1-[(2-butyloctyl)oxy]-3-(3,4-dihydroisoquinolinium-2-yl)propan-2-yl sulfate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

97.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Acute/short-term exposure - systemic effects

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate displays no acute toxicity up to 5000 mg/kg bw determined in rats for the oral and dermal route. No experimental data for the inhalation route are available. Therefore, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

 

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

 

Based on the available toxicological information, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate is not subject to classification for skin, eye and/or respiratory irritation and no worker DNEL for local effects following acute/short-term or long-term exposure is derived. In addition no skin sensitizing properties were observed.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-repsonse for human health".

 

Long-term exposure - systemic effects

 

For the dermal route, the NO(A)EL of 1000 mg/kg bw/day from the key subacute oral toxicity study (BASF, 2006) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal exposure to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate.

In a 28 -day repeated dose toxicity study with 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate no substance-related adverse findings were obtained. Therefore, the no-observed-adverse-effect level (NOAEL) was 1000 mg/kg body weight per day in both sexes. A worst case dermal absorption of 100 % was assumed.

 

For the inhalation route, the NO(A)EL of 1000 mg/kg bw/day from the same subacute oral toxicity study (BASF, 2006) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal inhalation to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate. A DNEL was derived even though significant exposure via inhalation except to aerosols is highly unlikely due to very low vapour pressure of <0.000001 hPa at 20 °C. This is why a factor of only 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human) × sRV(human)/wRV(human)

with:

oral NO(A)EL: 1000 mg/kg bw/day

sRV(rat): 0.38 m³/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV(human)/wRV(human): 6.7 m³/10 m³ [ratio of human standard respiratory volume to worker respiratory volume]

Accordingly, the oral NO(A)EL of 1000 mg/kg bw/day is transformed in an inhalation NO(A)EC of 1763 mg/m³.

 

The following assessment factors are used for the derivation of worker DNELs for dermal or inhalation exposure to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate:

Interspecies factor (rat to human): 4 [used for the dermal route only]

Intraspecies factor (worker): 3

Exposure duration factor: 6 (subacute to chronic) [for the dermal and inhalation route]

Quality of whole database factor: 1

 

The resulting worker DNELs are:

worker DNEL (dermal exposure) = 1000 mg/kg bw/day / (4 × 3 × 6 × 1 × 1) = 1000 mg/kg bw/day /72 = 13.9 mg/kg bw/day

worker DNEL (inhalation exposure) = 1763 mg/m³ / (3 × 6 × 1 × 1) = 1763 mg/m³ / 18 = 97.9 mg/m³

 

This is in line with ECETOC technical report no. 110, 2010 "Guidance on assessment factors to derive a DNEL". and ECETOC technical report no. 86, 2003 “Derivation of assessment factors for human health risk assessment”.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

Acute/short-term exposure - systemic effects

 

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified.

Referring to the available data on acute toxicity, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate displays no acute toxicity up to 5000 mg/kg bw determined in rats for the oral and dermal route. No experimental data for the inhalation route are available. Therefore, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate is not subject to classification for acute toxicity according to Directive 67/548/EEC and Regulation No 1272/2008, and consequently the derivation of worker DNELs for acute/short-term exposure - systemic effects is not required.

 

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

 

Based on the available toxicological information, 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate is not subject to classification for skin, eye and/or respiratory irritation and no general population DNEL for local effects following acute/short-term or long-term exposure is derived. In addition no skin sensitizing properties were observed.

This is in line with the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose[concentration]-repsonse for human health".

 

Long-term exposure - systemic effects

For the dermal route, the NO(A)EL of 1000 mg/kg bw/day from the key subacute oral toxicity study (BASF, 2006) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal exposure to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate.

In a 28 -day repeated dose toxicity study with 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate no substance-related adverse findings were obtained. Therefore, the no-observed-adverse-effect level (NOAEL) was 1000 mg/kg body weight per day in both sexes. A worst case dermal absorption of 100 % was assumed.

 

For the inhalation route, the NO(A)EL of 1000 mg/kg bw/day from the same subacute oral toxicity study (BASF, 2006) is considered to represent the appropriate dose descriptor for systemic effects related to long-term dermal inhalation to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate. A DNEL was derived even though significant exposure via inhalation except to aerosols is highly unlikely due to very low vapour pressure of <0.000001 hPa at 20 °C. This is why a factor of only 1 was assumed for route to route (oral to inhalation) extrapolation.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NO(A)EL is converted into an inhalation NO(A)EC according to the following formula:

inhalation NO(A)EC = oral NO(A)EL × 1/sRV(rat) × ABSoral(rat)/ABSinhalation(human)

with:

oral NO(A)EL: 1000 mg/kg bw/day

sRV(rat): 1.15 m³/kg bw/day [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

Accordingly, the oral NO(A)EL of 1000 mg/kg bw/day is transformed in an inhalation NO(A)EC of 869.56 mg/m³.

 

For the oral route, the NO(A)EL of 1000 mg/kg bw/day from the same subacute oral toxicity study (BASF, 2006) is considered to represent the appropriate dose descriptor for systemic effects related to long-term exposure to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate.

 

The following assessment factors are used for the derivation of general population DNELs for dermal, inhalation or oral exposure to 1-((2-Butyloctyloxymethyl)-2-(3,4-dihydro-isoquinolinium-2-yl)ethyl)sulfate:

Interspecies factor (rat to human): 4 [used for the dermal and oral route only]

Intraspecies factor (general population): 5

Exposure duration factor: 6 (subacute to chronic) [for the dermal, inhalation and oral route]

Quality of whole database factor: 1

 

The resulting general population DNELs are:

general population DNEL (dermal exposure) = 1000 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 1000 mg/kg bw/day / 120 = 8.3 mg/kg bw/day

general population DNEL (inhalation exposure) = 869.56 mg/m³ / (5 × 6 × 1 × 1) = 869.56 mg/m³ / 30 = 29 mg/m³

general population DNEL (oral exposure) = 1000 mg/kg bw/day / (4 × 5 × 6 × 1 × 1) = 1000 mg/kg bw/day / 120 = 8.3 mg/kg bw/day

 

This is in line withECETOC technical report no. 110, 2010 "Guidance on assessment factors to derive a DNEL". and ECETOC technical report no. 86, 2003 “Derivation of assessment factors for human health risk assessment”.