Butane-1,4-diol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

136 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

Dose descriptor starting point:

NOAEL

Value:

225 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

410 mg/m³

Explanation for the modification of the dose descriptor starting point:

This starting point was adjusted for molecular weight, a factor of 1 was used to modify the starting point for absorption from oral to inhalation, 2.6 was used to modify the starting point from oral to 8hr inhalation exposure, and 0.67 was used to modify the starting point to light work.

DD starting point	225	225 mg/kg, 2-yr oral, rat with GBL/96-48-0 (NTP, 1992)
MW adjustment	1.05	*BDO/GBL = 90.1g/mol/86.1g/mol
absorption	1	100%
route to route	2.60	*1/0,38 (8h inhalation)
no - light work	0.67	* 6,7 m3/10 m3

AF for dose response relationship:

1

Justification:

Default; study according to NTP guidelines with two doses per sex

AF for differences in duration of exposure:

1

Justification:

Default; chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

Default; no further allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

AF for other interspecies differences:

1

Justification:

Toxicokinetic study shows rapid metabolism of BDO resulting in formation of products entering tricarboxylic acid cycle. Considering this there is no need for an additional AF. Furthermore, see Justification for intraspecies AF.

AF for intraspecies differences:

3

Justification:

ECETOC proposes an AF of 3 for intraspecies x other interspecies factor (excluding allometry) for workers (ECETOC TR No. 110, 2010)

AF for the quality of the whole database:

1

Justification:

Sufficient reliable data available

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

958 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3

Dose descriptor starting point:

LOAEC

Value:

5 100 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

2 874 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL is valid for up to 15-minutes of exposure and was derived from a LOAEC 5100 mg/m3 (4-hour, rat) and corrected to a NOAEC which was corrected for light work a time correction (4h ->15 min) was also applied as calculated using modified Haber's Law.

no - light work	0.67	*6,7 m3/10 m3
LOAEC -> NOAEC	3	Standard conversion factor
time 4h -> 15 min		Factor: 2.51984 Justification: The factor 2.51984 = ^3√(4h/0.25h) is based on the modification for Haber´s Law C^n x t = k according to ECHA Guidance R.7a, v6.0, July 2017.

AF for dose response relationship:

1

Justification:

Acute data used: LOAEC to NOAEC taken into account when modifying starting dose.

AF for interspecies differences (allometric scaling):

1

Justification:

Inhalation study used to determine DNEL

AF for other interspecies differences:

1

Justification:

Toxicokinetic study shows rapid metabolism of BDO resulting in formation of products entering tricarboxylic acid cycle. Considering this there is no need for an additional AF. Furthermore, see Justification for intraspecies AF.

AF for intraspecies differences:

3

Justification:

ECETOC proposes an AF of 3 for intraspecies x other interspecies factor (excluding allometry) for workers (ECETOC TR No. 110, 2010)

AF for the quality of the whole database:

1

Justification:

Sufficient reliable data available

AF for remaining uncertainties:

1

Justification:

Default

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

19 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):

12

Dose descriptor starting point:

NOAEL

Value:

225 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

235 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The DNEL is valid for typical worker exposures and assumes 100% absorption of external dose. It was derived from a NOAEL of 225 mg/kg from a 2-year oral rat study on γ-butyrolactone (CAS 96-48-0, see Toxicokinetic Section for justification) as the starting point. This starting point was adjusted for molecular weight.

DD starting point	225	225 mg/kg, 2-yr oral, rat with GBL/96-48-0 (NTP, 1992)
MW adjustment	1.05	*BDO/GBL = 90.1g/mol/86.1g/mol
absorption	1	100%
route to route	1.00	oral - dermal

AF for dose response relationship:

1

Justification:

Default; study according to NTP guidelines with two doses per sex

AF for differences in duration of exposure:

1

Justification:

Default - chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Default; rat -> human

AF for other interspecies differences:

1

Justification:

Toxicokinetic study shows rapid metabolism of BDO resulting in formation of products entering tricarboxylic acid cycle. Considering this there is no need for an additional AF. Furthermore, see Justification for intraspecies AF.

AF for intraspecies differences:

3

Justification:

ECETOC proposes an AF of 3 for intraspecies x other interspecies factor (excluding allometry) for workers (ECETOC TR No. 110, 2010)

AF for the quality of the whole database:

1

Justification:

Sufficient reliable data available

AF for remaining uncertainties:

1

Justification:

Default

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

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:

DNEL (Derived No Effect Level)

Value:

8 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):

20

Dose descriptor starting point:

NOAEL

Value:

225 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

168 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

This starting point was chosen as the lowest, most relevant, and
most reliable guideline study result to prevent the critical effect of central nervous system depression (sedation) and was adjusted to account for the molecular weight difference between γ-butyrolactone and 1,4-butanediol by multiplying the starting point by 90/86 or 1.046. Consistent with Chapter R.8 (May
2008) of the REACH guidance and with ECETOC Technical Report No. 86 (February 2003), a factor of 0.71 was used to modify the starting point from 5 days per week to 7 days per week.

DD starting point	225	225 mg/kg, 2-yr oral, rat with GBL/96-48-0 (NTP, 1992)
MW adjustment	1.05	*BDO/GBL = 90.1g/mol/86.1g/mol
Study adjustment	0.71	5d/wk -> 7d/wk

AF for dose response relationship:

1

Justification:

Default; study according to NTP guidelines with two doses per sex

AF for differences in duration of exposure:

1

Justification:

Default: chronic study

AF for interspecies differences (allometric scaling):

4

Justification:

Default; rat -> human

AF for other interspecies differences:

1

Justification:

Toxicokinetic study shows rapid metabolism of BDO resulting in formation of products entering tricarboxylic acid cycle. Considering this there is no need for an additional AF. Furthermore, see Justification for intraspecies AF.

AF for intraspecies differences:

5

Justification:

ECETOC proposes an AF of 5 for intraspecies x other interspecies factor (excluding allometry) for GP (ECETOC TR No. 110, 2010)

AF for the quality of the whole database:

1

Justification:

sufficient reliable data available

AF for remaining uncertainties:

1

Justification:

Default

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