Butan-1-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

310 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: The long term local inhalation DNEL for worker is derived from the occupational exposure limit (OEL) established by the German MAK commission.

Overall assessment factor (AF):

1

Dose descriptor:

other: occupational exposure limit (OEL) by the German MAK commission

Value:

310 mg/m³

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:

1

Justification:

As the MAK OEL for inhalation is based on exposure during work for 8 h, no further assessment factor is needed.

AF for interspecies differences (allometric scaling):

1

Justification:

As the MAK OEL for inhalation is based on exposure during work for 8 h, no further assessment factor is needed.

AF for other interspecies differences:

1

Justification:

As the MAK OEL for inhalation is based on exposure during work for 8 h, no further assessment factor is needed.

AF for intraspecies differences:

1

Justification:

As the MAK OEL for inhalation is based on exposure during work for 8 h, no further assessment factor is needed.

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:

low hazard (no threshold derived)

DNEL related information

Justification:

The hazard is sufficiently covered by derivation of the respective DNEL for long term local effects.

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

WORKER

 

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA.

 

Workers – Hazard via inhalation route

 

Long term systemic inhalation DNEL, worker

A low hazard for long term systemic inhalation was identified. The hazard is sufficiently covered by derivation of the respective DNEL for local effects.

 

Short term systemic inhalation DNEL, worker

The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Long term local inhalation DNEL, worker

The long term local inhalation DNEL for worker is derived from the occupational exposure limit (OEL) established by the German MAK commission. The scientific OEL from MAK for n-butyl alcohol was determined to be 100 ppm (310 mg/m3). For details on the derivation of the OEL please refer to the section “Scientific OEL for inhalation”.

As the MAK OEL for inhalation is based on exposure during work for 8 h, no further assessment factor is needed.

In conclusion, long term local inhalation DNEL, workers = 310 mg/m3

 

Short term local inhalation DNEL, Worker

 

The hazard is sufficiently covered by derivation of the respective DNEL for long term local effects.

 

 

Workers – Hazard via dermal route

Long term systemic dermal DNEL, worker

For long term systemic dermal exposure a low hazard was identified. A qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E and ECHA Practical Guide 15 “How to undertake a qualitative human health assessment and document it in a chemical safety report”). Therefore gloves and further appropriate RMMs are carried into execution, protecting from both local and systemic effects. 

 

Short term systemic dermal DNEL, worker

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Long term local dermal DNEL, worker

The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E).Therefore gloves and further appropriate RMMs are carried into execution, protecting from both local and systemic effects.

 

Short term local dermal DNEL, worker

The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E).Therefore gloves and further appropriate RMMs are carried into execution, protecting from both local and systemic effects.

 

 

Worker – Hazard for the eyes

For exposure to the eyes a medium hazard was identified, as the test substance is classified for serious eye damage Cat.1according to Regulation (EC) No 1272/2008 (CLP). A qualitative risk assessment is conducted (in accordance with "Guidance on information requirements and chemical safety assessment", Part E and ECHA Practical Guide 15 “How to undertake a qualitative human health assessment and document it in a chemical safety report”).Therefore goggles and further appropriate RMMs are carried into execution.

 

Scientific OEL for inhalation

The German MAK commission determined a scientific OEL for n-butyl alcohol of 100 ppm (310 mg/m3), which was confirmed as a German OEL by the regulatory authorities at last in 2016 (TRGS 900).

According to earlier occupational-medical studies, the critical toxic effect of exposure to n-butyl alcohol is the irritative effect on the eyes. In a longitudinal study such symptoms occurred in persons exposed to average concentrations of 200 mL/m3. When the n-butyl alcohol concentration was reduced to 100 mL/m3, the workers were free of symptoms (Sterner et al. 1949). In the early observation phase, during which the workers were exposed to concentrations of 200 mL/m3 or more, some workers developed corneal inflammation with slight to moderate corneal oedema, lacrimation and sensitivity to light.

Volunteers in a toxicokinetic study exposed via breathing masks to concentrations up to 200 mL/m3 for 2 hours did not feel adverse effects (Astrand et al. 1976), and exposure of one eye for one hour did not produce effects up to concentrations of 300 mL/m3 (Hempel-Jørgensen et al. 1999). In an earlier study with 10 volunteers, however, sensory irritation of the nose and throat was reported after exposure to 25 mL/m3 for 3 to 5 minutes. Concentrations of 50 mL/m3 caused additionally sensory irritation of the throat in all the volunteers and in some cases slight headaches (Nelson et al. 1943). As a result of the contradictory findings for irritation of the throat and nose, and as irritation of the eye is documented at concentrations of twice the MAK value, an excursion factor of 1 has been provisionally set for peak limitation according to Category I.

Thus, with a MAK value of 100 mL/m3, no eye irritation is to be expected. Likewise systemic-toxic effects are not to be expected under these conditions, as in the only relevant study with rats given n-butyl alcohol by oral administration, up to the highest tested dose of 500 mg/kg body weight and day no adverse effects were observed apart from typical alcohol related effects on the central nervous system (see endpoint summary repeated dose toxicity). Assuming a body weight of 70 kg and a respiratory volume of 10 m3 per shift with pulmonary absorption of 60 %, with a MAK value of 100 mL/m3 a worker would absorb at most about 25 mg/kg body weight daily.

The MAK value for n-butyl alcohol of 100 mL/m3 can therefore be confirmed. With the exposure conditions expected at the workplace, the amount of n-butyl alcohol taken up by the skin cannot lead to adverse effects. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

55.357 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5.6

Dose descriptor starting point:

other: occupational exposure limit (OEL) established by the German MAK commission

Value:

310 mg/m³

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:

4.2

Justification:

Single assessment factors (AF) of 3 (extrapolation from 8 to 24 h exposition) and 1.4 (extrapolation from 5 to 7 days) were combined for exposure duration.

AF for interspecies differences (allometric scaling):

1

Justification:

As all values are based on human data no interspecies derivation was done.

AF for other interspecies differences:

1

Justification:

As all values are based on human data no interspecies derivation was done.

AF for intraspecies differences:

1.34

Justification:

A potentially higher sensitivity of consumer subpopulations than workers is calculated with a AF of 2 (intraspecies factor general 10 to worker 5) and a lower mean respiration volume of the general population is considered with an AF of 0.67 (6.7 m3 respiration volume/ "8h with no activity" divided by 10 m3 respiration volume/ "8h with light activity"). The combination of those AF lead to a AF of 1.34 for intraspecies differences.

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:

DNEL (Derived No Effect Level)

Value:

155 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

other: occupational exposure limit (OEL) established by the German MAK commission

Value:

310 mg/m³

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:

1

Justification:

Differences in duration of exposure not relevant for local effects based on irritation.

AF for interspecies differences (allometric scaling):

1

Justification:

As all values are based on human data no interspecies derivation was done.

AF for other interspecies differences:

1

Justification:

As all values are based on human data no interspecies derivation was done.

AF for intraspecies differences:

2

Justification:

A potentially higher sensitivity of consumer subpopulations compared to workers is considered by using an AF of 2 (intraspecies factor general 10 to worker 5).

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:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.125 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For details on calculations please refer to “Additional information – general population”.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

As the available data indicate only minor differences in effects caused by the substance and in its metabolism between rat and human no remaining interspecies differences were identified and an assessment factor of 1 was selected.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

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)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.562 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

80

Dose descriptor starting point:

NOAEL

Value:

125 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification is used as the same exposure route is considered.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (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:

As the available data indicate only minor differences in effects caused by the substance and in its metabolism between rat and human no remaining interspecies differences were identified and an assessment factor of 1 was selected.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

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 Population

 

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. 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. The oral and dermal systemic long-term consumer DNEL is calculated based on a NOEL ("No observed effect level") of 125 mg/kg from a 90 -day oral study in rats where the only effects observed at 500 mg/kg where transient signs of ataxia and hypoactivity lasting for up to one hour after dosing as well as minor effects on red blood cell count, packed cell volume and hemoglobin at the 30 -day interim evaluation only but not at the end of the study. Thus with respect to long-term systemic effects, 500 mg/kg can probably be regarded as NOAEL ("No observed adverse effect level") and thus an additional assessment factor for remaining uncertainties was already introcuded by using the more conservative NOEL of 125 mg/kg leading to an assessment factor of 4 instead of the factor of 2.5 recommended by ECHA.

In addition, the metabolism of butan-1 -ol is comparable in all mammals including humans: The alcohol is converted by alcohol dehydrogenase to butyraldehyde. The next step leads to conversion to butyric acid which can be fully metabolised to carbon dioxide and water by the beta-oxidation pathway and thus no further assessment factor for remaining uncertainties is needed.

 

General population – Hazard via inhalation route

 

Short term systemic inhalation DNEL, General population

The test material is not classified and labelled for acute systemic toxicity (inhalation), according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Long term systemic inhalation DNEL, General population

The long term systemic inhalation DNEL for general population is derived from the corresponding DNEL for workers (=310 mg/m3) as the relevant DNEL which is sufficiently protective for both local and systemic effects. This worker DNEL is based on the occupational exposure limit (OEL) established by the German MAK commission. Therefore, single assessment factors (AF) of 3 (extrapolation from 8 to 24 h exposition) and 1.4 (extrapolation from 5 to 7 days) are used. Additionally, a potentially higher sensitivity of subpopulations than workers is calculated with a AF of 2 (intraspecies factor general 10 to worker 5) and a lower mean respiration volume of the general population is considered with an AF of 0.67 (6.7 m3 respiration volume/ "8h with no activity" divided by 10 m3 respiration volume/ "8h with light activity"), leading to a total AF of 5.6.

 

In conclusion, long-term systemic inhalation DNEL, general population = 55.357 mg/m3

Long term local inhalation DNEL, General population

The long term local inhalation DNEL for general population is derived from the corresponding DNEL for workers (=310 mg/m3) as the relevant DNEL which is sufficiently protective for both local and systemic effects. Local effects are dose-dependent and thus a safety factor of 2 to cover for more susceptible consumer sub-populations is appropriate just in case there should be any differences between workers and consumers with respect to sensitivity to local effects caused by butan-1-ol.

In conclusion, long-term systemic inhalation DNEL, general population = 155 mg/m3

 

Short term local inhalation DNEL, General population

The hazard is sufficiently covered by derivation of the respective DNEL for long term effects.

 

 

General population – Hazard via dermal route

Long term systemic dermal DNEL, General population

The DNEL long-term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

 

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

The 90-day repeated dose toxicity study 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 NOEL is 125 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Data from several in vivo studies showed a difference by a factor of ca. 2 from the acute oral LD50 (mean LD50 = 2890 mg/kg bw) to acute dermal LD50 (mean LD50 = 5700 mg/kg bw) based on all animal data considered in ECETOC JACC No.41 (2003) for those endpoints. In addition a DermWin calculation estimated a Kp = 0.00278 cm/hr (DermWin 2017). The Kp value leads to a classification for dermal absorption as low, based on the “User Manual for the Internet Version of the Danish (Q)SAR Database” (Version 1, May 2005). Therefore the dermal uptake is considered to be 50 % of the oral uptake in the worst case.

Factor for dermal NOAEL= 100 % oral / 50 % dermal= 2

Frequency of exposure in study: 7 days/week

Frequency of general population exposure: 7 days/week

 

oral NOAEL 125 mg/kg bw/day * 2 * (7/7) = 250 mg/kg bw/day dermal NOAEL

 

Step 3: Use of assessment factors: 80

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

Interspecies AF, remaining differences: 1 (for explanation please refer to “General”)

Intraspecies AF (general population): 10

Exposure duration AF: 2

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, general population = 3.125 mg/kg bw/day

 

Short term systemic dermal DNEL, General population

The test material is not classified and labelled for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Long term local dermal DNEL, General population

The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted where necessary.

 

Short term local dermal DNEL, General population

The test material is classified for skin irritation toxicity cat. 2, according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted where necessary.

 

General population – Hazard via oral route

 

Long term systemic oral DNEL, General population

The DNEL long-term, systemic (oral) is derived from the repeated dose oral toxicity study.

 

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

The 90-day repeated dose toxicity study 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 NOEL is 125 mg/kg bw/day.

 

Step 2: Modification of the starting point:

No modification is used as the same exposure route is considered.

 

Step 3: Use of assessment factors: 80

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

Interspecies AF, remaining differences: 1 (for explanation please refer to “General”)

Intraspecies AF (general population): 10

Exposure duration AF: 2

Remaining uncertainties AF: 1

 

In conclusion, long term systemic oral DNEL, general population = 1.5625 mg/kg bw/day

 

Short-term systemic oral DNEL, General population

The test material is classified for acute oral toxicity cat. 4, according to Annex VI of Regulation (EC) No 1272/2008 (CLP). However experimental data from studies conducted similar to OECD guideline were presented showing LD50 acute oral values>2000 mg/kg bw in the most commonly used and recommended animal species (Key value: 2290 mg/kg bw). Based on these most relevant values no DNEL for short-term systemic oral for the general population was determined. The DNEL for long term exposure is considered to appropriately cover this endpoint.

 

General population – Hazard for the eyes

For exposure to the eyes a medium hazard was identified, as the test substance is classified for serious eye damage Cat.1according to Regulation (EC) No 1272/2008 (CLP). A qualitative risk assessment is conducted where necessary.