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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.22 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
Value:
166.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are reliable experimental data on repeated exposure by inhalation. No route to route extrapolation is needed.

AF for dose response relationship:
1
Justification:
clear dose response
AF for differences in duration of exposure:
6
Justification:
Default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not necessary, as no route-to-route extrapolation is applied and doses expressed as concentrations are assumed to be already scaled.
AF for other interspecies differences:
1
Justification:
default for remaining interspecies differences
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
read-across data (substance acts in a similar toxicological pattern)
AF for remaining uncertainties:
2.5
Justification:
Default value for remaining uncertainties
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:
1.14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC, Technical Report No. 110
Overall assessment factor (AF):
18
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
clear dose responce
AF for differences in duration of exposure:
6
Justification:
Default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling in case of local effects
AF for other interspecies differences:
1
Justification:
No other differences are identified
AF for intraspecies differences:
3
Justification:
As respiratory irritation due to the caustic property of 2-dibutylaminothanol is the leading effect, no huge differences within humans are expected. Therefore, the AF for worker intraspecies differences was set to 3 as recommended in "Guidance on assessment factors to derive a DNEL", Technical Report No. 110, ECETOC, 2010.
AF for the quality of the whole database:
1
Justification:
read-across data (substance acts in a similar toxicological pattern)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties are identified in case of respiratory irritation
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.92 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC, Technical Report No. 110, 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
471.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A systemic NOAEC of 236.3 mg/m³ from the Repeated Dose and Reproduction/Developmental Toxicity Screening Test in rats for the nearest analogue dibutylethanolamine (CAS 102-81-1) is available (BASF, 2013). This value was converted into the corrected dermal NOAEL.

AF for dose response relationship:
1
Justification:
clear dose response
AF for differences in duration of exposure:
6
Justification:
Default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling is applied.
AF for other interspecies differences:
1
Justification:
no significant systemic adverse effects were noted therefore no uncertainties in toxycodynamic are expected
AF for intraspecies differences:
5
Justification:
worker default
AF for the quality of the whole database:
1
Justification:
read-across data (substance acts in a similar toxicological pattern)
AF for remaining uncertainties:
1
Justification:
No other uncertainties are identified.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.” Assessment factors for DNEL derivations are based on "Guidance on Assessment Factors to derive DNEL" (ECETOC Technical Report No. 110, 2012).

 

Available dose descriptors:

For butylethanolamine (CAS 111-75-1), the following dose descriptors are available:

Hazard via inhalation route

Long-term exposure – systemic effects:

NOAEC of 236.3 mg/m³ for systemic effects established in a combined Repeated Dose and Reproduction/Developmental Toxicity Screening Test in rats (OECD 422; Inhalation exposure: OECD 413; BASF, 2013; Project No.: 87R0286/05I017) for the nearest analogue dibutylethanolamine (CAS 102-81-1) is taken for the systemic DNEL derivation for butylethanolamine (CAS 111-75-1). Since local effects prevail over systemic effects in this study, local NOAEC (20.6 mg/m³) < systemic NOAEC (236.3 mg/m³) and therefore NOAEC of 20.6 mg/m³ covers sufficiently systemic effects.

Acute short-term exposure – systemic effects:

According to the LC50 of > 24.69 mg/L established in the key acute inhalation study in rats (BASF AG, 1977), butylethanolamine (CAS 111-75-1) is not classified as toxic if inhaled (no mortalities occurred). Therefore no DNEL for short-term exposures needs to be derived.

Long-term exposure - local effects

Long-term inhalation DNEL for local effects is based on the lowest NOAEC of 20.6 mg/m³ .

Acute short-term exposure – local effects

Slight local effects (mucous membrane irritation) occurred in the key acute inhalation study in rats (BASF AG, 1977). Control of risk is addressed qualitatively.

Hazard via dermal route

Long-term exposure – systemic effects:

NOAEC of 236.3 mg/m³ (analytical concentration) for systemic toxicity established in a combined Repeated Dose and Reproduction/Developmental Toxicity Screening Test in rats (OECD 422; Inhalation exposure: OECD 413; BASF, 2013; Project No.: 87R0286/05I017) for the nearest analogue dibutylethanolamine (CAS 102-81-1) is taken for the DNEL derivation for butylethanolamine (CAS 111-75-1). The starting point can be obtained by conversion of inhalation NOAEC into dermal NOAEL (route-to-route extrapolation).

Acute short-term exposure – systemic effects:

According to the LD50 of > 2000 mg/kg bw in a dermal acute toxicity study in rabbits (Latven, 1977), butylethanolamine (CAS 111-75-1) is not classified as acutely toxic in contact with skin. Therefore, no DNEL for short-term exposures needs to be derived.

Long-term exposure - local effects

Long-term dermal DNEL for local effects should be sufficiently covered by the long-term dermal DNEL for systemic effects.

Acute short-term exposure – local effects:

Due to the fact that the substance is irritating to skin, local skin effects such as surface skin damage occur. The risk assessment is therefore performed qualitatively. This is done by considering specific RMMs and OCs that ensure controlled risk.

Modification of the starting point:

From all available data for the different human health endpoints it is clear that butylethanolamine (CAS 111-75-1) exerts its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance, reflecting the routes, the duration and the frequency of exposure.

Bioavailability (absorption)

There is no substance-specific information on absorption by the oral, dermal and inhalation routes available for butylethanolamine (CAS 111-75-1). The absorption rates are assessed based on the physico-chemical properties of the substance. Due to the high water solubility of the substance (1000 g/L), its log Kow of 0.64 and molecular weight of 117.19 g/mol, dermal absorption is expected to a minor extent (10%). With regard to the irritating properties of the substance, the penetration may be enhanced which is based on the skin surface damage. By contrast, a systemic dose cannot be reached since local effects prevail over systemic effects.

In addition, 100% oral absorption is considered appropriate based on the acute toxicity data and the physico-chemical properties which are in the range suggestive of absorption from the gastro-intestinal tract.

Furthermore, 50% absorption is considered for inhalation. This is based on the results of inhalation toxicity in the acute toxicity study in rats, log Pow of 0.64 and the low vapour pressure (13.94 Pa).

Route-to-route extrapolation:

Inhalation-to-dermal extrapolation is performed to obtain long-term dermal NOAEC for systemic effects. According to “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health; Section 8.4.2”, no default factor for absorption should be introduced in case of inhalation-to-dermal extrapolation, because a higher oral (or dermal) compared to inhalation absorption appears on empirical grounds not justified.

Therefore, the following formula was used: corrected dermal NOAEL = inhalation NOAEC x sRVrat x (6/8) where sRV described the standard Respiratory Volume and the factor (6/8) considers the differences in the exposure duration (rats were exposed for 6 hours while workers are exposed for 8 hours).

Exposure conditions:

The rats were exposed 6 hours to the test substance while workers are exposed 8 hours per day.

6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in case of the inhalation NOAEC established in the combined Repeated Dose and Reproduction/Developmental Toxicity Screening Test in rats (OECD 422; Inhalation exposure: OECD413; BASF, 2013; Project No.: 87R0286/05I017), which was used to derive the dermal long-term DNEL.No allometric scaling factor was applied in case of derivation of the inhalation DNEL from the inhalation NOAEC.

An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in case of derivation of systemic inhalation DNEL.

Intraspecies differences:

An assessment factor of 5 was applied for workers in cases of DNEL derivation for systemic effects by long-term exposure. A reduced assessment factor of 3 for workers was applied in case of DNEL derivation for local effects by inhalation.

Extrapolation of duration:

An assessment factor of 6 was applied for duration of exposure in case of DNEL derivation by route-to-route extrapolation using NOAEC from combined Repeated Dose and Reproduction/Developmental Toxicity Screening Test in rats (OECD 422; Inhalation exposure: OECD413; BASF, 2013; Project No.: 87R0286/05I017). Males were exposed 28 days to test material and sacrificed on day 29; females were exposed 50 days to test material and sacrificed on day 51 (exposure duration is rather sub-acute nor sub-chronic).

 

Quality of whole data base:

The assessment factors for uncertainties to the quality of the data base are used: 1 in cases where the data on the substance of interest has been used or the use of a read-across substance with similar toxicological behaviour is described. A similar toxicological pattern is expected for both butylethanolamine and dibutylethanolamine.

Issues related to dose response:

A default assessment factor of 1 is applied when NOAEC was used (clear dose response in the study).

Calculation of DNELs:

Long-term exposure by inhalation – systemic effects:

NOAEC of 20.6 mg/m³ (analytical concentration) can serve as the starting point. The inhalation rat NOAEC was converted into the inhalation human NOAEC corrected for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factor and by adjusting the time of exposure (rats were exposed 7 days/week, 6 h/day and worker is exposed 5 days/week, 8 h/day) (x 6.7 m³/10 m³ x 7/5 x 6/8). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 166.2 mg/m³/day.
236.3 mg/m³ x (6.7/10) x (7/5) x (6/8) = 166.2 mg/m³

DNEL = 166.2 mg/m³ / (6 x 2.5 x 5 x 1 x 1) = 2.21 mg/m³
where 6 - duration of exposure, 2.5 – remaining interspecies differences; 5 – Intraspecies (workers), 1 - dose response, 1 - quality of data base (read-across substance with similar toxicological behaviour).

Long-term exposure by inhalation – local effects:

The local NOAEC from a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test in rats via inhalation conducted according to OECD 422 (BASF SE 2013) was identified as the appropriate starting point for local DNEL derivation for long-term exposure following inhalation. The NOAEC for local irritation of respiratory tract was 20.6 mg/m³/day for rats. The assessment factors were applied according to the "Guidance on information requirements and chemical safety assessment", Chapter R.8, v 2.1, Nov. 2012 and "Guidance on assessment factors to derive a DNEL", Technical Report No. 110, ECETOC, 2010.

No modification of the starting point was necessary due to the local effects.

DNEL = 20.6 mg/m³ / (3 x 6 x 1 x 1) = 1.14 mg/m³ where 3 - intraspecies, 6 - duration of exposure, 1 - dose response, 1 - quality of data base (read-across substance with similar toxicological behaviour).

Long-term dermal exposure – systemic effects:

The systemic NOAEC from a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test in rats via inhalation conducted according to OECD 422 (BASF SE 2013) was identified as the appropriate starting point for systemic DNEL derivation for long-term dermal exposure. The NOAEC for systemic effects was 236.3 mg/m³/day for rats. The assessment factors were applied according to the "Guidance on information requirements and chemical safety assessment", Chapter R.8, v 2.1, Nov. 2012 and "Guidance on assessment factors to derive a DNEL", Technical Report No. 110, ECETOC, 2010.

Corrected dermal NOAEL = inhalation NOAEC x sRVrat x (6/8) x (7/5) x (ABSinhal rat / ABSdermal human) = 236.3 mg/m³ x 0.38 m³/kg bw x (6/8) x (7/5) x (50%/10%) = 471.4 mg/kg bw.

DNEL = 471.4 mg/kg bw / (4 x 5 x 6 x 1 x 1) =3.92 mg/kg bw.

Assessment factors are: 4 – interspecies, 5 – intraspecies, 6 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (read-across substance with a similar toxicological behaviour).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

No consumer uses are intended for butylethanolamine therefore no DNELs need to be derived.