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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: REACH guidance document R.8 and ECETOC TR86 (2003)
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
DNEL value:
14.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Oral toxicity value was extrapolated to inhalation value based on ECHA guidance. The ECHA default of a factor 2 when extrapolating from oral to dermal has been modified due to specific information on the substance and a more stringent factor of 5 has been used.

AF for dose response relationship:
1
Justification:
Effects show a clear dose response
AF for differences in duration of exposure:
1
Justification:
End point for NOAEL/NOAEC is based on a lifetime chronic study so no adjustment for duration is required
AF for interspecies differences (allometric scaling):
1
Justification:
No additional factor as already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no scientific justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. See the discussion for details.
AF for intraspecies differences:
3
Justification:
ECETOC reported in 2008 and 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for workers is 3 and not 5 as ECHA proposed see discussion for details
AF for the quality of the whole database:
1
Justification:
Data is from read across but it considered to represent appropriate data for the registered substance so no additional factor if necessary
AF for remaining uncertainties:
1
Justification:
No other factor for remaining uncertainty is considered necessary
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
66.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: REACH guidance document R.8 and ECETOC TR86 (2003)
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
DNEL value:
40 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral toxicity value was extrapolated to a dermal value by adjusting for the measured 20 fold lower dermal compared to oral absorption.

AF for dose response relationship:
1
Justification:
Effects show a clear dose response
AF for differences in duration of exposure:
1
Justification:
End point for NOAEL is based on a lifetime chronic study so no adjustment for duration is required
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is applied based on ECHA guidance for allometric scaling of data from rats to humans
AF for other interspecies differences:
1
Justification:
ECETOC reported in 2010 after an extensive review (see discussion) that there is no justification for the suggested additional factor of 2.5 for this, therefore a factor of 1 has been applied. See the discussion for details.
AF for intraspecies differences:
3
Justification:
3 ECETOC reported in 2008 and 2010 after an extensive scientific review that the appropriate factor for intraspecies differences for workers is 3 and not 5 as ECHA proposed see discussion for details
AF for the quality of the whole database:
1
Justification:
Data is from read across but it considered to represent appropriate data for the registered substance so no additional factor if necessary
AF for remaining uncertainties:
1
Justification:
No other factor for remaining uncertainty 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

Justification for using the ECETOC assessment factors in Deriving DNELs

Certain assessment factors that are recommended in the ECHA guidance have been extensively reviewed against available comparative data and a scientifically justified set of alternatives proposed by ECETOC in 2010.

Also there has been many years of work carried out in ERASM in CEFIC the joint research group between CESIO and AISE. Where in cooperation with Fraunhofer Institute for Toxicology and Experimental Medicine using their extensive Reptox database (the largest available database of comparative repeat dose study data in rats and mice).

Assessment factor for interspecies differences

ECHA (2012) based their proposed assessment factors for allometric scaling of oral and dermal exposure studies on the Geometric Means (GM) of the lognormal distribution of the available literature data, so they can be seen to be scientifically based.

Allometric scaling for inhalation exposure is also scientifically based as proposed with the adjustment allowing for the different metabolic rates between the animal in most cases the rat by adjusting for the difference and the breathing volume of the rat in hour and that of humans and then adjusting for the time of exposure.

Escher et al. (2013) published the results of the investigation into Interspecies extrapolation based on the RepDose database using a probabilistic approach. While this paper concentrated on comparing rat and mouse data as an example of interspecies extrapolation it also compared this to the available literature on the topic including extrapolation from laboratory animals to man. This included the key papers used by ECETOC in the 2010 review.

The scientific basis for the allometric scaling factor of 4 for rats is that it accounts for differences in toxicokinetics, related to difference in metabolic rate. An additional factor of 2.5 was suggested by ECHA (2012) to account for remaining interspecies difference, i. e. difference in toxicodynamics. The basis of the differences in toxicokinetics was based on analysis of the ratios of NOELs, benchmark doses etc. in different species. The results of this indicated that the median or geometric mean (GM) of the lognormal distribution for systemic effects correlates to species specific differences in calorific demand/metabolic rate (Schneider et al., 2004; Vermeire et al., 1999; Rennen et al., 2001; Bokkers and Slob, 2007).

However the allometric scaling for interspecies differences as proposed by ECHA including the additional factor can be considered to be overly conservative. The allometric scaling between rats and humans taking account of the different metabolic rates is 4 however an additional factor 2.5 is added to over other difference. This results in an overall factor of 10.

Escher et al. (2013) concentrated on comparing rats and mice, where they confirmed that after applying allometric scaling they had a GM of about 1.0. This supported the principle of allometric scaling according to calorific demand. They analyses different routes of exposure and all had a GM for their distribution curves of 1, indicating that both species were equally sensitive to equipotent doses.  They clarified this by stating that if the GM forms the basis for the assessment factor (ECHA, 2012), no further assessment factor on remaining uncertainties would be necessary.

When Escheret al. (2013) investigated the spread of the Geometric Standard Deviation (GSD) of the GM for interspecies differences, they found it was not due to differences in toxicodynamics but rather related strongly on the quality of the study pairs compared.

They went on to conclude that their data and those of the other key references based on NOAEL comparison (Vermeire/Rennenet al.2001; Schneider et al. 2002, 2005) all derive a GM of 1 for interspecies differences. “This supports the biological hypothesis that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover, such as intake via inhalation, drinking water or food.  Other uncertainties were are not just toxicodynamic difference between two species but also differences in study design such as dose spacing, number of animals and evaluated endpoints, and that they may include also inter-individual differences in susceptibility between animals in the same species.

They conclude “We therefore suggest a defaults interspecies extrapolation distribution animal /human with a GM identical to the allometric scaling factor, e. g. 4 rat/human, 7 mouse/human (ECHA 2012) for body doses (e.g. gavage), based on allometric principles and a factor of 1 for doses in ppm or mg/m3“. As this was the geometric mean, of the analysed distributions for interspecies differences in their publication.

Thus all the authoritative review comparing interspecies differences agree that an assessment factor based on allometric scaling taking into account the different metabolic rates is all that is required to account for interspecies differences in NOAELs.

Based on these conclusions, the present assessment does not include the additional factor of 2.5 when considering interspecies differences.

Assessment factors for intraspecies differences

ECHA (2012) proposed an assessment factor to account for intraspecies differences in the general human population of 10. For workers accepting that this population does not include the potentially more sensitive members of society i. e. the young and the elderly proposes an assessment factor of 5.

ECETOC (2010) reviewed the scientific basis for these assessment factors and updated its position first published in ECETOC (2003) and concluded that the assessment factor proposed by ECHA for the general population of 10 was too high. In 2003 ECETOC derived based on the scientific evidence on an assessment factor for workers of 3 and for the general population of 5 based on the literature in particular the data of Renwick and Lazarus (1998) and Hattiset al.(1987, 1999a). 

The GM for the 95thpercentile of the lognormal distribution from their data gave an assessment factor of 5 for the general population. While an assessment factor of 3 was recommended for workers based on the GM for 90thpercentile of the lognormal distribution, as the working population is in general more homogeneous and healthy with the more susceptible groups excluded. This approach using the GM from the lognormal distribution was consistent with that later taken by ECHA (2012) in proposing the assessment factors for allometric scaling.

Hattiset al. (2002) analysed a larger database compared that of Hattiset al. (1999b) but both included children. They applied their findings on extrapolation parameters, related to human variability, to many substances for which the US EPA had derived a reference dose. They arrived at a GSD of approximately 3 for the general population with or without including children. On the basis of the database, published by Hattiset al.(2002), the 95thor the 90thpercentile for the intraspecies assessment factor for the general population was estimated to be approximately 6 and 4, respectively. This clearly supports the view that the ECHA default assessment factor of 10 is too high, the assessment factor proposed by ECETOC of 5 for the general population is much more reasonable.

Therefore based on the review of the most relevant information we have used the ECETOC proposed assessment factors for intraspecies differences of 3 for workers and 5 for the general population.

References

Bokkers BGH and Slob W (2007). Deriving a data-based interspecies assessment factor using the NOAEL and Benchmark dose approach. Critical Reviews in Toxicology. 37:355-373.

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment. Brussels (Technical Report Nr. 86) 90pp.

ECETOC (2010). Guidance on Assessment Factors to Derive a DNEL. Brussels (Technical Report Nr. 110) 202pp.

ECHA (2012). Guidance on Information Requirements and Chemical Safety Assessment Chapter R.8: Characterisation of Dose [Concentration]-Response for Human Health. Version2.1. European Chemicals Agency. Helsinki, Finland.

Escher S, Batke E., Hoffmann-Doerr M, Messinger H and Mangelsdorf I. (2013). Interspecies extrapolation based on the RepDose database-A probabilistic approach. Toxicology Letters, 218:159-165.

Hattis D, Erdreich L and Ballew M (1987). Human variability in susceptibility to toxic chemicals: a preliminary analysis of pharmacokinetic data from normal volunteers. Risk Anal 7:415 - 426.

Hattis D, Banati P, Goble R and Burmaster DE (1999a). Human interindividual variability in parameters related to health risks. Risk Anal. 19(4):711-726.

Hattis D, Banati P and Goble R (1999b). Distributions of individual susceptibility among humans for toxic effects. How much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects? Uncertainty in the risk assessment of environmental and occupational hazards: an international workshop. Annals of the New York Academy of Sciences 895:286–316.

Hattis D, Baird S and Goble R (2002). A straw man proposal for a quantitative definition of the RfD. Drug Chem. Toxicol. 25:403-436.

Rennen MAJ, Hakkert B C, Stevenson H and Bos PMJ (2001). Data-base derived values for the interspecies extrapolation: a quantitative analysis of historical toxicity data. Comments in Toxicology 7:423-436.

Renwick AG and Lazarus NR. (1998). Human variability and noncancer risk assessment – an analysis of the default uncertainty factor. Regul. Toxicol. Pharmacol. 27:3-20.

Schneider K, Oltmanns J and Haussauer M (2004). Allometric principles for interspecies extrapolation in toxicological risk assessment=empirical investigations. Regulatory Toxicology and Pharmacology 39:334-347.

Schneider K., Haussauer M and Oltmanns J (Eds.) (2002). Überprüfung der maßgerechten Übertragung (Scaling) von Schadstoffen aus Tierversuchen auf den Menschen (Interspeziesextrapolation). (UFOPLAN) 201 65 202. Umweltforschungsplan des Bundesministeriums für Umwelt, Naturschutz und Reaktorsicherheit: Aktionsprogramm “Umwelt und Gesundheit”, Freiburg. Forschungs- u. Beratungsinstitut Gefahrstoffe GmbH (FoBiG), 257 pp.

Schneider K., Haussauer M, Oltmanns. J, Schuhmacher-Wolz U, Elmshäuser E and Mosbach-Schulz O (2005). Uncertainty analysis on workplace effect assessment. Research Report F 1824, F 1825, F 1826. Publication Series of the Federal Institute for Occupational Safety and Health, Dortmund, Germany, 249pp.

Vermeire T, Stevenson H, Pieters M N, Rennen M, Slob W and Hakkert B C (1999). Assessment factors for human health risk assessment: a discussion paper. CRC Critical Reviews in Toxicology 29:439-490.

Vermeire T, Pieters M N, Rennen M and Bos P (2001). Probabilistic assessment factors for human health risk assessment. RIVM Report 601516005. TNP Report V3489. RIVM Bilthoven. The Netherlands.

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