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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:
0.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
DNEL value:
8.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to the discussion.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidance for species differences including toxicodynamics.
AF for intraspecies differences:
3
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be half of oral absorption.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidance for species differences including toxicodynamics.
AF for intraspecies differences:
3
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General

 

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA REACH guidance (2010) and ECETOC (2003).

 

Acute/short-term-systemic effects

 

Hex-3-yn-2,5-diol is classified and labelled for acute oral toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the available test data for acute oral toxicity.

Hex-3-yn-2,5-diol is not classified and labelled for acute dermal and inhalation toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the available test data for acute dermal and inhalation toxicity. No worker DNEL (short-term, systemic) was derived due to missing dose-response relationship.

 

Acute/short-term and long-term exposure - local effects

 

Skin irritation/corrosion: The test substance has skin irritation potential and is classified as skin irritant, cat. 2 according to Regulation (EC) No 1272/2008 (CLP) and associated to the low hazard band. A qualitative risk assessment is conducted for acute/long-term local toxicity (dermal) in order to ensure an appropriate level of protection regarding skin irritation.

 

Skin sensitisation: Hex-3-yn-2,5-diol was shown to be a skin sensitiser in a LLNA (BASF SE, 2012). The substance is therefore classified as skin sensitiser, cat. 1 according to Regulation (EC) No 1272/2008 (CLP) and associated to the high hazard band. A qualitative risk assessment is conducted in order to ensure an appropriate level of protection regarding sensitisation.

 

Eye irritation:Hex-3-yn-2,5-diol causes serious eye damage in the available eye irritation studies in rabbits (BASF 1971, 1973). The test substance is classified as eye damaging, cat.1 according to Regulation (EC) No 1272/2008 and associated to the moderate hazard band.

 

Respiratory irritation: Irritation of the mucous membrane was observed in the available acute inhalation study (BASF, 1971). Hex-3-yn-2,5-diol is therefore associated to the low hazard band. Further, the DNEL derived for systemic long-term worker exposure via inhalation route is considered sufficiently protective regarding respiratory irritation.

 

Long term, systemic DNEL

Occupational exposure to the test item occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 422 study (BASF SE, 2012) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL, based on adverse alterations on stomach, spleen, liver and kidney in rats is 5 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Based on the hydrophilic properties (log Pow: -0.24 and high water solubility), it is assumed that the substance is removed from the air in the upper respiratory tract and is not completely absorbed by inhalation exposure. Therefore, inhalation absorption is considered to be the same than oral absorption.

 

Relevant dose descriptor (NOAEL): 5 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 1

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

 

Corrected inhalatory NOAEC for workers

= 5 mg/kg bw/d × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³)

= 8.8 mg/m³

 

Step 3: Use of assessment factors: 18

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Intraspecies AF (worker): 3

Exposure duration AF: 6

 

In conclusion, long term systemic inhalation DNEL, workers = 0.5 mg/m³

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 422 study (2012) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 5 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test item (based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12): Dermal absorption is supposed low for several reasons: 1. Highly soluble in water, 2. Log Pow < 0.

Therefore, dermal uptake is anticipated to be lower than oral uptake. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Thus, dermal absorption can be reasonably estimated to be 50 % of oral absorption.

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat /ABS dermal human]

= 5 mg/kg bw/day x (100/50)

= 10 mg/kg bw/day

 

Step 3: Use of assessment factors: 72

Interspecies AF, allometric scaling (rat to human): 4

Intraspecies AF (worker): 3

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, workers = 0.14 mg/kg bw/day

 

References

(not included as endpoint study record)

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

 

- ECETOC Technical Report No. 110 (2010). Guidance on assessment factors to derive a DNEL.

 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
3.75 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to the discussion.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidance for species differences including toxicodynamics.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be half of oral absorption.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidance for species differences including toxicodynamics.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high 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:
0.04 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is required since a repeated dose oral toxicity study is available.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidance for species differences including toxicodynamics.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General

 

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA REACH guidance (2010) and ECETOC (2003).

 

Acute/short-term- systemic and local effects

 

Dermal and by inhalation:

For the assessment of acute/short-term systemic and local effects for the general population please refer to the hazard assessment of the worker.

 

Oral:

Hex-3-yn-2,5-diol is classified and labelled for acute oral toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the available test data for acute oral toxicity. However, since no peak exposure via oral route is expected for the general population no oral DNEL (short-term, systemic) was derived.

 

Long-term, systemic DNEL

In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 422 study (BASF, 2012) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL, based on adverse alterations on stomach, spleen, liver and kidney in rats is 5 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Based on the hydrophilic properties (log Pow: -0.24 and high water solubility), it is assumed that the substance is removed from the air in the upper respiratory tract and is not completely absorbed by inhalation exposure. Therefore, inhalation absorption is considered to be the same than oral absorption.

 

Relevant dose descriptor (NOAEL): 5 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 1

AF for allometric scaling: 4

Body weight: 60 kg

General population respiratory volume (wRV) for 24 hours: 20 m³/person

 

Corrected inhalatory NOAEC for general population

= [(5 mg/kg bw/d / 4) × 60 kg] / 20 m³

= 3.75 mg/m³

 

Step 3: Use of assessment factors: 30

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Intraspecies AF (general population): 5

Exposure duration AF: 6

 

In conclusion, long-term, systemic inhalation DNEL, general population = 0.125 mg/m³

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 422 study (2012) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 5 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test item (based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12): Dermal absorption is supposed low for several reasons: 1. Highly soluble in water, 2. Log Pow < 0.

Therefore, dermal uptake is anticipated to be lower than oral uptake. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Thus, dermal absorption can be reasonably estimated to be 50 % of oral absorption.

In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat /ABS dermal human]

= 5 mg/kg bw/day x (100/50)

= 10 mg/kg bw/day

 

Step 3: Use of assessment factors: 120

Interspecies AF, allometric scaling (rat to human): 4

Intraspecies AF (general population): 5

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, general population = 0.08 mg/kg bw/day

 

Oral exposure:

 

Step 1: Selection of the relevant dose descriptor (starting point):

The OECD TG 422 study (2012) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 5 mg/kg bw/day.

 

Step 2: Use of assessment factors: 120

Interspecies AF, allometric scaling (rat to human): 4

Intraspecies AF (general population): 5

Exposure duration AF: 6

 

In conclusion, long term systemic oral DNEL, general population = 0.04 mg/kg bw/day

 

References

(not included as endpoint study record)

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

 

- ECETOC Technical Report 110 (2010). Guidance on assessment factors to derive a DNEL.