Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
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:
833.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
20 000 mg/kg bw/day
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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point). This is in line with the ECHA R8 guidance document.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used. This is in line with the ECHA R8 guidance document.
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
3
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of ETH50 resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
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

Acute/short term exposure – systemic and local effects

The test item did not induce any relevant systemic adverse effects in the acute (oral, inhalation, dermal) and repeated dose (oral, dermal) toxicity studies. It did not induce skin or eye irritation and was not sensitising in the LLNA. As the test item did neither show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not considered mandatory.

Long-term exposure – systemic effects

Inhalation:

There are no relevant experimental data on repeated dose exposure by inhalation. For derivation of a long-term systemic inhalation DNEL, 10 mg/m3 has been defined. This value is based on the general dust limit value (TRGS 900, established by AGS (Ausschuß für Gefahrstoffe), published by the German BMAS (Bundesministerium für Arbeit und Soziales")), since ETH50 does not pose any intrinsic hazard. Furthermore, the substance characteristics (low vapour pressure, high melting point, very low water solubility) indicate that an inhalation absorption of toxicologically significant amounts of the test item is unlikely.

Dermal:

The NOAEL of 1000 mg/kg bw/d from the repeated dose dermal toxicity study in rats (CIT 32404 TCR, 2008) is used as starting point for the derivation of the long term systemic worker DNEL. This starting point represents a worst case assumption, since no evident systemic and organ specific toxicity has been observed up to and including the limit dose (1000 mg/kg bw/d).

Concerning dermal penetration potential between rat and human, two comparative in vitro dermal penetration studies are available for rat and human skin using ETH50 in non-/nano form (RCC A00112; RCC B23624). No evident species differences have been observed based on ETH50, that penetrated fully through human skin membranes into the perfusate independent from its form. However, including the fraction found in the remaining skin (excluding the stratum corneum) an approx. 20 fold higher level of ETH50 was found in rat skin compared to human skin. This ratio was comparable between the different specifications of ETH50, i.e. 1.38% vs. 0.06% and 5.07% vs. 0.28% of the applied ETH50 dose for the nano and non-nano form, respectively.  Based on these differences in dermal absorption in humans and rat, the NOAEL from the the repeated dose dermal toxicity study in rats has been converted as follows:

NOAELcorr = dermal NOAEL * ABSdermal-rat/ABSdermal-human = 1000 mg/kg bw/d * 20 = 20000 mg/ kg bw/d.

Long-term exposure – local effects

The test item did not induce any local toxic effects. There was no evidence of toxicity in any of the available studies. Thus, the derivation of a long-term DNEL for local effects is not required. This is in line with the ECHA guidance document (2012).

References:

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical Report 110.

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characeterisation of dose[concentration]-response for human health. Version: 2.1, ECHA-2012 -G-19 -EN.

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

Based on the present toxicological data, the substance does not pose any hazard, leading to a non-classification according to the criteria laid down under67/548/ECC and CLP. Since all relevant uses are outside the scope of REACH and inside the scope of the Cosmetics Directive 76/768/EEC, no DNELS have been derived for the general population according to "Guidance on information requirements and chemical safety assessment (Chapter R8).