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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.85 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
240 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
296.21 mg/m³
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC)is obtained by conversion of the oral NOAEL of 240 mg/kg bw fromthe Repeated Dose 90-Day Oral Toxicity Studyof BAE in rats (according to OECD 408; Jadhav, 2020) taking into account the differences in bioavailability, differences between experimental and human exposure conditions and respiratory volumes.

In detail, 50 % oral absorption and 100% inhalation absorption (as specified in ECHA Reach Guidance for the case of oral-to-inhalation extrapolation), the sRV (standard respiratory volume of rats during 8 hours) of 0.38 m³/kg/day and a factor of 0.67 (derived of the standard respiratory volumes for workers under normal conditions and by light activity: 6.7 m³ and 10 m³) and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. rats (7 days continuous exposure) have been used.

corrected NOAEC = 240 mg/kg bw/day * (50 %/100 %)*(100 %/100 %)*(1/0.38 m³/kg/day)* 0.67 m³ * 1.4 = 296.21 mg/m³

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
1
Justification:
default (no allometric scalling should be applied in case of oral-to-inhalation extrapolation)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (no remaining uncertainties are identified)
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.36 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):
100
Dose descriptor starting point:
NOAEL
Value:
240 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
336 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The corrected dose descriptor starting point (NOAEC) is obtained by conversion of the oral NOAEL of 240 mg/kg bw from theRepeated Dose 90-Day Oral Toxicity Study in rats of N-Butylaminoethanol(according to OECD 408; Jadhav, 2020) taking into account the differences between experimental and human exposure conditions.

In detail, performing oral-to-dermal extrapolation no defalut factor (i.e. factor 1) was introduced (as dermal aborption will not be higher than oral aborption) and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. rats (7 days continuous exposure) have been used.

The bioavailability between experimental animals and humans at the relevant level of exposure is assumed to be the same; therefore no further correction was necessary.

corrected NOAEC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (7/5 exposure) = 240 mg/kg bw/day * (100 %/100 %) * 1.4 = 336 mg/kg bw/day

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
default (for extrapolation of subchronic to chronic exposure durations)
AF for interspecies differences (allometric scaling):
4
Justification:
default (for rats)
AF for other interspecies differences:
2.5
Justification:
default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)
AF for intraspecies differences:
5
Justification:
default (for workers)
AF for the quality of the whole database:
1
Justification:
default (GLP guideline study of high quality)
AF for remaining uncertainties:
1
Justification:
default (no remaining uncertainties are identified)
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)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

 

Available dose descriptors:

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

Hazard via inhalation route

Long-term exposure – systemic effects:

NOAEL of 240 mg/m³fromthe Repeated Dose 90-Day Oral Toxicity Study in ratsof N-butylaminoethanol (CAS 111 -75 -1; according to OECD 408; Jadhav, 2020)is taken for the systemic DNEL derivation.

Acute short-term exposure – systemic effects:

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute need to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.

However, for N-butylaminoethanol, "No hazard is identified” as it is not classified for acute hazards via the inhalation route of exposure and has additionally a very low volatility with a vapor pressure of only13.94 Pa at 20 °C(calculated value usingthe equation according to EU Technical Guidance Document on Risk Assessment (TGD, Part II; Section 2.3.2, Equation (2), 2003). As input parameters, the experimental values of the dynamic method according to OECD 104 (BASF AG, 1984) were used).

Moreover, the acute inhalation study on the test substance revealed an LC50 > 24.69 mg/L in rats (no mortalities occurred; BASF AG, 1977).

So based on results of animal studies and the low vapour pressure N-butylaminoethanol does not pose an inhalation hazard and inhalation is not a likely route of exposure. Therefore, no DNEL is required and a DNEL is not quantifiable and not relevant (No adequate route-specific information). Local effects can be covered sufficiently by the long-term DNEL for systemic effects.

Long-term exposure - local effects

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

N-butylaminoethanol has been found to be irritating to the respiratory system. A mucous membrane irritation occurred in the key acute inhalation study in rats conducted with butylethanolamine (BASF AG, 1977). Based on this, the Classification and labelling as STOT SE 3 - respiratory irritation (H335 -May cause respiratory irritation) has been derived. Furthermore, the substance has been found to have a low vapour pressure (13.94 Pa at 20 °C).

However, no adequate data is available for setting an long-term or acute / short-term inhalation DNEL for local effects.

Therefore, a DNEL is not quantifiable (No adequate route-specific information) and a "low hazard (no threshold derived)" is chosen according to ECHA's Guidance Part E (v3, May 2016) and this hazard is adressed in a qualitative assessment.

Acute short-term exposure – local effects

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

N-butylaminoethanol has been found to be irritating to the respiratory system. A mucous membrane irritation occurred in the key acute inhalation study in rats conducted with butylethanolamine (BASF AG, 1977). Based on this, the Classification and labelling as STOT SE 3 - respiratory irritation (H335 -May cause respiratory irritation) has been derived. Furthermore, the substance has been found to have a low vapour pressure (13.94 Pa at 20 °C).

However, no adequate data is available for setting an long-term or acute / short-term inhalation DNEL for local effects.

Therefore, a DNEL is not quantifiable (No adequate route-specific information) and a "low hazard (no threshold derived)" is chosen according to ECHA's Guidance Part E (v3, May 2016) and this hazard is adressed in a qualitative assessment.

Hazard via dermal route

Long-term exposure – systemic effects:

NOAEL of 240 mg/m³ from the Repeated Dose 90-Day Oral Toxicity Study in Rodentsof BAE (CAS 111 -75 -1) in rats (according to OECD 408; Jadhav, 2020) is taken for the DNEL derivation. The starting point can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

Acute short-term exposure – systemic effects:

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute need to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.

However, for N-butylaminoethanol, "No hazard is identified” according to ECHA's Guidance Part E (v3, May 2016) as it is not classified for acute hazards and has been shown to be not acutely toxic via the dermal route of exposure in rabbits (LD50 > 2000 mg/kg bw; Latven, 1977).

So based on results of animal studies, N-butylaminoethanol does not pose an acute dermal hazard. Therefore, no acute / short-term DNEL for the dermal route of exposure is needed. Moreover, a DNEL would not be quantifiable (No adequate route-specific information) and local effects can be covered sufficiently by the long-term DNEL for systemic effects, provided high-peak acute exposure can be avoided.

Long-term exposure - local effects

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.The substance N-butylaminoethanol was irritating to the skin of rabbits after 4-hour application of test material. Moreover, an LD50 value above 2000 mg/kg bw was reported based on an acute dermal toxicity study on rabbits. Furthermore, the substance is corrosive to the eyes (Eye Damage 1). However, no long-term dermal DNEL for local effects is quantifiable for N-butylaminoethanol (no adequate route-specific information), but as it had been found to be irritating to the skin (Skin irritation Category 2 - H 315), "low hazard (no threshold derived)" is chosen according to ECHA's Guidance Part E (v3, May 2016). Irritation is the primary effect and therefore any hazard of local effects on skin should be addressed qualitatively.

Acute short-term exposure – local effects:

Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.

The substance N-butylaminoethanol was irritating to the skin of rabbits after 4-hour application of test material. Moreover, an LD50 value above 2000 mg/kg bw was reported based on an acute dermal toxicity study on rabbits. Furthermore, the substance is corrosive to the eyes (Eye Damage 1).

However, no acute/short-term dermal DNEL for local effects is quantifiable for N-butylaminoethanol (no adequate route-specific information), but as it had been found to be irritating to the skin (Skin irritation Category 2 - H 315), "low hazard (no threshold derived)" is chosen according to ECHA's Guidance Part E (v3, May 2016). Irritation is the primary effect and therefore any hazard of local effects on skin should be addressed 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 endpointsbased on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substancereflecting 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 . With regard to the irritating properties of the substance, the penetration may be enhanced which is based on the skin surface damage. However, as there is no substance-specific information, the worst case assumption of 100 % is considered, also for the DNEL derivation purpose.

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:

Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation NOAEC for systemic effects.According to “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8, in case of oral-to inhalation extrapolation a default factor of 2 for absorption should be introduced.

The following formular was used:corrected inhalative NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (ABSinhalation-rat/ABS inhalation-human) x (6.7 m³/10 m³) x (7/5);

where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used:

corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), * 7d/5d;

where ABS is absorption, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)

Exposure conditions and respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the Repeated Dose 90-Day Oral Toxicity Study in Rodentsof BAE in rats (according to OECD 408; Jadhav, 2020) was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively. Furthermore, the different exposure condition in human workers and rats was taken into account (workers - 5 working days - versus - rats - 7 days continuous exposure).

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 oral NOAEC from the subchronic Repeated Dose 90-Day Oral Toxicity Study in Rodents of BAE in rats (according to OECD 408; Jadhav, 2020)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 above mentioned oral 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.

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (subchronic study).

 

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 is applied when the NOAEL form the subchronic Repeated Dose 90-Day Oral Toxicity Study in Rodentswas used (three doses were tested, using a spacing range of 2-4 fold).

Calculation of DNELs:

Long-term exposure by inhalation – systemic effects:

The oral rat NOAEL of 240 mg/kg bw was converted into the inhalation NOAEC:

Modification of the starting point: corrected NOAEC = 240 mg/kg bw x (1/0.38 m³) * (50 %/100 %) * (100 %/100 %)* (6.7/10)m³ * (7d/5d) = 296.21 mg/m³.

Derivation of DNEL: corr. NOAEC / (1 * 2 * 1 * 2.5 * 5 * 1 *1) = corr. NOAEC / 25 = 296.21 mg/m³ / 25 = 11.85 mg / m³

(Assessment factor of 2 for subchronic-to-chronic extrapolation; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 25)

Long-term dermal exposure – systemic effects:

For the oral rat NOAEL of 240 mg/kg bw the following conversion was necessary:

corrected dermal NOAEC = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) x (exposure of animals per week)

correc. dermal NOAEC = 240 x (100 %/100 %) x (100 %/ 100 %) x (7/5) = 336 mg/kg bw

DNEL: corr. NOAEC / (1 * 2 * 4 * 2.5 * 5 * 1 *1) = corr. NOAEC / 100 = 336 mg/m³ / 100 = 3.36 mg / kg bw/days

(Assessment factor of 2 for subchronic-to-chronic extrapolation; 4 for allometric scaling; 2.5 for remaining interspecies differences and 5 for workers; as such the overall assessment factor is 100)

General Population - 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:
low hazard (no threshold derived)
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:
no hazard identified
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:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

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