Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: based on other data

Dose descriptor starting point:

other: not applicable

Modified dose descriptor starting point:

other: not applicable

Explanation for the modification of the dose descriptor starting point:

Not applicable

Justification:

See additional information - workers.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.95 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECETOC, 2003;2010

Modified dose descriptor starting point:

NOAEL

Value:

5.69 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No study by dermal route available, data derived from a well-conducted subchronic 90 day inhalation study in mouse and rat.

Justification:

default for subchronic to chronic

Justification:

Allometric scaling is not necessary since the DNEL is derived from the 90 day mouse inhalation study NOAEC (27.6 mg/m3) (R8)

Justification:

An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993, Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Compositional information:

These hydrocarbon streams meet the regulatory definition of UVCB substances, with inherent variations in composition present due to differences in manufacturing history. This variability is documented in the Category Justification (appended to IUCLID section 13), which lists the chemical marker substances present along with an indicative concentration range for each

The approach developed by the LOA Exposure Working Group on the selection of category constituents for use in human health exposure assessments was implemented for Category H. The primary constituents used are benzene and DCPD. A full description of this approach is available in Section 13.

Uses:

These hydrocarbon streams are used as intermediates, in manufacture and as fuels. These DNELs address concerns linked to the CMR properties of the marker substances or their potential to cause other long-term health effects leading to an equivalent level of concern.

Substance selection for risk characterization:

See "Selection of constituents for HH exposure" in section 13.2.

Intrinsic hazards of marker substances and associated DN(M)ELs:

The following hazard information and DNELs are available for marker substances present in this Category.

An Explanation for the Worker DNEL at 0.25 ppm (0.8 mg/m3) as an 8-hour TWA

Background

The DMEL used in the original versions of the REACH benzene dossier was based on the EU BOELV of 1 ppm which was derived from the position on benzene toxicology presented by SCOEL in SUM 140 (SCOEL, 1991). Our analysis of the body of research that has developed since then agrees with the conclusion of DECOS (Netherlands) that the evidence on benzene justifies the setting of a DNEL rather than a DMEL (DECOS, 2014). This position is based on the view that benzene is not a direct-acting mutagen, that clastogenic events will have a threshold and that the key toxicity is haematotoxicity. If haematotoxicity is avoided, then progression to oncological disease would not be expected (LOA 2017).

The use of the EU BOELV as a basis for a DMEL was based on the provision in REACH guidance that allows a DNEL/DMEL to be based on accepted formal workplace limits providing that no data exist that would contradict the basis of the formal workplace limit. (ECHA Guidance R8 Appendix 13). Pending the setting of a new EU BOELV value for benzene, LOA believes that the DECOS document and other recent literature provide enough justification to contradict the 1 ppm 8h TWA EU BOELV. As an interim position LOA previously saw that haematological data reviewed by the DECOS, as well as more recent research provided justification for a DNEL of 0.6 ppm as an 8h TWA.

In 2017, ECHA’s Risk Assessment Committee (RAC) was tasked with providing an Opinion on a Benzene OEL. This was provided in March 2018 and proposed an OEL of 0.05 ppm as an 8h TWA. RAC also believed that benzene could be seen as a threshold carcinogen, where avoidance of structural and numerical chromosomal aberrations and micronuclei would protect against cancer risk. (ECHA 2018) During and subsequent to this RAC review of the benzene OEL by the Risk Assessment Committee of ECHA (RAC), LOA have reassessed the data on benzene in greater detail.

0.25 ppm/8h TWA OEL Recommendation based on LOA’s Detailed work 2017-2020

Using a Study Quality Assessment tool to decide the studies that are the of the highest quality for OEL setting, LOA have judged that the weight of evidence LOAEC for haematological and genotoxic effects (i.e. chromosomal aberrations, aneuploidy, and micronucleus formation) in high-quality studies of workers is 2 ppm/8h TWA and that the NOAEC for these effects is ~0.5 ppm/8h TWA. The basis for this decision is summarized in the Annex below and is presented in full in Schnatter et al 2020.

Given the high quality of studies used for LOAEC and NOAEC derivation, the significant number of workers covered by these studies (including from potentially more sensitive populations) and a more conservative LOAEC selection LOA believe that an assessment factor of 4 is sufficient for LOAEC to NOAEC extrapolation (2) and intraspecies differences (2). This would give an OEL of 0.5 ppm / 8h which is in line with the actual NOAEC observed. However, given uncertainties raised in the RAC assessment about whether the bone marrow is potentially more susceptible to damage than can be ascertained by examining effects in peripheral blood (i.e. in the available studies in workers) an extra assessment factor of 2 could apply until further research clarifies this issue. Thus, an interim proposed OEL of 0.25 ppm/8h TWA is recommended.

The scientific case for these values has been presented at a conference (Cefic APA , Helsinki. 11thSeptember 2019) and is elaborated in the peer -reviewed paper Schnatter et al 2020.

Registrants should also be aware that consequent to deliberations by DG Employment’s Working Party on Chemicals, the Advisory Committee on Safety and Health has proposed that an OEL of 0.5 ppm/8hTWA should be adopted in the short term (within 2 years of the entry into force of the Directive amendment) with this reducing to an OEL of 0.2 ppm (within 4 years of the Directive amendment entering force). It is also proposed that another review of the benzene OEL for the EU should start in 2028. Given that the exact timing of these regulatory changes depends on the regulatory process Registrants are advised to monitor the situation via trade associations and other channels.

LOA believe that the available data show that an OEL of 0.25 ppm/8hTWA is sufficient to protect all aspects of worker health (i.e. cancer, haematological and genotoxic effects). The protection for carcinogenic effects is driven by the evidence for benzene having a thresholded mode of action of cancer, thus the OEL would protect against benzene induced cancer (i.e. Acute Myeloid Leukemia).

Note that Registrants referring to a DNEL of 0.25 ppm (8h TWA) will still be subject to the requirements of the Carcinogens and Mutagens Directive (Council Directive 1999/38/EC as amended) which requires substitution where feasible, exposure minimisation and monitoring of workers. (For references see section 13 "Worker DNEL Explanation").”

Annex: Summary of the Scientific Basis for LOA’s 0.25 ppm/8h TWA OEL Recommendation

The scientific case for these values has been presented at a conference (Cefic APA 2019) and in a peer-reviewed paper. (Schnatter et al 2020) Additionally papers on the mode of action of benzene and on considerations of cancer risk have been written. (North et al 2020a, 2020b).

However, in summary, after identifying relevant haematotoxicity and genotoxicity studies in workers by means of literature searches and accessing existing reviews, 43 haematotoxicity and 94 genotoxicity studies were screened for eligibility to be scored for study quality. This was achieved by a trained panel of scientists from appropriate disciplines using a tool modified from that proposed by Vlaanderen et al 2008 to make it appropriate to the task. Thirty-six haematology studies from 31 unique study populations and 77 genotoxicity studies from 56 unique study populations were scored using this tool. Studies were ranked by the quality score to give a haematotoxicity ranking and a genotoxicity ranking, and these rankings were divided into tertiles. For each ranking, the high-quality studies were identified as being in the top tertile or above the median of study quality value.

Where the data allowed, LOAECs and NOAECs were assigned to studies in the top tertile and above the median quality score. LOAECs and NOAECs were additionally characterised as being more certain or less certain based on key characteristics of the study from which the value was derived. Genotoxicity studies were further characterised by the specificity of the exposure context for benzene with “Factory” exposures having a predominant exposure to benzene being seen as more specific than “Fuel” (i.e. petroleum product exposure) and that in turn being more specific than exposure to “Ambient Air” ( polluted urban air). LOAECs and NOAECs were assigned to genetic toxicology endpoints shown to be relevant to cancer (structural and numerical chromosomal aberrations and micronuclei).

Consideration of the high-quality haematotoxicity studies with more certain LOAECs gave a cluster with LOAECs in the range 2-3.5 ppm ( 3 studies – Lan et al 2004 - >2 ppm [~ 2.2 ppm]; Qu et al 2003 – 2.26 ppm and Zhang et al 2016 – >2.1 ppm ) and a cluster with LOAECs in the range 7-8 ppm (4 studies - Schnatter et al 2010- 7.8 ppm, Ward et al 1996- 7.2 ppm- Rothman et al 1996- 7.6 ppm and Bogadi-Sare et al 2003 – 8.0 ppm). Similarly, analysis of NOAECs from the high-quality studies gave clusters indicating possible NOAECs in the ranges 2-3.5 ppm, 0.6-0.8 ppm and 0.2-3 ppm. Sensitivity analysis and selecting the lowest LOAEC pointed to a LOAEC of 2 ppm/8h and a NOAEC of 0.5 ppm/8h as being a robust position.

Consideration of the high-quality genotoxicity studies with more certain LOAECs gave LOAECs in the range >1.6 – 3.07 ppm (4 studies – Qu et al 2003-3.07 ppm. Xing et al 2010- >1.6 ppm (calculated arithmetic mean), Zhang et al 2012 - >2.64 ppm and Zhang et al 2014-2 ppm) after the exclusion of a study with a higher LOAEC value of 13.6 ppm (Zhang et al 2007). The mean LOAEC was 2.33 ppm / 8h. The best available NOAEC values came from two “Fuel” studies (Carere et al 1995 = 0.47 ppm and Pandey et al 2008 = 0.9 ppm) giving a mean NOAEC from quality studies of 0.69 ppm.

Comparison of data from the haematotoxicity and the genotoxicity LOAEC/NOAEC analyses indicated that an overall LOAEC of 2.0 ppm/8h and a NOAEC of 0.5 ppm/8h should be appropriate based on the highest quality literature on both endpoints.

Given the high quality of studies used for LOAEC and NOAEC derivation, the significant number of workers covered by these studies (including from potentially more sensitive populations) and a more conservative LOAEC selection LOA believe that an assessment factor of 4 is sufficient for LOAEC to NOAEC extrapolation (2) and intraspecies differences (2). This would give an OEL of 0.5 ppm / 8h which is in line with the actual NOAEC observed. However, given uncertainties raised in the RAC assessment about whether the bone marrow is potentially more susceptible to damage than can be ascertained by examining effects in peripheral blood (i.e. in the available studies in workers) an extra assessment factor of 2 could apply until further research clarifies this issue. Thus, an interim proposed OEL of 0.25 ppm/8h TWA is recommended.

References

Carere A, Antoccia A, Crebelli R, Degrassi F, Fiore M, Iavarone I, Isacchi G, Lagorio S, Leopardi P, Marcon F, et al (1995) Genetic effects of petroleum fuels: cytogenetic monitoring of gasoline station attendants. Mutat Res 332: 17-26.

Bogadi-Sare A, Zavalic M, Turk R. (2003) Utility of a routine medical surveillance program with benzene exposed workers. Am J Ind Med 44(5):467-73.

DECOS [Dutch Expert Committee on Occupational Safety of the Health Council of the Netherlands] (2014) Benzene, Health-based recommended occupational exposure limit, No. 2014/03, The Hague: The Health Council of the

Netherlands, February 21, 2014. Accessed:https://www.gezondheidsraad.nl/en/task-and-procedure/areas-of-activity/healthyworking-conditions/benzene-health-based-recommended

ECHA (2018) Committee for Risk Assessment RAC Opinion on scientific evaluation of occupational exposure limits for Benzene ECHA/RAC/ O-000000-1412-86-187/F Adopted 9 March 2018 Accessed:https://echa.europa.eu/documents/10162/13641/benzene_opinion_en.pdf/4fec9aac-9ed5-2aae-7b70-5226705358c7

Lan Q et al. (2004). Haematotoxicity in workers exposed to low levels of benzene. Science 306: 1774-1776.

LOA (2017). Potential derived no effect level (DNEL) for benzene based on haematotoxicity. Published in 2017 REACH Dossier for Benzene (2017-11-07).

North CM et al (2020a) Modes of Action Considerations in Threshold Expectations for Health Effects of Benzene Toxicology Letters (submitted). Preprint:https://doi.org/10.5281/zenodo.3784971

Dicyclopentadiene

The potential of dicyclopentadiene to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

For DCPD, the following NOAEL/NOAECs are available:

Oral:

sub-chronic effects: male rat NOAEL = 4 mg/kg bw/d

reproductive effects: rat NOAEL = 50 mg/kg bw/d

developmental toxicity: rat NOAEL = 60 mg/kg bw/d

Inhalation:

sub-chronic effects: mouse NOAEC = 27.6 mg/m3

sub-chronic effects: rat NOAEC = 276 mg/m3

Worker – long-term systemic inhalation DNEL

Dose descriptor

A mouse inhalation NOAEC of 27.6 mg/m3 will be used to derive the DNEL_{l-t inhalation}.

Modification of dose descriptor

Correct the NOAEC to adjust for differences in duration in the animal study (6 h) and the worker (8 h) and light work following the TGD Figure R.8-2:

27.6 mg/m³x [6 h / 8 h] x [6.7 m³/ 10 m³] = 13.9 mg/m³

It is assumed that DCPD is similarly and efficiently (100%) absorbed after inhalation by mice and humans.

Assessment factors

An assessment factor of 6 is used based on worker intraspecies differences (3)and correction for duration of exposure (sub-chronic to chronic = 2).

DNEL_{l-t inhal}= 13.9 mg/m³/ 6 = 2.3 mg/m³

Worker - long-term systemic dermal DNEL

Dose descriptor

A mouse inhalation NOAEC of 27.6 mg/m3will be used to derive the dermal DNEL.

Based on 20% mortality at 276 mg/m3 (51 ppm). It is assumed that absorption via the skin will not exceed that by inhalation, and the NOAEC was not modified for route-to-route extrapolation.

The NOAEC was modified to starting point using sRV(mouse, 6h) and adjusting for exposure duration and respiratory volume of workers:

27.6*0.41*0.75*0.67 = 5.69 mg/kg bw/day.

(The reference for the mouse sRV is a risk assessment document for chloroform (page 10). The French Authority used 0.41 as a 6h respiratory volume of 0.41 m3/kg bw (45 mL/min / 40g bw = 1.125 L/min/kg bw) for the mouse)(ECHA 2007).

An assessment factor of 6 is used based on worker intraspecies differences (3) and correction for duration of exposure (sub-chronic to chronic = 2).

DNEL dermal = 5.69 mg/kg bw /day 6 = 0.95 mg/kg bw/day

Isoprene

Isoprene has been shown to be carcinogenic to mice and rats. When inhaled in concentrations of 70 ppm and above, it was found to induce tumours in a range of tissues in male mice while tissue responses in females were more limited. No statistically significant increases in tumours were reported in either sex at a dose level of 10 ppm. Inhalation by rats of concentrations above 220 ppm caused a significantly increased incidence of mammary gland, testicular and kidney tumours in males, and mammary gland tumours in females. At the lowest dose tested, 220 ppm, a statistically significant increase in only mammary gland fibroadenoma was observed in females.

Worker – long-term systemic inhalation DNEL

In accordance with REACH guidance (Appendix R.8-13), the established MAK (2009) value of 3 ppm (equivalent to 8.4 mg/m³) - 8 hr TWA will form the basis of the inhalation DNEL for workers. It was concluded by the MAK Commission that a maximum admissible concentration can be established for humans and that the carcinogenic and genotoxic effects of isoprene is low. There would be no appreciable increase of carcinogenic risk in humans if this value is not exceeded.

DN(M) EL_{l-t
inhalation}=8.4 mg/m³

Worker - long-term systemic dermal DNEL

The long-term dermal DN(M) EL is calculated from the inhalation DN(M) EL using route-to-route extrapolation, having determined the net inhalation uptake or dose. Filser et al (1996) determined the rates of isoprene metabolism (µmol/hr/kg bw) in humans, rats, and mice at steady-state over a range of atmospheric concentrations to validate a PT model for isoprene. Metabolism of isoprene is linear up to 50 ppm. At the isoprene exposure concentration of interest 8.4 mg/m³(3 ppm), the rate of metabolism (µmol/hr/kg bw) can be determined and subtracted from the rate of metabolism at 0 mg/m³(0 ppm). At an exposure concentration of 3 ppm, the rate of isoprene metabolism is 0.13 µmol/hr/kg bw and in an 8-hr workday, net inhalation uptake (or dose) is: 0.13 µmol/hr/kg bw x 8 hr i. e. 1.04 µmol/kg (equivalent to 71 µg/kg). This value is adjusted for the low absorption factor of 0.003% giving a DN(M) EL of 23.7 mg/kg bw/d.

Ethylbenzene

The cooperation of the Styrenics Steering Committee in providing DNELs for ethylbenzene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for ethylbenzene.

Worker – long-term systemic inhalation DNEL

There is no IOELV for ethylbenzene, therefore the DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). Correct the NOAEC to adjust for activity driven and absorption percentage differences following ECHA TGD (2008b) guidance:

DNEL_{l-t inhalation}= 500 mg/m3x [6.7 / 10] x [ABS_inhal-rat/ ABS_inhal-human] = 500 mg/m³x 0.67 x [45 / 65] = 232 mg/m³

An assessment factor of 3 is used for intraspecies differences within worker population:

DN(M)EL_{l-t inhalation}= 232 mg/m³/ 3 = 77 mg/m³

Worker – long-term systemic dermal DNEL

The DNEL is based on sub-chronic effects (ototoxicity) in the rat following inhalation exposure: extrapolated NOAEC = 500 mg/m³(114 ppm). The NOAEC is corrected into a human dermal NOAEL (mg/kg bw/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of ethylbenzene after inhalation in rats is 45%.

_correctedDermal NOAEL = NOAEC_{l-t inhalation}x sRVrat-8hr^[1]x 0.45 = 500 x 0.38 mg/kg bw/d = 86 mg/kg bw/d

A value of 4% used for dermal absorption in humans (Susten et al, 1990):

_correctedDermal NOAEL = 86 mg/kg bw/d x [100 /4] = 2150 mg/kg bw/d

An assessment factor of 12 is used based on interspecies differences for the rat (4) and intraspecies differences within worker populations (3).

The DNEL for long-term dermal exposure is derived as follows:

DN(M)EL_{l-t dermal}= 2150 mg/kg bw/d / 12 = 180 mg/kg bw/d

Styrene

The cooperation of the Styrenics REACH consortia in providing DN(M)ELs for styrene is acknowledged. Documentation supporting these values is in the Styrenics REACH consortium dossier for styrene.

The EU transitional RAR(2008c) identified the following end-points as of concern for human health: acute toxicity (CNS depression), skin, eye and respiratory tract irritation, effects on colour vision discrimination following repeated exposure, effects on hearing (ototoxicity) following repeated exposure, developmental toxicity.

Worker – long-term systemic inhalation DNEL

The DN(M)EL is based on ototoxicity in humans (Triebig et al, 2009). A NOAEC for humans of 20 ppm (85 mg/m³) can be derived as starting point from this study. As the DNEL is derived from studies on exposed workers an assessment factor is not necessary.

DN(M)EL_{l-t inhalation}= 85 mg/m³

Worker – long-term systemic dermal DNEL

The DN(M)EL is based on long term inhalation NOAEC of 20 ppm (86 mg/m³) for ototoxicity in workers. The dose descriptor is corrected into a human dermal NOAEL. Using a respiratory volume for workers under light physical activity of 10 m³/person/day and a body weight of 70 kg (ECHA, 2008b) the external exposure would be 86 x 10/70 = 12.3 mg/kg bw/d.

This is then converted to a dermal dose by adjusting for differences in exposure. Absorption of styrene from the respiratory tract is considered to be 66% based on a study in 7 volunteers at 50 ppm under light physical activity (50 Watt) (Engström et al, 1978). In humans only 2% of a dermal dose of liquid styrene is likely to be absorbed (EU, 2008c).

Dermal NOAEL = 12.3 x [ABS_inhal-human/ ABS_dermal-human] = 12.3 x [66/2] = 406 mg/kg/d.

Since the worker-DNEL long-term for dermal exposure was directly derived from that for inhalation exposure no further assessment factors are necessary.

DN(M)EL_{l-t dermal}= 406 mg/kg bw/d

Toluene

Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neurophysiological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments.

Documentation supporting the IOELV (SCOEL, 2001) concluded that an exposure limit of 50 ppm (192 mg/m³) would protect against chronic effects hence, in accordance with REACH guidance and since no new scientific information has been obtained under REACH which contradicts use of the IOELV for this purpose, the established IOELV of 50 ppm (192 mg/m³)^[b]– 8 hr TWA (EU, 2006) will be used as the starting point for calculating the chronic dermal DNEL for workers.

Worker – long-term systemic inhalation DNEL

The IOELV will be used with no further modification

DN(M)EL_{l-t
inhalation}= IOELV = 192 mg/m³

Worker – long-term systemic dermal DNEL

The dermal DNEL for toluene is based on the internal dose achieved by a worker undertaking light work and exposed to the IOELV for 8 hr, assuming 50% uptake by the lung and 3.6% uptake by skin (ten Berge, 2009).

As the IOELV is based on worker life-time exposure no assessment factor is needed.

Dermal NOAEL = IOELV x wRV_8-hourx [50/3.6] = [192 x 0.144 x 13.89]

DNEL_{l-t
dermal} = 384 mg/kg bw/d

n-Hexane

Background information supporting the SCOEL decision on n-hexane is not available, however ACGIH (2001) and ATSDR (1999) identify peripheral polyneuropathy as the lead effect for n-hexane in humans. Since n-hexane is not a core LOA substance, it has been assumed that no significant new information has come available to challenge the SCOEL position, and that the IOELV (included in the 2^ndlist of indicative occupational exposure limit values - EU, 2006) remains valid.

Worker – long-term systemic inhalation DNEL

The long-term systemic DNEL for n-hexane will therefore be based upon the IOELV with no further modification:

DN(M)EL_{l-t
inhalation}= IOELV = 72 mg/m³

Worker – long-term systemic dermal DNEL

The dermal NOAEC is extrapolated from the IOELV. The IOELV (mg/m³) is converted into a human dermal NOAEL (mg/kg bw/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

Information cited by ACGIH indicates that uptake of n-hexane after inhalation is in a range 5-28%, with pulmonary retention of 25% reported for volunteers involved in work. ACGIH briefly reports a human case report which described “severe intoxication” following percutaneous absorption. However, the UK HSE (1990) concluded that “there is limited absorption of liquid through the skin” although no quantitative information is provided. No substance-specific data are available, hence a conservative default of 10% uptake will be used.

Dermal NOAEL = IOELV xwRV_8-hour^[a] x [ABS_inhal-human/ABS_dermal-human] = 72 x 0.144 x [25 / 10] = 25.9 mg/kg bw/d

As the IOELV is based on human data no assessment factor is needed.

DN(M)EL_{l-t dermal} = 25.9 mg/kg bw/d

Xylene isomers

Worker – long-term systemic inhalation DNEL

For xylenes, the following rodent inhalation NOAECs are presented in the IUCLID dossier:

Sub-chronic effects – ototoxicity (deficits in brainstem auditory evoked response)

m-xylene and o-xylene = 1800 ppm (7817 mg/m3)

mixed xylene (2 samples) = 500 ppm (2171 mg/m3) or 1000 (4342 mg/m3)

p-xylene = 450 ppm (1954 mg/m3)

The lowest overall NOAEC for repeated dose effects after inhalation is 450 ppm (1954 mg/m3; ototoxicity, p-xylene). It is noted that (relative to other xylene isomers) this is a conservative no-effect concentration.

The equivalent worker NOAEC (Example A.2, ECHA Guidance, Chapter R.8) is therefore:

Worker NOAEC = inhalatory NOAEC x [sRVhuman / wRV]

= 1954 mg/m3 x [6.7 m3 / 10 m3]

= 1309.2 mg/m3

Assessment factors:

Long-term DNEL Assessment Factors (Worker, inhalation)
AF for dose response relationship	1	NOAEC used as starting point
AF for differences in duration of exposure	2	Default (correction for sub-chronic to chronic exposure)
AF for interspecies differences (allometric scaling)	1	Default (none required inhalation route)
AF for other interspecies differences	1	An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for xylene isomers, together with information available for chemically-related structures do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.
AF for intraspecies differences	3	There are no data to quantify variability in susceptibility to the effects of exposure to xylene isomers in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.
AF for quality of the whole data base	1	No issues with quality of the whole database identified
AF for remaining uncertainties	1	None identified (conservative NOAEC used as starting point)
Overall AF	6

The DNEL for long-term inhalation exposure is therefore:

DNEL l-t inhalation = Worker NOAEC / AF = 1309.2 mg/m3 / 6 = 218.2 mg/m3

As the magnitude of the DNEL l-t inhalation is essentially identical to the IOELV, the IOELV of 221 mg/m3 (50 ppm, 8h TWA) should provide adequate protection and is proposed as the worker DNELl-t inhalation.

Worker – long-term systemic dermal DNEL

Dose descriptor

The IOELV of 50 ppm (221 mg/m3, 8h TWA) will be used for derivation of the worker DNELl-t dermal.

Modification of dose descriptor

The IOELV (mg/m3) is corrected into a human dermal NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of xylenes after inhalation is 100% with a value of 15% for dermal absorption (ten Berge, 2009):

correctedDermal NOAEL = IOELV x wRVhuman-8hr x [ABSinhal-human/ABSdermal-human]

correctedDermal NOAEL = 221 x 0.144 x (100/15) = 212 mg/kg bwt/d

Note:

worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV8-hour = (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw)

No assessment factor is necessary.

Naphthalene

The cooperation of the REACH for Coal Chemicals (R4CC) consortium in permitting access to DNEL information present on the ECHA Dissemination pages for naphthalene is acknowledged.

Worker – long-term systemic inhalation DNEL

The long-term systemic DNEL for naphthalene is based upon (EU and USA) OEL values of generally 50 mg/m³, with an assessment factor of 2:

DN(M) EL_{l-t
inhalation}= 50 mg/m³/ 2 = 25 mg/m³

Worker – long-term systemic dermal DNEL

The long-term dermal DNEL is based upon the systemic dose achieved following 8 hr exposure at the DNEL of 25 mg/m³.

DN(M) EL_{l-t
dermal}= 3.57mg/kg bw/d

2-methyl-2-butene

Since 2 -methylbut-2-ene (2M2B) is concluded to be an in vivo mutagen (Cat 2, H341 under GHS/CLP) with no relevant dose-response information and no cancer data, neither a DMEL nor a DNEL can be derived.

A qualitative assessment is therefore considered. Since 2M2B is assigned the H-phrase H341 (suspected of causing genetic defects), it is allocated to the high hazard category on the basis that exposure to such substances should be strictly contained because they may cause serious health effects for which a dose threshold is not usually identifiable (TGDSection E.3.4).

With the strict control measures for a non-threshold mutagen, applying the RMMs/OCs as stipulated for the high hazard category, exposure control is considered to be sufficient and will cover any other relevant effects for which DNELs can be derived, for all routes of exposure.

In accordance with REACH guidance, it is concluded that this qualitative risk characterisation is sufficient and there is no need to conduct a quantitative risk characterisation.

1,3-Butadiene

1,3-Butadiene is a multi-species carcinogen. In the mouse, it is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours. In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher than in the mouse. In humans, 1,3-butadiene is a recognised carcinogen. A positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukaemia). Various models have established a dose response-relationship for cumulative exposure to 1,3-butadiene, especially concentrations above 100 ppm. The estimates for occupational and population human risk are based on these models.

Worker – long-term systemic inhalation DNEL

The association between 1,3-butadiene exposure and leukaemia has been extensively modeled using Cox and Poisson regression models and the excess risk of leukaemia determined. The preferred model for workers is the Cox continuous model (Cheng et al, 2007) as employed by Sielken et al (2008), using the exposure metric that excluded exposure that occurred more than 40 years ago or excluded the 5% of workers with the highest cumulative 1,3-butadiene exposures and included as covariate, the cumulative number of exposures to 1,3-butadiene concentrations > 100 ppm (the number of High Intensity Tasks [HITs]). This model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. The estimate of the excess risk of death from leukaemia as a result of exposure to a DMEL of 2.21 mg/m³(1 ppm) is 0.33 x 10^-4(with an upper bound of 0.66 x 10^-4based on a one-sided 95% upper confidence limit for the regression parameter).

This estimate is less than 0.4 x 10^-4, which has been proposed as a future limit for acceptable occupational risk (AGS, 2008). Regression coefficients from other Cox regression models reported by Cheng et al (2007) and TCEQ (2008), and estimates from Poisson regression models, indicate that other risk estimates are generally close to 0.4 x 10^-4, even if based on regression models that do not adjust for 1,3-butadiene HITs. All of the estimates are considerably lower than the current limit for acceptable occupational risk of 4 x 10^-4that has recently been proposed (AGS, 2008).

DN(M) EL_{l-t inhalation}= 2.21 mg/m³

Worker – long-term systemic dermal DNEL

As 1,3-butadiene is a gas a dermal DNEL is not quantifiable.

Anthracene

The toxicological properties of anthracene have been reviewed (EU, 2009), with a conclusion that it is of low toxicity following repeated exposure (NOAEC of 1000 mg/kg/day in mouse oral toxicity study) and is not of concern for mutagenicity or carcinogenicity. Although data are lacking with respect to reproductive and developmental toxicity no detectable toxic effects on the reproductive system of mice were seen during a 90-day feeding study it was concluded that anthracene may possess weak, if any, developmental toxicity. However, extensive studies in animals and humans demonstrate that anthracene possess phototoxic potential following exposure in combination with UV light.

Based on the lack of systemic toxicity no substance-specific DNELs will therefore be developed for this marker substance. It is considered that the low concentration of anthracene present in this stream would not impact on the overall toxicity assessment and that risk management measures and occupational controls intended to minimise human exposure to the other toxicologically-active marker substances also present would limit exposure to anthracene.

References

ACGIH (2001). n-Hexane: TLV Documentation, 7th Edition, p1-16.

AGS (2008). Committee on Hazardous Substances. Guide for the quantification of cancer risk figures after exposure to carcinogenic hazardous substances for establishing limit values at the workplace. 1. Edition. Dortmund: Bundesanstalt für Arbeitsschutz und Arbeitsmedizin. Available from:http://www.baua.de/nn_21712/en/Publications/Expert-Papers/Gd34,xv=vt.pdf

ATSDR (1999).Toxicological Profile for n-Hexane. http://www.atsdr.cdc.gov/toxprofiles/tp113.html

ATSDR (2005).Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene.http://www.atsdr.cdc.gov/toxprofiles/tp67.pdf

Blank IH, McAuliffe DJ (1985). Penetration of benzene through human skin. J. Invest. Dermatol. 85, 522–526.

Cheng H, Sathiakumar N, Graff J, Matthews R, Delzell E (2007). 1,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships. Chem Biol Interact, 166,15-24.

Engstrom K, Harkonen H, Pekari K and Rantanen J. (1978). Evaluation of occupational styrene exposure by ambient air and urine analysis. Scand. J. Work Environ. Health, 4 (Suppl. 2):121-123.

EU (1999). Council Directive 1999/38/EC of 29 April 1999 amending for the second time Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work and extending it to mutagens. Official Journal of the European Communities, L138, 66-69, 1 June 1999.

EU (2000). Council Directive 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values (IOELV) in implementation of Council Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work.Official Journal of the European Communities, L142, 47-50.

EU (2003b). Risk assessment report for naphthalene. http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/naphthalenereport020.pdf EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.

EU (2006). Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/EEC and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.

EUROPEAN UNION RISK ASSESSMENT REPORT, Styrene. CAS No: 100-42-5 EINECS No 202-851-5; Draft for publication, June 2008. United Kingdom. EU RAR Styrene, UK

EU (2009). Anthracene (CAS No 120-1207; EINECS No 204-371-1): Summary risk assessment report, October 2009. Available from: http://ecb.jrc.ec.europa.eu/risk-assessment/

Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, Kessler W, Kreuzer PE, Putz C, Shen JH, Stei P.(1996). Toxicokinetics of isoprene in rodents and humans. Toxicology 113:278-287.

MAK (2009). MAK Commission 46 Lieferung.

Maibach HI, Anjo DM (1981). Percutaneous penetration of benzene and benzene contained in solvents used in the rubber industry. Arch. Environ. Health 36, 256–260.

Schnatter AR, Kerzic P, Zhou Y, Chen M, Nicolich M, Lavelle K, Armstrong T, Bird M, Lin l, Hua F and Irons R (2010). Peripheral blood effects in benzene-exposed workers. Chem Biol Interact (2009) doi:10.1016/j. cbi.2009.12.020.

SCOEL (2001). Recommendation from the Scientific Committee on Occupational Exposure Limits for toluene108-88 -3. http://ec.europa.eu/social/BlobServlet?docId=3816&langId=en

SCOEL (2010) Consolidated Indicative Occupational Exposure Limits Values (IOELVs). Available from http://ec.europa.eu/social/main.jsp?catId=153&langId=en&intPageId=684

Sielken RL, Valdez-Flores C, Delzell E (2008). Quantitative Risk Assessment of Exposures to Butadiene in European Union Occupational Settings Based on the University of Alabama at Birmingham Epidemiological Study: All Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, and Chronic Myelogenous Leukemia. Unpublished report to Lower Olefins Sector Group, Brussels, Belgium.

Susten, AS et al (1990). In vivo percutaneous absorption studies of volatile organic solvents in hairless mice II; Toluene, ethylbenzene and aniline. J. Appl. Toxicol. 10: 217-225.

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TCEQ (2008). Texas Commission on Environmental Quality. Development Support Document. 1,3-Butadiene. Chief Engineer’s Office. Available from:http://tceq.com/assets/public/implementation/tox/dsd/final/butadiene,_1-3-_106-99-0_final.pdf

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[1] Standard respiratory volume (sRV) of a 250 g rat = 0.38 m3/kg bw (TGD Table R.8-2)

[a] Data reported as 3.5 ppm, and converted to mg/m3 using tool available from http://www.cdc.gov/niosh/docs/2004-101/calc.ht

[b] Worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV8-hour= (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.14 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: based on other data

Dose descriptor starting point:

other: not applicable

Modified dose descriptor starting point:

other: not applicable

Explanation for the modification of the dose descriptor starting point:

See additional information - General Population.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL derivation method:

other: ECETOC, 2003; 2010

Modified dose descriptor starting point:

NOAEL

Value:

2.83 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Data derived from well-conducted subchronic 90 day mouse inhalation study.

Justification:

default for subchronic to chronic

Justification:

Allometric scaling is not necessary for the inhalation route if derived from an inhalation study (R8)

Justification:

an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.)

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

According to REACH Annex XVII, benzene shall not be placed on the market as a constituent of other substances, or in mixtures, in concentrations >0.1% by weight with the exception of motor fuels which are the subject of a separate directive (98/70/EC). Since these streams all contain at least 0.1% benzene, their supply to the general population is prohibited (with the exception of consumer fuel use) and no formal risk characterisation is therefore required. General population DN(M)ELs for benzene have been developed, however, to support risk assessment of man exposed via the environment with the background discussed below.

The starting points for derivation of the Benzene General Population DNEL were the LOAEC and NOAEC used to derive the benzene worker DNEL as detailed in Schnatter et al 2020. Appendix R8-15 of the ECHA Guidance (Use of Human data in the derivation of DNEL and DMEL) was consulted.

Selection and modification of the relevant dose descriptors

The dose descriptors derived from workers studies used in the derivation of an OEL for benzene by Schnatter et al 2020 (LOAECs and NOAECs) were modified to adjust for the intended target population of the General Population.

The dose descriptor was modified to adjust for the longer exposure time involved in General Population exposure compared to worker exposure and also to take account of the lower average breathing rate the following factor was used:

24/8 * 7/5*6.7/10 = 2.814

Applying this modification factor to the aggregate LOAEC and aggregate NOAEC derived by Schnatter et al 2020 would yield the following modified dose descriptors (mDDs) for consideration in deriving a General Population DNEL :

LOAEC_{(for deriving General Population
DNEL)} = 2.0 ppm / 2.814 = 0.7107ppm

NOAEC_{(for deriving General Population
DNEL)} = 0.5 ppm / 2.814 = 0.1777ppm

Selection and justification of the Assessment Factors

Intraspecies Differences

Considering both haematoxicity and genotoxicity data from high quality studies Schnatter et al 2020 took the following view:

Based on the derived LOAECs an assessment factor of 2 was justified for the derivation of a Worker DNEL/OEL (Because the LOAECs are based on large aggregate populations and also based on selecting lower LOAECs from the available high quality worker studies. It was noted that an assessment factor of 1 could have been justified but this was not selected thus making the analysis more conservative.

Based on the derived NOAECs an assessment factor of 1 was justified in deriving a worker DNEL/OEL. (Because it is derived from an adequate NOAEC.)

However, in deriving a DNEL for the General Population the point made in ECHA’s R8 Guidance document Appendix R-8 -15 (section 7.A.1 iv – page 160) is relevant. This states that“In cases where eg children, elderly or sick people or people having a special diet were not represented or were excluded from the study sample, the use of a low AF would not be justified”.

On that basis therefore the default assessment factor from Table R. 8-6 should be used. Table R. 8-6 uses an assessment factor of 10 for intraspecific differences for the General Population. However, the worker default assessment factor is 5 implying the component to cover the extra difference for the General Public is a factor of 2. If the assessment factors justified for workers by Schnatter et al 2020 are multiplied by 2 therefore this would provide protection for the greater sensitivity of the General Population.

This would derive the following intraspecific assessment factors:

for LOAECs of 2 x 2 = 4 (AF = 4)
for NOAECs of 1 x 2 .=2 (AF = 2)

Duration of Exposure

Based on the Mode of Action reviewed in North et al 2020, Schnatter et al 2020 assessed the benzene data on the basis that the critical toxicities (haematotoxicity and genotoxicity) had a threshold. Logically if a toxicity threshold is not exceeded (based on maintaining exposure below the DNEL) then toxicity after 75 years of exposure (General Population) should not differ from that after 40 years of exposure (for a worker) i.e. no toxicity occurs. Consequently, no adjustment has been made for the difference in long term duration of exposure that relates to the General Population compared to workers. (AF=1)

Dose-response relationship

Considering both haematoxicity and genotoxicity data from high quality studies Schnatter et al 2020 took the following view:

Based on the derived LOAECs an assessment factor of 2 was justified on the basis that of the available LOAECs the lower ones were selected and also that there was overlap between these LOAECs and the NOAECs derived in other studies.

Based on the derived NOAECs an assessment factor of 1 was justified on the basis that of the available LOAECs the lower ones were selected and also that there was overlap between these LOAECs and the NOAECs derived in other studies.

So for Dose-Response Relationship:

LOAECs should have AF =2
NOAECs should have AF = 1

Quality of human data (including exposure data)

The methods applied to the benzene data by Schnatter et al 2020 result in identification of the highest quality data – both in terms of effect and exposure assessment. On that basis an assessment factor of 1 is proposed for data quality.

Additional Factor

Consideration of Bone Marrow being more sensitive than peripheral blood markers.

As described in Schnatter et al 2020 an additional assessment factor was used pending clarification as to whether bone marrow is a more sensitive marker of these effects of benzene compared to observations in peripheral blood. Schnatter et al 2020 propose a value of 2 for this additional assessment factor. (AF=2)

Integration of human and animal data and selection of the critical DNEL for the risk characterisation

As argued in Schnatter et al 2020 given the volume and quality of the human data on the key endpoints of haematotoxicity and genotoxicity it is justified to use the LOAECs and NOAECs from studies in workers as dose descriptors for deriving the DNEL. On that basis human data is used in this derivation and animal data is not utilised.

The modified dose descriptor (mDD) (as above) is therefore multiplied by the assessment factors:

DNEL General Population = mDD* AF_{(Intraspecies)}* AF_{(Duration of Exposure)}* AF_{(Dose-Response)}*AF_{(Quality
of data)}* AF_{(bone marrow sensitivity)}

Starting from the modified descriptor as above:

LOAEC_{(for deriving General Population
DNEL)} = 0.7107ppm

DNEL General Population_{(based on LOAEC)}= 0.7107*4*1*2*1*2 = 0.7107 / 16 = 0.0442 ppm

Starting from the modified descriptor as above:

NOAEC_{(for deriving General Population
DNEL)}= 0.1777 ppm

DNEL General Population_{(based on NOAEC)}= 0.1777*2*1*1*1*2 = 0.1777 / 4 = 0.0444 ppm

Both the LOAEC and NOAEC approaches therefore agree that the General Population DNEL_(Inhalation)= 0.044 ppm (0.140mg/m³)

Note: On the assumption that approximately 50% of inhaled benzene is absorbed (Nomiyama and Nomiyama 1974, Pekari et al 1992) then inhalation at this General Population DNEL concentration would give a body burden of:

20m³*0.5*0.140 mg/m3 = 1.4 mg / 24 hours equating to 20µg/kg body weight for a 70 kg person.

References

ECB 2008European Union Risk Assessment Report BENZENE. Final version of 2008:https://echa.europa.eu/documents/10162/be2a96a7-40f6-40d7-81e5-b8c3f948efc2

ECHA (2012) Guidance on information requirements and chemical safety assessment Chapter R8 Characterisation of dose[concentration]-response for human health Reference ECHA 2010-G-19

Nomiyama, K., Nomiyama, H. (1974): Respiratory retention, uptake and excretion of organic solvents in man: Benzene, toluene, n-hexane, trichloroetehylene, acetone, ethyl acetate, and ethyl alcohol. Int. Arch. Arbeitsmed. 32: 75-83

North, C.M., Rooseboom, M., Aygun Kocabas, N., Schnatter, A.R., Faulhammer, F., Williams, S.D., (2020). Modes of Action Considerations in Threshold Expectations for Health Effects of Benzene. Submitted to Toxicology Letters.

Pekari, K., Vainiotalo, S., Heikkila, P. et al. (1992): Biological monitoring of occupationalexposure to low levels of benzene. Scand. J. Work Environ. Health 18: 317-322

Schnatter, A.R., Rooseboom, M., Aygun Kocabas, N., North, C.M., Dalzell, A., Twisk, J.J., Faulhammer, F., Rushton, E., Boogard, P.J., Ostapenkaite, V., Williams, S.D., (2020) Derivation of an Occupational Exposure Limit for Benzene Using Epidemiological Study Quality Assessment Tools. Submitted to Toxicology Letters. https://doi.org/10.1016/j.toxlet.2020.05.036