for the assessment and control of risks due to skin sensitization. Consequently no DNELs for local effects were derived for acute/short-term and long-term exposure (neither for the dermal nor for the inhalation route of exposure). An adequate selection of the respective risk management measures (RMMs) at the workplaces can be performed in accordance to the REACh guidance part E.

  

Long-term exposure – systemic effects – dermal DNEL

As described above, the NOAEL of 125 mg/kg bw/day from the 90-day repeated dose oral study in the rat was taken as the relevant starting point.

In a first step a route-to-route extrapolation is made for the rat. On the assumption that, in general, dermal absorption will not be higher than oral absorption (default factor = 1) no modification of the dose descriptor is necessary to set the correct starting point when performing oral-to-dermal extrapolation. This assumption is supported by acute data indicating a higher toxicity on the oral route of exposure.

 

Oral NOAEL (rat) = dermal NOAEL(rat) = 125 mg/kg bw/day

 

The DNEL long-term dermal, systemic is calculated by applying assessment factors to the NOAEL. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 24 was calculated using the adapted concept provided by ECETOC (Guidance on Assessment Factors to derive a DNEL, Technical Report No. 110, 2010).

The ECETOC AFs are broadly consistent with those recommended by ECHA but taking into account substance specific data. e.g. in case of known mechanisms of action. The use of these “informed AF” over “default AF” for hazard and risk assessment was supported by a broad review of the available scientific data. 

This concept seems to be particularly applicable for 2-butyne-1,4-diol, ethoxylated (>1 < 4.5 mol EO), since the critical systemic health effect was identified as unspecific liver toxicity. Unspecific liver enzyme induction is not known to considerably differ, with respect to inter- and intra-species differences. Therefore in addition to adapting the factors for inter- and intra-species differences, the factor of remaining differences was omitted. In this specific case, and based on the well established, unspecific primary health effect, no concern for further inter- and/or intra-species differences can be derived, as this would e.g. be the case for specific autosomally regulated enzyme polyploidies.

Following AF were identified: 

-      Inter-species differences = 4

-      Intra-species differences = 3

-      Exposure duration: Conversion from a sub-chronic study to a chronic study = 2

 

Worker-DNEL long-term, dermal, systemic = 100/24 = 5.2 mg/kg bw/day

                                 

 

Long-term exposure – systemic effects – inhalation DNEL 

The NOAEL of 125 mg/kg bw/day from the 90-day repeat dose oral study in the rat was taken as dose descriptor. The NOAEC worker (8h) was calculated as prescribed by the guidance:

Corrected inhalatory NOAEC = rat oral NOAEL x (1/sRVrat) x (ABSoral rat/human inhal) x (sRVhuman/wRV)

 

-      N = 125 x (1/0.38) x 1 x (6.7/10)

-      N= 125 x 2.63 x 0.67 = 220.3 mg/m³.

 

The DNEL long-term inhalation, systemic is calculated by applying assessment factors to the NOAEC. Since the starting point for the DNEL calculation is a NOAEL and the study is of good/standard quality no default factors (i.e. factor 1) are introduced for “Issues related to dose-response” and “Quality of whole database”, respectively.

 

For the remaining uncertainties in extrapolation procedure and in the available data an overall assessment factor of 18 was calculated using the ECETOC document (2010), see above for justification. Following AF were identified: 

-      Inter-species differences = 1

-      Intra-species differences = 3

-      Exposure duration: Conversion from a sub-chronic study to a chronic study = 6

 

Worker-DNEL long-term inhalation, systemic = 220.3 mg/m³/5 = 44.1 mg/m³

 

 

 

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
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

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
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

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
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

See discussion.

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

No consumer uses are supported be the CSR and therefore no DNELs were derived for the general population.