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EC number: 292-637-8 | CAS number: 90641-13-7 A complex combination of hydrocarbons produced by the distillation of the products from a steam cracking process thereafter treated with hydrogen in the presence of a catalyst. It consists predominantly of aromatic hydrocarbons having carbon numbers in the range of C9 through C10 and boiling in the range of approximately 140°C to 200°C (284°F to 392°F).
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
There are substantial data on the genotoxicity of a number of specific constituents present in some streams. Of these, benzene, buta-1,3 -diene, and isoprene have been shown to be mutagenic in vivo. Since benzene is a Category 1B (H340) mutagen according to the CLP Regulation, and is present in all streams at a concentration of 0.1% or greater. Therefore, the High Benzene Naphtha streams are also classified as mutagenic in vivo.
Genetic toxicity in vivo
Description of key information
There are substantial data on the genotoxicity of a number of specific constituents present in some streams. Of these, benzene, isoprene, and 1,3-butadiene have been shown to be mutagenic in vivo. Since benzene is a Category 1B (H340) mutagen according to the CLP Regulation, and is present in all streams at a concentration of 0.1% or greater. Therefore, the High Benzene Naphtha streams are also classified as mutagenic in vivo.
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Not GLP, but key cytogenetic parameters measured comparable to guideline study.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
- Deviations:
- yes
- Remarks:
- only 3-4 animals/group
- Principles of method if other than guideline:
- Mice given single oral gavage dose of benzene (1 mL/kg bw) and chromosomal aberrations in bone marrow and spermatogonal cells assessed at time points up to 48 h post-treatment.
- GLP compliance:
- not specified
- Type of assay:
- other: bone marrow chromosome aberration assay and mammalian germ cell cytogenetic assay
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Valco Co., Italy
- Age at study initiation: 2 months
- Weight at study initiation: 30-35 g
- no further details
ENVIRONMENTAL CONDITIONS
- no data
IN-LIFE DATES:
- no data - Route of administration:
- oral: gavage
- Vehicle:
- - Olive oil
- Duration of treatment / exposure:
- Single oral dose
- Frequency of treatment:
- Single oral dose
- Post exposure period:
- Up to 48 h
- Remarks:
- Doses / Concentrations:
1 mL/kg
Basis:
actual ingested - No. of animals per sex per dose:
- 3-4 male mice
- Control animals:
- yes, concurrent vehicle
- Tissues and cell types examined:
- Bone marrow and spermatogonal cells
- Statistics:
- The binomial dispersion test was applied to test homogeneity of results from control animals. Statistical differences between treated and solvent control groups were determined by Fisher's exact test. To compare the sensitivity of the two cell types the doubling doses were calculated. The doubling dose (DD) is defined as the dose that induces as many aberrations as occur spontaneously per cell generation. Based on the linear dose-response, Y = a + b D, where Y is the yield of aberrant cells, a the spontaneous frequency and b the linear regression coefficient, the doubling dose is calculated as the ratio of a to b (DD = a/b).
- Sex:
- male
- Genotoxicity:
- positive
- Remarks:
- Chromosomal aberration test; mouse (bone marrow)
- Toxicity:
- not specified
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- not applicable
- Sex:
- male
- Genotoxicity:
- positive
- Remarks:
- Germ cell chromosome aberration test; mouse (spermatogonia)
- Toxicity:
- not specified
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- not valid
- Conclusions:
- Interpretation of results (migrated information): positive Chromosomal aberration test (mouse bone marrow) and Germ cell chromosome aberration test (mouse spermatogonia)
Benzene was positive in the chromosomal aberration test (mouse bone marrow) and germ cell chromosome aberration test (mouse spermatogonia), following a single oral dose of 1 mL/kg to male mice. - Executive summary:
The ability of benzene to induce chromosome damage in vivo was assessed by determining the frequencies of chromosomal aberrations in bone marrow and spermatogonial cells of male Swiss CDI mice. Initially a single dose of 1 mL benzene/kg (880 mg/kg) was assessed using a wide range of times (6, 12, 18, 24, 30, 36, 42 and 48 hours) to determine the time of maximum response. Benzene showed high clastogenic activity with a peak between 24 and 30 hours in bone marrow cells or 24 hours in differentiating spermatogonia. The effect in bone marrow cells was greater than in spermatogonia. Secondly, the dose response 24 hours after treatment was determined. Additional doses of benzene used were: 0.1 mL/kg (88 mg/kg) and 0.5 mL/kg (440 mg/kg) for bone marrow cells; 0.25 mL/kg (220 mg/kg) and 0.5 mL/kg (440 mg/kg) for differentiating spermatogonia.
Benzene was positive in this test with dose dependent clastogenic effects in both cell types. All dose levels showing a statistically significant increase in the incidence of aberrant cells.
It is concluded that benzene is a clastogen in male germ cells and the bone marrow of mice.
Reference
Bone Marrow:
Benzene showed high clastogenic activity in bone marrow cells at all sampling times with a peak at 24 and 30 hours (approx. 20% aberrant cells (excl. gaps) versus 1% in controls). The dose-response was determined 24 h after treatment with 0.1, 0.5 or 1.0 mL/kg benzene (equivalent to 88, 440 and 880 mg/kg bw). All three doses were clearly positive and a dose-dependency was established.
Chromatid aberrations in bone marrow cells of mice treated with 1 mL/kg (880 mg/kg) of benzene: time-response
Time (h) |
No. cells scored a |
No. of aberrations |
Highly damaged cells (n) b |
Aberrant cells (%±SE) |
|||
|
|
gaps |
breaks |
exchanges |
|
including gaps |
excluding gaps |
Control |
1000 |
24 |
11 |
- |
- |
3.2 ± 0.6 |
1.1 ± 0.1 |
6 |
600 |
47 |
29 |
- |
- |
11.3 ± 0.1 |
4.3 ± 0.6** |
12 |
600 |
89 |
98 |
7 |
- |
24.6 ± 2.4 |
16.6 ± 0.4** |
18 |
600 |
59 |
112 |
7 |
3 |
22.6 ± 4.5 |
15.3 ± 3.0** |
24 |
600 |
53 |
206 |
6 |
13 |
25.1 ± 2.7 |
20.8 ± 3.3** |
30 |
600 |
117 |
237 |
15 |
13 |
28.7 ± 7.4 |
19.8 ± 0.5** |
36 |
600 |
10 |
24 |
- |
- |
4.8 ± 0.4 |
3.5 ± 0.5** |
42 |
600 |
26 |
31 |
- |
- |
8.6 ± 1.4 |
5.3 ± 0.4** |
48 |
600 |
41 |
44 |
- |
- |
12.0 ±1.7 |
6.3 ± 1.1** |
**P <0.01 (Fisher's exact test).
a 200 cells scored per animal.
b Cells with more than 10 aberrations.
Spermatogonia:
After administration of 1 mL/kg (880 mg/kg bw) the maximum response was obtained 24 h after treatment (6.3% aberrant cells versus 1.2% in negative controls). In the dose-response study, all doses tested (0.25, 0.5 and 1.0 mL/kg bw, equivalent to 220, 440 and 880 mg/kg bw) increased the aberration frequency in a dose-dependent manner; at 880 mg/kg again 6.3% of the spermatogonia were aberrant. Since bone marrow clastogenicity was investigated in parallel, it can be concluded that clastogenicity in bone marrow cells and spermatogonia was induced in the same dose range, although effects were less pronounced in spermatogonia.
Chromatid aberrations in differentiating spermatogonia of mice treated with 1 mL/kg (880 mg/kg) of benzene: time-response
Time (h) |
No. cells scored a |
No. of aberrations |
Aberrant cells (%±SE) |
|||
|
|
gaps |
breaks |
exchanges |
including gaps |
excluding gaps |
Control |
1000 |
49 |
12 |
- |
5.5 ± 0.9 |
1.12 ± 0.2 |
6 |
600 |
32 |
6 |
- |
6.3 ± 0.1 |
1.0 ± 0.3 |
12 |
600 |
63 |
18 |
1 |
12.3 ± 0.3 |
3.3 ± 0.4** |
18 |
600 |
67 |
24 |
- |
13.3 ± 1.2 |
4.0 ± 0.5** |
24 |
600 |
54 |
36 |
3 |
14.8 ± 2.6 |
6.3 ± 1.6** |
30 |
600 |
33 |
16 |
1 |
7.8 ± 1.6 |
2.6 ± 0.5* |
36 |
600 |
31 |
23 |
1 |
8.3 ± 1.0 |
3.5 ± 0.5** |
42 |
600 |
21 |
14 |
- |
5.2 ± 1.3 |
2.0 ± 0.5 |
48 |
600 |
19 |
23 |
- |
18.2 ±2.0 |
3.5 ± 0.7** |
**P <0.01 (Fisher's exact test).
a 200 cells scored per animal.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
Additional information
Benzene
in vitro data
Benzene has been extensively examined for the core endpoints of gene mutation in bacteria, gene mutation in mammalian cells and chromosomal damage in mammalian cells in a number of laboratories (EHC/IPCS, 1993). The results have been conflicting, with predominantly negative results being reported from earlier studies, especially with bacterial systems. However, a number of positive results have been reported with these core endpoints, including studies with enclosed systems together with auxiliary metabolic activation. Positive results have been reported for bacterial mutation (Glatt et al, 1989), mammalian cell gene mutation (Tsutsui et al, 1997) and mammalian cell chromosomal damage (Ishidate and Sofuni, 1985). A similar profile of mixed results has been reported for additional endpoints including DNA repair, DNA strand breaks and cell transformation (Ashby et al 1985, Tsutsui et al, 1997; EHC/ IPCS, 1993). It is considered that containment of the material in contact with the target cells, together with an appropriate source of metabolism is required to allow the identification of a mutagenic response. Overall, it is concluded that benzene shows some evidence of mutagenic potential in vitro (EHC/IPCS 1993, EU RAR 2008).
in vivo data
The key studies in animal in vivo systems are considered to be cytogenetic studies in the bone marrow and germ cells Ciranni et al, 1991; Farris et al, 1996. A gene mutation study in somatic cells Mullin et al , 1995). has been reported but this and other similar studies have been observed to have limitations.
Of the in vivo cytogenetic studies benzene was studied in a rodent bone marrow cytogenetic assay in which male Swiss SD1 mice were exposed to a single oral dose of 0, 88, 440 or 880 mg/kg and samples of bone marrow cells taken for cytogenetic analysis. Samples of differentiating spermatagonia were similarly taken after 0, 220, 440 or 880 mg/kg benzene exposure. Dose-related significant increases in chromosomal aberrations were found in both tissues. Benzene was mutagenic in this assay in both the bone marrow and germ cells (Ciranni et al, 1991). Additionally in a bone marrow micronucleus assay, male B6C3F1 mice were exposed to benzene by the inhalation route at atmospheres of 0, 1, 10, 100, 200, 400 ppm over an 8 week exposure period. A dose-related increase in micronucleus incidence was reported (Farris et al, 1996). A number of other studies have confirmed the clastogenicity of benzene in both rats and mice (EU RAR, 2008). Benzene was also active in a comet assay in mice measuring DNA strand breaks, but only showed marginal activity for sister chromatid exchange induction in rats and mice (EU RAR, 2008).
The predominance of clastogenic activity rather than gene mutation activity is suggestive of benzene not being a direct acting mutagen. In cases where DNA adduct formation has been claimed this is likely to be associated with protein contamination of the examined DNA samples 32P post labelling studies have been suggested to show DNA adducts in mice however very high dose regimes much higher than the dose required to cause cancer in mice, , administration by the intraperitoneal route which is not relevant to human exposure and inconsistent dose responses point to this not being credible evidence of DNA adducts with relevance to human exposure. (Pathak et al 1995, Li et al 1996, Whysner et al 2004, DECOS 2013)
Whilst there are reports of findings of mutation in transgenic rodents exposed to benzene (Mullin et al 1995, Mullin et al 1998 and Provost et al 1996) these studies variously have design limitations ( eg sample size , species differences in organs affected by cancer compared to man, limitations in statistical analysis) marginal findings and inappropriate delays in sampling periods which have led to their outcome being discounted (Whysner et al 2004, DECOS 2013).
Overall the evidence points to the genetic toxicology of benzene being based on clastogenicity and benzene not being a direct acting mutagen. The mechanisms of action for benzene genotoxicity have been attributed to events with a threshold of action (DECOS 2013)
Human information
There are a number of reports showing that benzene exposure induces genotoxic effects in human lymphocytes in vivo. These are primarily cytogenetic investigations. Reliable conclusions, however cannot be drawn from many such studies due to poor exposure data and methodological deficiencies (EU RAR, 2008). However more recently significant efforts have been made to investigate cytogenetic aberrations in workers using more refined methods and with better definition of exposure. In particular work using Fluorescence In situ Hybridisation (FISH) methodology on chromosome 9 aberrations by Zhang et al 1996 (extended by Zhang et al 1998 and Smith et al 1998 to cover chromosomes 5,7 ,8 and 21) has shown that such aberrations are associated with contemporary 8 hour TWA exposures of >31 ppm. There has been concern however that in studies which have taken substantial steps to define current exposure there may be some aberrations which persist and reflect previous historic exposures of greater magnitude, duration or intensity than current exposures. In contradiction to this Smith et al 1998 found that the frequency of some aberrations to chromosomes 8 and 21 correlated better with current measured exposure rather than with cumulative exposure metrics (ppm years) which took account of historic exposure in earlier work.
It was noted by Smith et al 1998 that the significant translocation [t(8;21) ] associated with benzene exposure is also found with topisomerase inhibitor drugs. Coupled with the fact that some benzene metabolites (e.g. hydroquinone, etc.) are known poisons of topoisomerase II this provides a plausible mechanism for a threshold basis for benzene associated cytogenetic aberrations.
Rothman et al 1995 examined a group of Chinese workers (n=24) with a very high benzene exposure (median 8h TWA = 66ppm) and a mean duration of employment of 6.9 +/- 4.9 years (range 0.7-16,5 years). Median lifetime benzene exposure was 270ppm years. The study looked at Glycophorin A gene loss in individual heterogenous at the GPA locus and compared GPA gene mutation frequency with that in 23 matched non benzene exposed controls. The mutations were not attributed to point mutations, deletions or gene inactivating mutations but rather to gene duplicating mutations probably by mitotic recombination.
Attempts by Qu et al 2003 to replicate the FISH methodology of Zhang et al 1996 in a large well organised study with measurement of current benzene exposure were not successful but Qu et al instead reported findings from traditional cytogenetic studies on these workers and matched non- exposed controls. Their findings whilst showing statistically significant exposure related trends for chromosome and chromatid aberrations and acentric fragments showed anomalous dose responses . The lowest dose group (>0-5ppm exposure) showed aberration frequencies higher than intermediate dose groups and verging on the levels achieved in the high dose group (>30ppm exposure) which led to the authors questioning if prior exposure rather than current measured exposure might be linked to currently observed aberrations by virtue of long lasting stable aberrations.
A review of some individuals who suffered significant haematotoxicity from high benzene exposure and showed cytogenetic aberrations at the time was carried out by Forni, 1996. It was noted that approximately 20 years later after recovery from benzene induced haematotoxicity there were still higher levels of chromosome aberrations in surviving cases (n=4) compared to controls (n=7), although this was not statistically significant. When complex aberrations with more than one break were considered the difference between control and exposed was greater. Hyperdiploid cells were more frequent in surviving cases than contols (0.036> p 0.021). This would suggest that elevated aberrations can persist long after high levels of exposure ceased
Given these uncertainties it is not clear what the NOAEL is for cytogenetic aberrations in workers is but the work of Zhang et al 1996 and Smith et al 1998 would suggest that it is > 31ppm as an 8 hour TWA.
Justification for selection of genetic toxicity endpoint Results obtained for the key component benzene (present in all streams at greater than 0.1%) are considered indicative of the overall genotoxic potential of these streams.
REFERENCES
Ashby et al (1985). Assays to measure the induction of unscheduled DNA synthesis in cultured hepatocytes, (Eds) Progress in Mutation Research, Vol 5, pp 371-373
Ciranni R et al (1991). Dose related clastogenic effects induced by benzene in bone marrow cells and in differentiating spermatogonia of Swiss CD1 mice, Mutagenesis6(5) 417-421
DECOS (2014). Benzene- Health-based recommended occupational exposure limit. Health Council of the Netherlands, Publication no.2014 /3 The Hague
IPCS (1993). Environmental Health Criteria No. 150. Benzene.
EU RAR (2008). Risk Assessment. Benzene.
Farris GM et al (1996). Benzene-induced micronuclei in erythrocytes: an inhalation concentration -response study in B6C3F1 mice, Mutagenesis.11(5) 455-462
Forni A (1996). Benzene induced chromosome aberrations: a follow up study, Environ. Health Perspect.104suppl. 6 1309-1312
Glatt et al (1989). Multiple activation pathways of benzene leading to products with varying genotoxic characteristics, Environmental Health Perspectives.82, 81-89
Li G et al (1996). Tissue distribution of DNA adducts and their persistence in blood of mice exposed to benzene, Environ. Health Perspect.104suppl. 6 1337-8
Mullin AH et al (1995). Inhalation of benzene leads to an increase in the mutant frequencies of alacItransgene in lung and spleen tissues of mice, Mutat Res.327121-129
Mullin AH et al (1998). Inhaled benzene increases the frequency and length oflacIdeletion mutations in lung tissues of mice, Carcinogenesis.19(10) 1723-1733
Pathak DN et al (1995). DNA adduct formation in the bone marrow of B6C3F1 mice treated with benzene, Carcinogenesis.16(8) 1803-8
Provost GS et al (1996). Mutagenic response to benzene and tris(2.3-dibromopropyl)-phosphate in the lambda lacI transgenic mouse mutation assay: a standardized approach to in vivo mutation analysis, Environ Mol Mutagen.28(4) 342-7
Qu et al (2003). Validation and evaluation of biomarkers in workers exposed to benzene in China, Res Rep Health Eff Inst. (115) 1-72
Rothman N et al (1995). Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans, Proc. Natl. Acad. Sci. 924069-4073
Smith MT et al (1998). Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene, Cancer Research.582176-2181
Tsutsui T et al (1997). Benzene, catechol, hydroquinone and phenol induced cell transformation, gene mutations, chromosome aberrations, aneuploidy, sister chromatid exchanges and unscheduleded DNA synthesis in Syrian Hamster embryo cells, Mutat Res.373 (1) 113-23
Whysner J et al (2004). Genetic toxicology of benzene and its metabolites, Mutat Res.566(2) 99-130
Zhang L et al (1996). Interphase cytogenetics of workers exposed to benzene Environ. Health Perspect.104suppl. 6 1325-1329
Zhang et al (1998). Increased Translocations and Aneusomy in Chromosomes 8 and 21 Among workers exposed to Benzene, Cancer Research.582176-2181
Justification for selection of genetic toxicity endpoint
The marker substance benzene has been shown to be mutagenic. Results for the key component benzene (present in all streams at greater than 0.1%) are considered indicative of the overall genotoxic potential of these streams.
Justification for classification or non-classification
High Benzene Naphtha streams contain ≥0.1% benzene and therefore are considered to be mutagenic.
It is proposed that High Benzene Naphtha streams are classified as Cat 1B, H340 under Reg (EC) 1272/2008.
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