Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.4 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):
75
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 230 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.67 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):
300
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

Additional information - workers

Selection of the relevant dose descriptors:

NOAEL(general toxicity) = 1000 mg/kg bw/d (rat, OECD TG 422)

NOAEL(development) = 300 mg/kg bw/d (rat, OECD TG 414; read-across from Oxooil LS9)

 

The same type of effects typical for low molecular weight hydrocarbons – i.e. centrilobular hypertrophy, which can be considered an adaptive change and not adverse, and hydrocarbon nephropathy in male rats – was observed in studies conducted with the source substances Oxooil LS9 and Oxooil LS13 with, however, lower effect levels in the studies with Oxooil LS9. These effects were already observed in the subacute studies conducted with both source substances. Whereas no such effects were noted in the OECD TG 422 study conducted with Tetrabutane up to the limit dose of 1000 mg/kg bw/d.

These results demonstrate a clear trend towards higher effect levels with increasing molecular weight. This is in line with the hypothesis, that based on lower molecular weight, lower log Kow and higher water solubility, a higher bioavailability of the source substance Oxooil LS9 can be expected and the source substance Oxooil LS9 represents a worst case.

The subchronic studies conducted with the source substances Oxooil LS9 and Oxooil LS13 further show, that qualitatively no additional effects occur after prolonged exposure to the substances compared with the subacute studies. From a quantitative point of view, the NOAELs obtained in the subchronic studies were lower by a factor of 2 compared to the NOAELs from the subacute studies.

Therefore, the NOAEL of 1000 mg/kg bw/d obtained in the OECD TG 422 study conducted with the target substance Tetrabutane can be used as starting point for DNEL derivation when applying the default assessment factors for time extrapolation (factor 3 for extrapolation from subacute to subchronic).

 

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of the source substance Oxooil LS9 (molecular weight < 500 g/mol and a log Kow of approx. 4) are in general favourable for absorption. The second source substance Oxooil LS13 has a molecular weight of approx. 168 g/mol and a log Kow >6.2. The target substance Tetrabutane has a molecular weight of approx.226 g/moland a log Kow of 9.5 to 10.1.

The available repeated dose toxicity studies indicate that both source substances Oxooil LS9 and Oxooil LS13 are absorbed to some extent and reach the liver and kidneys following oral exposure. In the study conducted with the target substance Tetrabutane no systemic toxicity was noted. Therefore, no conclusion on oral bioavailability can be drawn. The physicochemical properties, especially water solubility and log Kow, however, suggest a rather low bioavailability. By default an oral bioavailability is assumed in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017.

 

Dermal absorption

The relatively low molecular weight of all three substances favours a dermal absorption. However, the log Kow of >4 might limit dermal penetration by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above a log Kow of 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017).

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.

 

DERIVATION OF DNELs

DNELs derived from the subacute repeated dose toxicity NOAEL (OECD guideline 422)

 

Worker-DNEL long-term for inhalation route (systemic): 16.4 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1230 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x correction for exposure conditions (7 d / 5 d)

                                             = 1000 x 1/0.38 x 50/100 x 6.7/10 x 1.4

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 1230 mg/m³ (8h-TWA)

 

Overall AF: 1*6*1*2.5*5*1*1 = 75

 

 

Worker-DNEL long-term for dermal route (systemic):  4.67 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1400 mg/kg bw/d

 

corrected dermal NOAEL          = oral NOAEL x correction for exposure conditions (7 d / 5 d)

                                              = 1000 x 1.4

                                               = 1400 mg/kg bw/d

 

Overall AF: 1*6*4*2.5*5*1*1 = 300

 

 

 

DNELs derived from the prenatal developmental toxicity study 

No time extrapolation is required for a prenatal developmental toxicity study, since the susceptible window is fully covered.

 

Worker-DNEL long-term for inhalation route (systemic): 21.1 mg/m³

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 264.32 mg/m³

 

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x correction for exposure conditions (7 d / 5 d)

                                             = 300 x 1/0.38 x 50/100 x 6.7/10 x 1.4

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 264.32 mg/m³ (8h-TWA)

 

Overall AF: 1*1*1*2.5*5*1*1 = 12.5

 

 

Worker-DNEL long-term for dermal route (systemic):  8.4 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 420 mg/kg bw/d

 

corrected dermal NOAEL          = oral NOAEL x correction for exposure conditions (7 d / 5 d)

                                              = 300 x 1.4

                                               = 420 mg/kg bw/d

 

Overall AF: 1*1*4*2.5*5*1*1 = 50

 

The DNELS derived from the oral subacute toxicity study are also protective for developmental effects.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
DNEL (Derived No Effect Level)
Value:
1.67 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):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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:
1.67 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):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

Selection of the relevant dose descriptors:

NOAEL(general toxicity) = 1000 mg/kg bw/d (rat, OECD TG 422)

NOAEL(development) = 300 mg/kg bw/d (rat, OECD TG 414; read-across from Oxooil LS9)

 

The same type of effects typical for low molecular weight hydrocarbons – i.e. centrilobular hypertrophy, which can be considered an adaptive change and not adverse, and hydrocarbon nephropathy in male rats – was observed in studies conducted with the source substances Oxooil LS9 and Oxooil LS13 with, however, lower effect levels in the studies with Oxooil LS9. These effects were already observed in the subacute studies conducted with both source substances. Whereas no such effects were noted in the OECD TG 422 study conducted with Tetrabutane up to the limit dose of 1000 mg/kg bw/d.

These results demonstrate a clear trend towards higher effect levels with increasing molecular weight. This is in line with the hypothesis, that based on lower molecular weight, lower log Kow and higher water solubility, a higher bioavailability of the source substance Oxooil LS9 can be expected and the source substance Oxooil LS9 represents a worst case.

The subchronic studies conducted with the source substances Oxooil LS9 and Oxooil LS13 further show, that qualitatively no additional effects occur after prolonged exposure to the substances compared with the subacute studies. From a quantitative point of view, the NOAELs obtained in the subchronic studies were lower by a factor of 2 compared to the NOAELs from the subacute studies.

Therefore, the NOAEL of 1000 mg/kg bw/d obtained in the OECD TG 422 study conducted with the target substance Tetrabutane can be used as starting point for DNEL derivation when applying the default assessment factors for time extrapolation (factor 3 for extrapolation from subacute to subchronic).

 

 

Modification of the relevant dose descriptors to the correct starting point: 

Oral absorption

The physicochemical properties of the source substance Oxooil LS9 (molecular weight < 500 g/mol and a log Kow of approx. 4) are in general favourable for absorption. The second source substance Oxooil LS13 has a molecular weight of approx. 168 g/mol and a log Kow >6.2. The target substance Tetrabutane has a molecular weight of approx.226 g/moland a log Kow of 9.5 to 10.1.

The available repeated dose toxicity studies indicate that both source substances Oxooil LS9 and Oxooil LS13 are absorbed to some extent and reach the liver and kidneys following oral exposure. In the study conducted with the target substance Tetrabutane no systemic toxicity was noted. Therefore, no conclusion on oral bioavailability can be drawn. The physicochemical properties, especially water solubility and log Kow, however, suggest a rather low bioavailability. By default an oral bioavailability is assumed in accordance with theGuidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017.

 

Dermal absorption

The relatively low molecular weight of all three substances favours a dermal absorption. However, the log Kow of >4 might limit dermal penetration by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above a log Kow of 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow (Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017).

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in accordance with Guidance on Information Requirements and Chemical Safety Assessment, R8.

 

DERIVATION OF DNELs

DNELs derived from the subacute repeated dose toxicity NOAEL (OECD guideline 422)

 

General population-DNEL long-term for inhalation route (systemic): 2.9 mg/m³

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 435 mg/m³

 

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                             = 1000 x 1/1.15 x 50/100

 

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 435 mg/m³ (24 h)

Overall AF: 1*6*1*2.5*10*1*1 = 150

 

 

general population-DNEL long-term for dermal route (systemic):  1.67 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 1000 mg/kg bw/d

Overall AF: 1*6*4*2.5*10*1*1 = 600

 

general population-DNEL long-term for oral route (systemic):  1.67 mg/kg bw/d

Start value: 1000 mg/kg bw/d

Route of original study: oral

Overall AF: 1*6*4*2.5*10*1*1 = 600

 

 

DNELs derived from the prenatal developmental toxicity study 

No time extrapolation is required for a prenatal developmental toxicity study, since the susceptible window is fully covered.

 

General population-DNEL long-term for inhalation route (systemic): 5.2 mg/m³

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 130.5 mg/m³

 

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC  = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human

                                             = 300 x 1/1.15 x 50/100

 

The corrected inhalation NOAECgeneral population (24 h) is therefore:

                                             = 130.5 mg/m³ (24 h)

Overall AF: 1*1*1*2.5*10*1*1 = 25

 

 

general population-DNEL long-term for dermal route (systemic):  3 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 300 mg/kg bw/d

Overall AF: 1*1*4*2.5*10*1*1 = 100

 

general population-DNEL long-term for oral route (systemic):  3 mg/kg bw/d

Start value: 300 mg/kg bw/d

Route of original study: oral

Overall AF: 1*1*4*2.5*10*1*1 = 100

 

The DNELS derived from the oral subacute toxicity study are also protective for developmental effects 

 

Categories Display