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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Acute toxicity - systemic effects

Benzene is legally classified as cancer Cat 1A in the EU. According to ECHA Guidance Part E: Risk Characterisation, Version 3.0 the substance belongs to the high hazard category, no threshold was derived as the substance is only used as intermediate.

Acute toxicity – local effects

The risk management measures in place for carcinogenicity will provide adequate protection against the occurrence of local effects following acute exposure.

Sensitization

No hazard with respect to skin or respiratory sensitization has been identified in animal studies or in humans and, consequently, no DNEL can or will be proposed.

Oral

The oral route is not relevant to workers and a DN(M)EL will not be proposed.

Dermal

The risk management measures in place for carcinogenicity will provide adequate protection against the occurrence of dermal effects.

Inhalation

The risk management measures in place for carcinogenicity will provide adequate protection against the occurrence of inhalation effects.

Long-term local effects

The (interim) systemic long term threshold and risk management measures in place for carcinogenicity will provide adequate protection against the occurrence of local long-term effects.

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

 

North CM et al (2020b) Event-informed Risk Models for Benzene-induced Acute Myeloid Leukemia Toxicology Letters (in preparation)

 

Pandey AK, Bajpayee M, Parmar D, Kumar R, Rastogi SK, Mathur N, Thorning P, de Matas M, Shao Q, Anderson D, Dhawan A (2008) Multipronged evaluation of genotoxicity in Indian petrol-pump workers. Environ Mol Mutagen 49: 695-707.

 

Qu Q, et al. (2003). Validation and evaluation of biomarkers in workers exposed to benzene in China. Res Rep Health Eff Inst 115: 1-72; discussion 73-87.

 

Rothman N et al. (1996). Hematotoxicity among Chinese workers heavily exposed to benzene. Am J Ind Med. 29(3):236-46.

 

Schnatter AR et al. (2010). Peripheral blood effects in benzene-exposed workers. Chem Biol Interact 184: 174-181.

 

Schnatter AR et al (2020) Derivation of an Occupational Exposure Limit for Benzene Using Epidemiological Study Quality Assessment Tools. Toxicology Letters  https://doi.org/10.1016/j.toxlet.2020.05.036

 

Vlaanderen, J., Vermeulen, R., Heederik, D., Kromhout, H. (2008). Guidelines to evaluate human observational studies for quantitative risk assessment. Environ Health Perspect. 116(12):1700-5.

 

Ward, et al. (1996). Risk of low red or white blood cell count related to estimated benzene exposure in a rubber worker cohort (1940-1975). Am J Ind Med. 29(3):247-57.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
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 related information
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.

Justification:
.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Benzene is registered as a transported intermediate under strictly controlled conditions and consumer uses for this substance are therefore not supported by LOA.

The Benzene General Population DNEL is derived for the purpose of exposure assessment of LOA streams containing benzene, for which consumer exposure may occur, for example, permitted motor fuels.

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 2008 European 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