Registration Dossier

Administrative data

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
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:
Not applicable
Justification:
See additional information - workers.
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

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 be thresholded, 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 2017-2019

Using a Study Quality Assessment tool to decide the studies that are 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.

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 2019) and is elaborated in the papers being submitted to a peer-reviewed toxicology journal. These papers will be referenced in this dossier once accepted for publication.

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 (ie. 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 the papers being submitted to a peer-reviewed toxicology journal. These papers will be referenced in this dossier once accepted for publication. However, in summary, after identifying relevant haematotoxicity and genotoxicity studies in workers by means of literature searches and accessing existing reviews, 42 haematotoxicity and 95 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-five haematology studies from 30 unique study populations and 77 genotoxicity studies from 59 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” ( ie 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. The mean LOAEC was 2.3 ppm / 8h. The best available NOAEC values came from two “Fuel” studies (Carere et al 1995 = 0.46 ppm and Pandey et al 2008 = 2 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 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).

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

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

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.

Xing C, Marchetti F, Li G, Weldon RH, Kurtovich E, Young S, Schmid TE, Zhang L, Rappaport S, Waidyanatha S, Wyrobek AJ, Eskenazi B (2010) Benzene exposure near the U.S. permissible limit is associated with sperm aneuploidy. Environ Health Perspect 118: 833839.

Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, Guo W, Hubbard AE, McHale CM, Rappaport SM, Hayes RB, Linet MS, Yin S, Smith MT, Rothman N (2012) Leukaemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers. Leukaemia 26: 2494-2498.

Zhang GH, Ye LL, Wang JW, Ren JC, Xu XW, Feng NN, Zhou LF, Ru JG, Hao YH, Tian W, Sun P, Au WW, Christiani DC, Xia ZL (2014) Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China. Int J Hyg Environ Health 217: 726-732.

Zhang GH, Ji BQ, Li Y, Zheng GQ, Ye LL, Hao YH, Ren JC, Zhou LF, Xu XW, Zhu Y, Xia ZL (2016) Benchmark Doses Based on Abnormality of WBC or Micronucleus Frequency in Benzene-Exposed Chinese Workers. J Occup Environ Med 58: e39-44.

General Population - Hazard via inhalation route

Systemic effects

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

Thresholds for consumers have not been derived as Benzene is registered as a transported intermediate under strictly controlled conditions, and consumer uses are not supported.