Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
147 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Where relevant data are available, local and systemic DNELs for worker exposure to the substance have been developed based animal experimental results obtained for NExBTL renewable diesel (a UVCB substance of similar composition to the substance: see analogue approach justification document) and assessment factors (AF) recommended by ECHA (2010: Guidance on Information Requirements and Chemical Safety assessment: chapter R.8 – characterisation of dose [concentration] - response for human health. pp 185, ECHA, Helsinki, December 2010), ECETOC (2003: Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No. 86, pp 86, ECETOC, Brussels, February 2003) and ECETOC (2010: Guidance on Assessment Factors to Derive a DNEL. Technical Report No. 110, pp 198, ECETOC, Brussels, October 2010).

Acute toxicity

A DNEL for acute toxicity should be derived if a hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. The TGD notes that such peaks are normally associated with inhalation exposure but are less common for skin contact and ingestion (ECHA, Appendix R.8-8). Results for acute oral and acute dermal toxicity both return LD50 values greater than 2000 mg/kg bwt (i.e. no classification required).

With regard to inhalation exposure, information available for a series of C9-C13 n-alkanes indicates that the acute (4 -hr) inhalation LC50 of the substance vapour (comprising predominately i-C8 to i-C18) will exceed 20 mg/l, with exposure to such concentrations unlikely given the low saturated vapour concentration of the components present. No mortality, clinical signs or CNS depression were apparent in mice exposed to 63.6 mg/l n-heptane for 30 min, equivalent to a 4 hr inhalation exposure (derived using the modified Haber’s Law calculation) of 31.8 mg/l. Taken together, this information indicates that no classification of the substance is necessary with regard to acute inhalation hazards.

The derivation of DNELs for acute toxicity is therefore not appropriate or necessary for the substance.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. However results from GLP-compliant guideline tests conducted on NExBTL renewable diesel (a UVCB substance of similar composition to the substance) indicate it is not irritating to skin or eye, making the derivation of DNELs for these endpoints for the substance not appropriate or necessary.

Long-term systemic effects

The potential of the substance to cause long-term systemic effects can judged from results of repeated dose (neuro)toxicity and reproductive (2-generation) testing on the related UVCB substance NExBTL renewable diesel.

For NExBTL renewable diesel, the following NOAELs are presented in the IUCLID dossier:

sub-chronic effects: rat oral NOAEL = 1000 mg/kg bwt/day

reproductive effects: rat oral NOAEL = 1000 mg/kg bwt/day

developmental toxicity: rat oral = 1000 mg/kg bwt/day

Oral

No oral DNEL is required for Workers.

Dermal

Dose descriptor

A rat oral sub-chronic NOAEL of 1000 mg/kg bwt/d will be used with appropriate modification to derive a dermal DNEL for the substance. No additional correction of the animal NOAEL is required since both NExBTL renewable diesel and the substance are UVCB substances, comprising mainly C8-C18 i-alkanes with iC15-iC18 predominating in both.

Modification of dose descriptor

In the absence of information to the contrary it is assumed that oral uptake and dermal uptake are identical (ECHA, Section R.8.4.2, Ad2).

For workers, no modification of the NOAEL is required.

Assessment factors and DNELs

Uncertainty

AF

Justification

Interspecies differences

4

Default AF for dermal route (allometric scaling, rat)

Intraspecies differences

3

Informed AF for workers: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

Remaining differences                                      

1

Informed AF for worker population: it is unlikely that the toxicokinetics and toxicodymics of the i-alkanes that predominate in this substance will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). Use of AF=1 is also consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

Differences in duration of exposure

2

Default AF for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

Quality of database

1

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

Overall AF

24

The magnitude of the overall AF is adequate when applied to a substance that produced no adverse effects following subchronic exposure at a limit dose of 1000 mg/kg bw/d. It should lead to a DNEL that is protective of health without the need for excessive or unnecessary risk management measures.

DNELworker-dermal = 1000 / 24 = 42 mg/kg bwt/d

Inhalation

Dose descriptor

A rat oral NOAEL of 1000 mg/kg bwt/d will be used with appropriate modification to derive an inhalation DNEL for the substance.

Modification of dose descriptor. No additional correction of the animal NOAEL is required since both NExBTL renewable diesel and the substance are UVCB substances, comprising mainly C8 -C18 i-alkanes with iC15 -iC18 predominating in both.

In the absence of data to the contrary, it has been assumed that the extent of inhalation uptake of the substance is double that following oral exposure (ECHA, Section R.8.4.2, Ad2).

The corrected inhalatory NOAEC is calculated as follows:

NOAECinhalation = NOAELoral x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 1000 x 1/0.38 x 1/2 x 6.7/10

Corrected inhalation NOAECworker = 881 mg/m3

Assessment factors and DNELs

Uncertainty

AF

Justification

Interspecies differences

1

Default AF for inhalation route (no allometric scaling necessary)

Intraspecies differences

3

Informed AF for workers: the applied AF reflects the 90thpercentile from analyses of human toxicokinetic and toxicodynamic data for men and women of differing ages and disease states, and is scientifically supportable (ECETOC, 2003; 2010). Furthermore while human polymorphisms may lead to variability in toxicokinetics, the effect of such variations is minor at low (non-saturating) substrate concentrations (ECETOC, 2010). The overall AF derived here will result in low internal exposures that will limit any intraspecies differences in toxicological response.

Remaining differences               

1

Informed AF for worker population: it is unlikely that the toxicokinetics and toxicodymics of the i-alkanes that predominate in this substance will differ markedly between rats and humans, with any variations that are present accounted for by the multiplication product of the AFs for inter- and intraspecies variability (ECETOC, 2010). This is consistent with ECHA guidance indicating that care should be taken to avoid “double counting” when multiplying individual AFs (ECHA, 2010).

Differences in duration of exposure

2

Default AF for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

Informed AF: substances that produce no adverse effects at a limit dose of 1000 mg/kg bw/d are non-hazardous, with no classification required for potential effects on human health.

Quality of database

1

Informed AF: data originate from a modern, well reported, GLP-compliant guideline study.

Overall AF

6

The magnitude of the overall AF is adequate when applied to a substance that produced no adverse effects following subchronic exposure at a limit dose of 1000 mg/kg bw/d. It should lead to a DNEL that is protective of health without the need for excessive or unnecessary risk management measures.

DNELworker-inhalation = 881 / 6 = 147 mg/m3

Long-term local effects

NExBTL renewable diesel was not irritating to skin or eye, nor were there any signs of gastric irritation following repeated oral (gavage) administration to rats at a dose of 1000 mg/kg bwt/d for 90 days. It is concluded, based on this information, that the substance will also not cause local (site of contact) toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
exposure based waiving
Acute/short term exposure
Hazard assessment conclusion:
exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The substance is used as a blending component for commercial aviation fuel. It is not supplied to the general population, nor is it available in blended fuels used by non-commercial aeroplanes. DNELs for the general population have therefore not been developed.