3,3'-[butane-1,4-diylbis(oxy)]bispropanamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

59 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

Value:

1 058 mg/m³

Explanation for the modification of the dose descriptor starting point:

There is only an acute study available for the inhalation route, where local effects, but no primarily systemic effects were found. Thus, the use of the oral dose toxicity study for route-to-route extrapolation is justified.

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: sub-acute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.

AF for other interspecies differences:

1

Justification:

There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used (ECETOC).

AF for intraspecies differences:

3

Justification:

The (ECETOC) default value for the relatively homogenous group "worker" 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 of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

176 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):

3

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: VCI (2010)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: based on Protective Action Criteria value (2012)

Workers - 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

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

Value:

600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

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: sub-acute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling is applied.

AF for other interspecies differences:

1

Justification:

There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used (ECETOC).

AF for intraspecies differences:

3

Justification:

The (ECETOC) default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The qualitiy of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach of the DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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:

medium hazard (no threshold derived)

Additional information - workers

WORKER

The information related to acute/short-term and long-term exposure hazards via the different exposure routes has been already commented/discussed above. For exposure hazards, where a more detailed discussion is appropriate, additional information is provided below.

 

Systemic effects via the inhalation route

Acute/short term exposure

 

The DNEL (acute/short term inhalation exposure, systemic effects) of 176 mg/m³ has been set at three times the corresponding long-term DNEL derived by oral-to-inhalation route extrapolation from the OECD 422 study.

In the 4-hour acute inhalation study (BASF AG, 1979) toxicity was dominated by local effects in the respiratory tract. Systemic effects occurred only secondary to local toxicity at concentration levels of 0.81 mg/L and higher. Taking 0.81 mg/L as NOAEC for systemic toxicity and applying Haber’s law (Cⁿx t = k) with n = 3 for extrapolation from 4 hour exposure to the acute exposure period of 15 min results in a NOAEC of 2.04 mg/L or 2040 mg/m³.

Correction of the NOAEC to adjust the respiratory volume from rest to light activity (factor 0.67) and application of the assessment factor 3 for intraspecies differences and 2 for dose response (to adjust for the rather large spacing factor of almost 5 between the concentration level of 0.17 mg/L and 0.81 mg/L) leads to the DNEL of 2040 mg/m³ x 0.67 / (3 x 2) = 228 mg/m³.

As this DNEL is higher than the DNEL of 176 mg/m³ derived by oral-to-inhalation route extrapolation the selection of the latter value as the most appropriate DNEL (acute/short term inhalation exposure, systemic effects) is justified.

 

Local effects via inhalation route

 

Due to the corrosive properties of the substance respiratory irritation following inhalation exposure is likely. However, the experimental data set regarding inhalation exposure is limited to a 4-hour acute inhalation toxicity study in which no detailed histopathological examination of the respiratory tract was performed. Due to this limitation the generic threshold for respiratory irritation of 1 mg/m³ (VCI, 2010) was set as DNEL (long term inhalation exposure, local effects). With regard to local effects after acute inhalation exposure the PAC-1 value of 13 mg/m³ published for the comparable compound 3,3’-oxybis(ethyleneoxy)bis(propylamine) was used as DNEL (acute inhalation exposure, local effects) in a read-across approach (see IUCLID chapter 13 for justification of the read-across).

The PAC-1 value is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. These effects are not disabling and are transient and reversible upon cessation of exposure. The PAC-1 value is a conservative value with regard to the acute exposure situation at the workplace as workers represent a more homogenous population group than the general population and peak exposure is limited to 15 min whereas the PAC-1 value covers exposures up to 60 min. Thus, the use of the PAC-1 value as DNEL(acute/short-term inhalation exposure, local effects) is justified.

 

In the following local DNELs are derived on the basis of the existing acute inhalation toxicity study and compared with the above DNELs in order to justify their selection.

1)    DNEL (long term inhalation exposure, local effects)

The 4-hour acute inhalation toxicity study (BASF AG, 1979) revealed a NOAEC of 0.17 mg/L based on clinical signs indicative for local effects in the respiratory tract at the next higher concentration level (0.81 mg/L). Correction of the NOAEC to adjust for the exposure time of 4 hours in comparison to the 8-hour work day (factor 0.5) and for the respiratory volume for rest to light activity (factor 0.67) leads to the corrected NOAEC of 0.057 mg/L or 57 mg/m³.

The following assessment factors (AF) are considered for DNEL derivation from the corrected NOAEC:

AF for differences in duration of exposure: The factor of 6 is considered as appropriate for extrapolation from acute to chronic exposure. This factor contains extrapolation from acute to subacute (factor 3) and from subacute to chronic exposure (factor 2). They are sufficient as local effects are mainly concentration and only to a lesser extent time dependent.

AF for intraspecies differences: The factor of 3 for the relatively homogenous group “worker” is used (ECETOC, 2010).

AF for quality of whole database: The factor of 2 is used to compensate for the fact that the local NOAEC is based on clinical effects and not on detailed histopathological examination of the respiratory tract.

The use of the above assessment factors results in a DNEL (long term inhalation exposure, local effects) of 57 mg/m³ / (6 x 3 x 2) = 1.6 mg/m³.

2)    DNEL (acute inhalation exposure, local effects)

Correction of the NOAEC of 0.17 mg/L from the 4-hour acute inhalation toxicity study (BASF AG, 1979) for rest to light activity (factor 0.67) leads to the corrected NOAEC of 0.114 mg/L or 114 mg/m³.

As Haber’s rule for extrapolation from the 4-hour exposure to a 15-min acute exposure is not considered applicable for local effects, the NOAEC of 114 mg/m³ is used as starting point for DNEL derivation. Application of the AF of 3 for intraspecies differences and 2 for quality of whole database (as justified above) results in the DNEL (acute inhalation exposure, local effects) of 114 mg/m³ / (3 x 2) = 19 mg/m³.

 

The DNELs of 1.6 mg/m³ (long term exposure)and 19 mg/m³ (acute exposure) derived on the basis of the acute inhalation toxicity study (BASF AG, 1979) are in the same range as the generic threshold for respiratory irritation of 1 mg/m³ (VCI, 2010) and the PAC-1 value of 13 mg/m³, respectively. Since the latter values are slightly lower their selection as DNEL (long term inhalation exposure, local effects) and DNEL (acute inhalation exposure, local effects), respectively, is justified.

References:

VCI (Verband der Chemischen Industir e.V.) (2010). Ableitung von DNEL für lokal reizende Stoffe mit guter Datenlage zur systemischen Toxizität, aber limitierter Datenlage zur Inhalationstoxizität Published 21.01.2010.

PAC (Protective Action Criteria). Rev. 27, February 2012.http://www.atlintl.com/DOE/teels/teel.html

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

GENERAL POPULATION

No consumer uses have been identified, and exposure to the general population is not to be expected. Therefore, no DNELs and/or DMELs for the general population have been derived.