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Diss Factsheets

Toxicological information

Endpoint summary

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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, has 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 Aliphatics and Cyclics C5 and Higher streams are also classified as mutagenic in vivo.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

There are substantial data on the genotoxicity of a number of specific components present in some streams. Of these, benzene has been shown to be mutagenic in vivo. As benzene is a Category 2 mutagen and is present in all streams at a concentration of 0.1% or greater then Aliphatics and Cyclics C5 and Higher streams are considered to be mutagenic in vivo.

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Not GLP, but key cytogenetic parameters measured comparable to guideline study.
Reason / purpose for cross-reference:
read-across: supporting information
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

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.

 

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Additional information

The specific constituents which have been identified as present in some streams and shown to be mutagenic in vivo are benzene and isoprene.

Benzene (Classification: Category 1B, H340): Benzene has been extensively examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. It has shown mixed results for mutagenicity in vitro although in mammalian cells there is overall evidence for potential mutagenic activity (EU RAR, 2008). Benzene has been shown to be mutagenic in vivo in both somatic cells and germ cells (Ciranni et al, 1991).

Isoprene (Classification: Category 2 H341) has been examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. It has shown negative results for mutagenicity in vitro in the core endpoints of bacterial mutation and cytogenetic damage, both with and without S9. However, isoprene inducedDNAdamage (strand breaks) at high concentrations in a mammalian cell line in vitro. These effects were only observed in the presence of S9. There are several reports of isoprene inducing micronuclei in the bone marrow of mice exposed for different times from 12 days through to 80 weeks. A single examination in the rat reported a negative result for micronucleus induction, although this was in lung fibroblasts and not in bone marrow cells. A direct comment on the relative sensitivity to genotoxic effects of isoprene in the mouse and rat is therefore not possible. Isoprene is considered to be genotoxic in vivo, having shown clear effects in the mouse. 

References

EU RAR (2008). European Union Risk Assessment Report for Benzene. EC Joint Research Centre. http: //ecb. jrc. ec. europa. eu/documents/Existing-chemicals/RISK_ASSESSMENT/REPORT/benzenereport063. pdf.

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.

Isoprene 

In vitro data

Two key studies are considered to be a bacterial mutation assay (HLS, 2004) and a mammalian cell cytogenetic assay (NTP, 1995).  These are two recognised core assay types for investigating mutation in vitro. An additional key study is a recent mammalian cellDNAdamage (comet) assay (Fabiani, 2007).  

Isoprene was tested using vapour phase exposure in a standard Ames test with S. typhimurium strains TA1535, TA1537, TA98, and TA100 and E. coli WP2uvrA (pKM101). Exposure concentrations were 0.25 to 25% isoprene monomer, and tests were carried out in the absence or presence of an auxiliary metabolic activation system of S9 or microsomes prepared from uninduced mice. Isoprene was negative under these conditions. Similar negative results have been reported from other bacterial mutagenicity studies including Mortelmans et al, 1986 and Madhusree et al, 2002. The conditions used in these latter studies included the pre-incubation protocol for theAmesassay with dose levels up to 10 mg/plate, and exposure together with S9 from Aroclor-induced rat and hamster liver. Isoprene has therefore been examined in a range of bacterial strains, with and without auxiliary metabolic activation and as a liquid or vapour phase, and is reported as non-mutagenic.

Isoprene was examined for the ability to induce chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells, both in the presence and absence of Aroclor-induced rat liver S9 (NTP, 1995). Isoprene was tested at dose levels up to 5000 µg/ml. No significant increase in chromosomal aberrations was observed.  

Fabiani (2007) examined isoprene in cultured human promyelocytic leukemia cells (HL60) forDNAdamage using the single cell gel electrophoresis method for examiningDNAstrand breaks (comet assay). Isoprene was tested in the absence or presence of liver S9 from rats that were uninduced or induced with phenobarbital or ethanol. High concentrations of isoprene were tested (up to 30mM in the absence of auxiliary metabolic activation and 15 mM in its presence), and isoprene was negative in the absence of S9, but positive in the presence of both uninduced and induced S9 fractions.

 

An additional endpoint examined in cultured cells was the sister chromatid exchange endpoint (NTP, 1995), and isoprene was negative.

 

Isoprene has been shown to be negative for the induction of bacterial mutagenicity and chromosomal damage in mammalian cells, but positive at high concentrations for the induction ofDNAdamage in mammalian cells, in the form ofDNAstrand breaks, only in the presence of S9.

 

 

In vivo data

 

The key studies are considered to be those examining the cytogenetic endpoint (Tice et al, 1988, NTP, 1999, Placke et al, 1996). This is a recognised core assay type for investigating mutationin vivo.

 

Male mice were exposed to isoprene by inhalation for 6 hours/day at concentrations of 438, 1750, or 7000 ppm for 12 days (Tice et al, 1988). Examination of the peripheral blood showed increased incidences of micronucleated polychromatic and normochromatic erythrocytes (MPE and MNE) over controls at all exposure levels. A dose related decrease in the percentage of polychromatic erythrocytes (PCE) in the erythrocyte population was also seen indicating an accompanying toxic effect on the bone marrow.

In separate studies, similar positive results (increase in MPE and/or MNE) were observed in both male and female mice exposed to isoprene at dosed levels up to 7000 ppm for 13 weeks (NTP, 1999) and in male and female mice exposed to isoprene at dose levels up to 2200 ppm for 40 or 80 weeks (Placke et al, 1996).

In contrast to the above positive results with the micronucleus endpoint, exposure of mice to isoprene for 6 hours/day at concentrations of 438, 1750, or 7000 ppm for 12 days did not induce a statistically significant increase in the frequency of chromosomal aberrations measured in metaphase cells from the bone marrow (Tice et al, 1988). However, in the same paper, an examination of the sister chromatid exchange endpoint in animals exposed to the same conditions resulted in a significant increase over controls at all the dose levels studied. A negative result was also reported for the micronucleus endpoint in a study that examined lung fibroblasts in rats exposed to isoprene at doses up to 7000 ppm for 4 weeks.

Isoprene is genotoxic in the mouse, inducing chromosomal damage in bone marrow cells.

Human information

There is no information indicating any adverse effects of isoprene.

Xylene:

In view of the lack of significant genotoxicity observed in the in vitro studies, and the available negative results examining for chromosomal damage in vivo, mixed xylenes and the individual isomers are considered not to have genotoxic potential.

Justification for selection of genetic toxicity endpoint
Results obtained for the key constituent 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 classification or non-classification

All Aliphatics and Cyclics C5 and Higher streams contain ≥0.1% benzene which is an in vivo mutagen in mammals, inducing chromosomal aberrations and micronuclei. It is proposed, therefore, that Aliphatics and Cyclics C5 and Higher streams are classified Cat 1B, H340 under CLP Reg (EC) 1272/2008.