Einecs-no.: 202-849-4 Strategy For Limiting Risks Human Health Draft of November 2008



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Ethylbenzene

(1st Priority List)

CAS-No.: 100-41-4

EINECS-No.: 202-849-4



Strategy For Limiting Risks

Human Health

Draft of November 2008

The rapporteur for Ethylbenzene is the Federal Institute for Occupational Safety and Health.



Contact point:

Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA)

Anmeldestelle Chemikalien / Zulassungsstelle Biozide

(Federal Institute for Occupational Safety and Health

Division for Chemicals and Biocides Regulation)

Friedrich-Henkel-Weg 1-25

44149 Dortmund (Germany)

fax: +49(231)9071-2679

e-mail: chemg@baua.bund.de

CONTENT


1.Workers 21

Directive 96/82/EC on the control of major accident hazards involving dangerous substances, Annex I, OJ (L 10) 13, 14 Jan 1997, as amended by Directive 2003/105/EC, OJ (L 345) 97, 31 Dec 2003 25

EU. Directive 2002/96/EC on waste electrical and electronic equipment (WEEE), Annex II, as amended by Directive 2008/34/EC, OJ (L 81) 65, 20 March 2008 25

EU. Commission Decision 96/335/EC establishing an inventory and a common nomenclature of ingredients employed in cosmetic products (INCI), as amended by Decision 2006/257/EC (OJ (L 97) 1, 5 Apr 2006) 25

EU. Toy Safety: Limits of Organic Chemical Compounds. European Norm EN 71-9, Tables 2(A-I) (February 2005) 25

The TGD requires that possible further risk reduction options be examined against the following criteria 27


0 Summary

Ethyl benzene is produced by a catalyzed reaction of ethylene and benzene at approx. 40 bar and temperatures around 250 °C. All manufacturers use ethyl benzene as the raw material for the production of styrene monomer. Therefore the ethyl benzene production plant and the styrene monomer plant are often situated at the same site and directly connected to each other. In some cases ethyl benzene is shipped in bulk to a styrene monomer plant. Another production method is the fractionation of mixed xylene streams which is, however, employed to a much lesser extent. These streams occur in petroleum refineries during distillation of cruide oil into petroleum products and contain ~ 80 % o-, m-, p-xylenes (“mixed xylene stream) and ~ 15-20 % ethyl benzene.

Ethyl benzene is mainly a raw material for the production of styrene (99.5 %). Styrene is further processed in the chemical industry to polystyrene which is used in large volumes in the automobile industry, in the building industry and for packaging. A small percentage of ethyl benzene (0.5 %) is used as a chemical intermediate, e.g. in the manufacture of acetophenone, cellulose acetate, diethyl benzene, propylene oxide.

The current classification of ethyl benzene according to Annex I of Directive 67/548/EEC (19. ATP, Index-Nr. 601-023-00-4) is F; R11 (Highly flammable) - Xn; R20 (Harmful by inhalation). Ethyl benzene has to be labelled with F, Xn; R11-20; S(2-)16-24/25-29.

The rapporteur (of the RAR) proposed to add the following classification and labelling:
R 36/37/38 Irritating to eyes, respiratory tract and to skin
R 48/20 Harmful: Danger of serious damage to health by prolonged exposure through inhalation
R 65 Harmful: May cause lung damage if swallowed

This proposal has not yet been discussed in the EU-Working group on classification and labelling of dangerous substances under Directive 67/548/EEC.



Workers

It has been concluded from the risk assessment that there is a need for limiting the risks. The most important toxicological endpoints are repeated dose toxicity and developmental toxicity of ethylbenzene.

Conclusion (iii) applies to dermal and combined exposure in scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) for repeated dose toxicity and developmental toxicity. Dermal exposure should be controlled to levels in the range of 1.7 mg/kg/day or 120 mg/person/day (critical exposure level for systemic effects of repeated dose toxicity). If the exposure is reduced to this level, dermal risks from other endpoints, as developmental toxicity would similary and effectively be mitigated too.

Concerning inhalation exposure, the critical exposure level is 9.3 mg/m3. The exposure values of scenario 1 (production and processing) and scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) are below this value, thus not resulting in concern.



The risk reduction strategy recommends the following measures:

  • information on the need of technical and organisational measures, specific training, and occupational hygiene on company level in the framework of Directive 98/24

  • to revise the occupational exposure limit value established at community level according to Directive 98/24/EEC .

  • to apply the following revised classification:
    R11 Highly flammable

R20 Harmful by inhalation

R 36/37/38 Irritating to eyes, respiratory tract and to skin


R 48/20 Harmful: Danger of serious damage to health by prolonged
exposure through inhalation
R 65 Harmful: May cause lung damage if swallowed

Background

In the framework of EU Regulation 793/93 on the evaluation and control of the risks of existing substances data are gathered, priority substances are selected, their risks are assessed and, if necessary, strategies for limiting the risks are developed. The risk assessments cover the risks to man exposed directly at the workplace or as a consumer and indirectly through the environment and the risks to the environment. Ethyl benzene is a substance on the first priority list (Regulation (EC) No. 1179/94 of the Commission of 25.05.1994).

Ethylbenzene is a highly flammable liquid at 25 °C. The Melting point is - 94.949 °C, the Boiling point is 136.186 °C at 1013hPa, the Relative density is 0.8670 at 20 °C, the Vapour pressure is 9.3 hPa at 20 °C. The Water solubility is 160 mg/l at 25 °C, the Partition coefficient is log Pow 3.13 at 25 °C, the Flash point is 23 °C, the Autoflammability is 430 °C.

Production

Ethyl benzene is produced by a catalyzed reaction of ethylene and benzene at approx. 40 bar and temperatures around 250 °C. All manufacturers use ethyl benzene as the raw material for the production of styrene monomer. Therefore the ethyl benzene production plant and the styrene monomer plant are often situated at the same site and directly connected to each other. In some cases ethyl benzene is shipped in bulk to a styrene monomer plant. All ethyl benzene plants are completely closed systems, working under controlled conditions. The process is highly automated and runs continuously. Another production method is the fractionation of mixed xylene streams which is, however, employed to a much lesser extent. These streams occur in petroleum refineries during distillation of crude oil into petroleum products and contain ~ 80 % o-, m-, p-xylenes (“mixed xylene stream) and ~ 15-20 % ethyl benzene.



Uses

Ethyl benzene is mainly a raw material for the production of styrene (99.5 %). Styrene is further processed in the chemical industry to polystyrene which is used in large volumes in the automobile industry, in the building industry and for packaging. A small percentage of ethyl benzene (0.5 %) is used as a chemical intermediate, e.g. in the manufacture of acetophenone, cellulose acetate, diethyl benzene, propylene oxide.



The Risk Assessment

  1. Workers
Introductory remarks

For occupational risk assessment of ethylbenzene the MOS approach as outlined in the TGD (Human Health Risk Characterisation, Final Draft) is applied. This occupational risk assessment is based upon the toxicological profile of ethylbenzene and the occupational exposure assessment. The threshold levels identified in the hazard assessment are taken forward to this occupational risk assessment.
Systemic availability for different routes of exposure

Experimental data from humans and animals for ethylbenzene show different absorption percentages for the different routes of exposure: According to the RAR-chapter 4.1.2.1 on toxicokinetics, metabolism and distribution an adsorption percentage up to 100% is taken for the oral route. 65% is assumed for the inhalation route in humans, 45% absorption percentage after inhalation in animals. Concerning dermal absorption, percentages of 50% for humans and 70% for animals is taken for the risk characterisation.
Occupational exposure and internal body burden

Table 2.1.A: Ethylbenzene exposure levels which are relevant for occupational risk assessment and internal body burden

Exposure scenario

Inhalation
shift average

Dermal contact
shift average

Internal body burden of workers
after repeated exposure

Inhalation(1)

Dermal(2)

Combined

mg/m3

mg/p/day

mg/kg/day

mg/kg/day

1.

Production and further processing

1.3

4.2(3)

0.06

0.12

0.03

0.15

2.

Use of paints, lacquers, inks (containing 20% ethylbenzene)

7

2000(4)

28.5

0.65

14.3

14.95

(1) based on the assumption of 65% inhalation absorption; breathing volume of 10 m3 per shift
(2) based on the assumption of 50 % systemic availability of ethylbenzene after dermal contact
(3) EASE (90 % protection by suitable gloves)
(4)Analogous data (TGD)
MOS Approach

The MOS approach for human risk characterisation is described in detail in the TGD (Human Health Risk Characterisation, Final Draft). The following chapter contains a short introduction to the MOS approach used. The basic principle of the MOS approach is a comparison of scenario-specific MOS values (the relationship between the experimental NOAEL respectively the adjusted starting point and the exposure level) with a reference MOS (product of various assessment factors).
MOS calculation and the adequate starting point

Basically, MOS values are calculated as quotient of a relevant NOAEL from experimental animal testing or human studies and actual workplace exposure levels. In specific situations, the MOS approach requires a conversion of the original NOAEL into an adequate starting point or corrected NOAEL previously to MOS calculation in order to be directly comparable to the exposure assessment. If the route of application in animal or human studies is different from the actual occupational exposure, the dose units of the experimental data should be converted to the dose unit of the exposure data. Additionally, possible differences in bioavailability between routes, as well as possible differences in bioavailability between animals and humans should be accounted for the calculation of the corrected NOAEL. If route-specific information on oral and inhalation absorption is not available, the TGD recomments to assume 50% oral absorption and 100% inhalation absorption. For ethylbenzene 65% absorption after inhalation, 50% absorption after dermal contact and 100% absorption after oral exposure are assumed (experimental values).

For occupational risk assessment, the corrected inhalation NOAEC accounts for the difference of the standard respiratory volume (6.7 m³) and the respiratory volume for light activity (10 m³).

MOS values are calculated for different routes of exposure and for different toxicological endpoints. The routes of exposure specifically considered in occupational risk assessment are exposure by inhalation and dermal contact.

In addition, for risk assessment of combined exposure (exposure by inhalation and dermal contact) an adequate NOAEL is derived from external NOAELs and specific information on route-specific absorption. For MOS calculation, the adjusted internal starting point is divided by the internal body burden. Depending on route-specific exposure and absorption, inhalation exposure and/or dermal exposure may contribute to the internal body burden. With respect to the possible outcome of an assessment for combined risks, interest focuses on scenarios with conclusion ii at both exposure routes. Based on theoretical considerations, combined exposure will not increase the most critical route-specific risk component more than twice.



Reference MOS

The MOS values calculated have to be compared with a reference MOS. The reference MOS is an overall assessment factor, which is obtained by multiplication of individual assessment factors. The Technical Guidance Document emphasises several aspects which are involved in the extrapolation of experimental data to the human situation. For these assessment factors, default values are recommended. It is important to point out that any relevant substance-specific data and information may overrule the defined default values.

Interspecies extrapolation on the one hand is based on allometric scaling (factor 4 for rats, factor 7 for mice, and factor 2 for rabbits). For remaining interspecies differences the TGD proposes an additional factor of 2.5.

For workers, an adjustment factor for intraspecies differences of 5 is recommended. Based on an evaluation of empirical data by Schneider et al. (2004) it is anticipated that a factor of 5 will be sufficient to protect the major part of the worker population (about 95%).

For chemical substances it is usually expected that the experimental NOAEL will decrease with increasing duration of application. Furthermore, other and more serious adverse effects may appear with prolonged exposure duration. For duration adjustment, a default factor of 6 is proposed for extrapolation from a subacute to chronic exposure. The duration adjustment factor is lower (a factor of 2) for the transition from subchronic experimental exposure to chronic exposure. For ethylbenzene the factor of 2 for an adaptation from subchronic to chronic exposure is used.

The TGD defines two further adjustment factors (uncertainty in route-to-route extrapolation and dose-response relationship including severity of effect). In specific cases these factors may be different from one.



Comparison of MOS and reference MOS

The MOS values for different toxicological endpoints and different exposure scenarios are compared with the substance- and endpoint-specific reference MOS. MOS values clearly above the reference MOS do not lead to concern, whereas MOS values that are clearly below the reference MOS are cause for concern. There may be various risk-related aspects which are not covered by default assessment factors. These additional qualitative aspects should be carefully considered when performing a risk assessment and should have an adequate influence on finding of conclusions.



Critical Exposure Levels

In a parallel procedure, which gives identical but more direct results, the adjusted toxicological starting point is directly divided by the reference MOS. As a result, an exposure level (in mg/m³ or mg/kg/d) is identified, which may serve as a direct trigger for decisions when compared with the occupational exposure levels. In the context of this risk assessment report this trigger value is called “critical exposure level”. Concern will be expressed for scenarios with occupational exposure levels higher than the relevant “critical exposure level”.


Occupational risk assessment
Acute toxicity

Inhalation

Human data on the acute toxicity of ethylbenzene are not available. Animal data show, that high concentrations of ethylbenzene result in deaths of experimental animals. An LC50 of 17 600 mg/m3 after 4 hours of ethylbenzene inhalation in rats is reported. The concentration of 8 800 mg/m3 resulted in 2 of 6 dead rats within 14 days after inhalation period.

In another, shortly reported subacute study F344 rats, B6C3F1 mice and New Zealand rabbits were exposed for 6 hours/day on 4 consecutive days at vapour concentrations of 0, 1 700, 5 300, and 10 6000 mg/m3 (Biodynamics, 1986). The NOAEC in rats and mice was 1 700 mg/m3 with increased kidney and liver weights without histopathological changes. For rabbits the NOAEC was 10 600 mg/m3.

Comparing the LC50-value of ca. 17 600 mg/m3 and the concentration of 1 700 mg/m3 without histopathological changes with the highest exposure concentration of 7 mg/m3 (scenario 2) a relevant risk concerning acute toxicity is not expected under normal workplace conditions.

Conclusion: ii

Dermal contact

Oral and dermal toxicity of ethylbenzene is low with LD50 values above 2 000 mg/kg: an oral LD50 of 3 500 mg/kg was determined for rats in general, and an oral LD50 of 5 460 mg/kg specifically for male rats; the acute dermal toxicity was tested with rabbits and revealed a dermal L50 of 15 500 mg/kg.

Comparing the LD50 of above 2 000 mg/kg with the highest dermal exposure of 28.5 mg/kg (scenario 2, use of paints, laquers and inks) a relevant risk concerning acute toxicity is not expected under normal workplace conditions.

Conclusion: ii


Irritation/Corrosivity

Acute Inhalation

In humans, high concentrations of ethylbenzene vapours are irritating to mucous membranes of the eyes, nose and respiratory tract.

Chemical burns of the eyes, mouth, face, and trunk after a leakage of a pipeline with ethylbenzene are reported.

Acute exposure to vapours of ethylbenzene in air concentrations of 0.5% and 1% (equivalent to 5000 and 10 000 ppm) produced immediate intense irritation to the conjunctiva and nasal mucous membranes in guinea pigs. A concentration of 0.2% (2 000 ppm) produced moderate eye and nasal irritation within one minute and a concentration of 0.1% (1 000 ppm) caused slight nasal irritation.

Comparing the value of 1 000 ppm (corresponding to 4 340 mg/m3) with the exposure value of 7 mg/m3 a relevant risk concerning to irritation is not expected under normal workplace conditions.

Conclusion: ii



Sensory irritation

Sensory irritation by airborne ethylbenzene was reported from animal data. A test, made with male Swiss-Webster mice showed a RD50-value of 4 060 ppm. Alarie introduced the air concentration of 0.03 x RD50 as prediction of an exposure level with a minimal or low degree of sensory irritation in humans. The according air concentration for ethylbenzol calculates to 122 ppm or 530 mg/m3 (4 060 ppm x 0.03). Analysis of experimental and human data on sensory irritation mainly is based on the relationship between RD50 values in animals and human thresholds for sensory irritation (and not on the corresponding relationship for minimal experimental effects). For that reason it is preferred to start risk assessment with the general approach (0.03 x RD50) instead of using lower experimental effect levels for which there is no specific experience as to adequate adjustment factors.

In workers the stinging and burning sensation caused by stimulation of the trigeminus nerve which is closely connected to respiratory depression is generally perceived within few minutes after exposure. Thus stimulation of the trigeminus nerve, unlike other effects, does not depend significantly on exposure duration. The main trigger for effects seems to be the air concentration of the substance. Risk assessment therefore does not correct for exposure duration and short term values are also included in MOS calculation.

The exposure level of about 530 mg/m3 is chosen as starting point concerning respiratory depression. In this range of exposure a relevant effect is not anticipated to occur in humans. For evaluation of the resulting MOS values no further aspects have to be taken into account. The corresponding reference MOS is considered to be 1.

The highest identified inhalative exposure values are described for scenario 2 with an exposure value of 7 mg/m3. Based on the combined interpretation of the RD50 data and human experience conclusion ii is applied for these occupational exposure scenarios with respect to sensory irritation of ethylbenzene.

Conclusion: ii

Table 2.1.B: MOS values for sensory irritation of ethylbenzene




Inhalation

Starting point for MOS calculation

530 mg/m3

Reference MOS

1

Critical exposure level

530 mg/m3




Exposure (mg/m3)

MOS

Conclusions

1.

Production and further processing

1.3

407

ii

2.

Use of paints, lacquers, inks (containing 20% ethylbenzene)

7

76

ii

Dermal/Eyes

Data on skin irritation tests according to international test guidelines are not available. On the basis of two available tests with rabbits a moderate skin irritation potential after single application of the substance and a high defatting potential leading to severe effects after repeated skin contact can be concluded.

Ethylbenzene caused grade 2-3 injury of the eyes of rabbits out of a scale of 10, based on the degree of corneal necrosis after instillation of various amounts and concentration of the chemical.

A classification and labelling as Xi, Irritant, R 36/38 irritating to the eys and skin is warranted.

On the grounds that control measures exist which can minimise dermal exposure and corresponding risk of irritation, conclusion ii is proposed. However, these controls must be implemented and complied with to reduce the risk of damage to skin and the eyes.

Conclusion: ii


Sensitization

Dermal contact

Animal data on skin sensitisation tests are not available.

Kligman conducted a maximisation test with 10% ethylbenzene (no data on purity) in petrolatum on 25 volunteers. Ethylbenzene produced no sensitisation reactions. No concern is expressed.

Conclusion: ii



Inhalation

No information on respiratory sensitisation is available. However, in view of the fact that during all the years of use specific case reports have not been reported, ethylbenzene seems at least not to be a strong respiratory sensitizer in humans. For the time being no animal model is available which would be able to verify the question of respiratory sensitisation. In summary concern is not expressed.

Conclusion: ii

Repeated dose toxicity

Local effects

Inhalation and dermal contact

See under chapter of Irritation. No further realizable information concerning local effects are available.

Conclusion: ii

Systemic effects

Repeated exposure of ethylbenzene (oral and inhalation route) affects the nervous system and leads to effects at the liver and kidney in experimental animals.



Inhalation exposure

An increase in liver and kidney weight of rats and mice without histopathological alterations has been found in several studies. According to the RAR-chapter 4.1.2.5 these changes are most probably related to enzyme induction. The NOAEL in a guideline oral 90 day study with rats was 75 mg/kg bw/d (LOAEL 250 mg/kg bw/d) based on indications for a mild regenerative anemia and liver changes indicative of microsomal enzyme induction.

Repeated inhalation exposure to ethylbenzene vapor was irreversibly ototoxic in rats (Gagnaire et al., 2007). Auditory dysfunction was localised in the mid frequencies and corresponded to the loss of cochlear outer hair cells, the sensory cells in the inner ear. Hearing loss and cell damage increased with concentrations exposed. In a 90 day rat inhalation study (6 hours/day, 6 day/week) the NOAEC for ototoxicity was extrapolated to be 114 ppm (500 mg/m3). According to several case reports, where hearing deficits in humans occupational exposed to organic solvents or from people after solvent abuse is described (for review cf Risk Assessment Reports on toluene and styrene) this rat data are taken to be relevant for humans.

Thus, this extrapolated NOAEC of 114 ppm (500 mg/m3) is taken for the risk assessment of repeated dose toxicity.

The extrapolated NOAEC of 114 ppm (500 mg/m3) from the rat is (1) multiplied with a factor of 0.45 (for rat absorption percentage of 45%), divided by a divisor of 0.65 (for human absorption percentage after inhalation of 65%) and (2) multiplied by a factor of 6.7/10 for activity-driven differences of respiratory volumes in workers. Further differences regarding the the experimental inhalation duration (6 hours/day, 6 days/week) and the working conditions (8 hours/day, 5 days/week) are not considered, because they roughly balance each other. The calculation results in an adjusted inhalation starting point of 232 mg/m3 (500 • 0.45 / 0.65 • 6.7/10).

The following adjustment factors are applied for the identification of the reference MOS. For (1) interspecies differences the default factor is 2.5 (the factor for allometric scaling is already implicitly applied), for (2) intraspecies differences (workers) the default factor is 5, and for (3) duration adjustment a factor of 2 is used. Thus the reference MOS calculates to 25 (2.5 • 5 • 2). The critical inhalation exposure level at the workplace is identified as 9.3 mg/m3 (232 / 25).

The highest shift average value for inhalation is reported in scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) with a value of 7 mg/m3. With a critical exposure level of 9.3 mg/m3 there results no concern for this endpoint. For corresponding MOS values see table 2.1.C.

Conclusion: ii



Dermal contact and combined exposure

No information is available for systemic toxicity after repeated dermal exposure. Therefore the extrapolated NOAEC of 114 ppm (500 mg/m3) from the 90 day inhalation rat study is taken for dermal risk assessment.

Expressed as (external) dose the value of 500 mg/m3 corresponds to 190 mg/kg/day (500 mg/m3 • default respiratory volume for the rat for 8 hours of 0.38 m3/kg). With a rat adsorption percentage of 45% after inhalation the internal starting point corresponds to 86 mg/kg/day (190 mg/kg/day • 0.45). To get the (external) value for dermal contact the dermal absoption percentage of 50% for humans has to be included. Thus the internal value has to be multiplied with a factor of 2. This results in an adjusted external starting point of 172 mg/kg/day (86 mg/kg/day • 2).

The following adjustment factors are applied for the identification of the reference MOS. For (1) interspecies differences the adjustment factor is 4 • 2.5 (factor 4 for allometric scaling and factor 2.5 for remaining interspecies differences), for (2) intraspecies differences (workers) the default factor is 5, and for (3) duration adjustment a factor of 2 is used. Thus the reference MOS calculates to 100 (4 • 2.5 • 5 • 2). The critical external dermal exposure level at the workplace is identified as 1.7 mg/kg/day (172 / 100). The internal critical exposure level is 0.86 mg/kg/day (86 / 100).

The exposure scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) for dermal contact is reported as 28.5 mg/kg/day. The exposure level in this occupational scenario is nearly 15 fold higher than the critical dermal exposure value of 1.7 mg/kg/day. Concern is expressed for dermal exposure of this scenario 2. Because of the concern for dermal exposure also for combined exposure of scenario 2 concern is expressed as well. Scenario 1 does not reach concern. For corresponding MOS values see table 2.1.C.

Conclusion: iii



Table 2.1.C: MOS values for repeated dose toxicity of ethylbenzene, systemic effects




Inhalation

Dermal

Combined

Starting point for MOS calculation

233 mg/m3

172 mg/kg/day

86 mg/kg/day

Reference MOS

25

100

100

Critical exposure level

9.3 mg/m3

1.7 mg/kg/day

0.86 mg/kg/day




Exposure (mg/m3)

MOS

Conclusions

Exposure (mg/kg/d)

MOS

Conclusions

Internal body
burden (mg/kg/d)

MOS

Conclusions

1.

Production and further processing

1.3

180

ii

0.06

2 870

ii

0.15

573

ii

2.

Use of paints, lacquers, inks (containing 20% ethylbenzene)

7

33

ii

28.5

6

iii

14.95

5.7

iii


Mutagenicity

Ethylbenzene produced consistently negative results in bacterial gene mutation tests and in the yeast assay on mitotic recombination. In mouse lymphoma mammalian mutation assays a weak positive response was reported but only at doses with strong cytotoxicity. No clear conclusion can be drawn regarding in vitro chromosomal aberration. Without S-9 mix there were equivocal increases in chromosomal aberration frequencies and micronuclei in CHO and SHE cells, respectively, or a negative result in a rat liver cell line. With S-9 mix ethylbenzene did not cause chromosomal aberrations in CHO cells. An in vitro SCE test was clearly negative with and without S-9 mix. In vivo, ethylenzene was clearly negative in two micronucleus assays and in a mouse liver UDS assay. In conclusion, on the basis of various mutagenicity tests in vitro and in vivo, there is currently no relevant indication that ethylbenzene is a germ cell mutagen.

Conclusion: ii


Carcinogenicity

Long-term inhalation exposure on rats and mice (0, 75, 250 and 750 ppm ethylbenzene for 104 weeks, 6 hours/day, 5 days/week) was carcinogenic in F344 rats and B6C3F1 mice. A significant increase of tumor incidences has been observed in the kidneys (renal tubule adenoma and carcinoma), testis (interstitial cell adenoma), liver (adenoma and carcinoma) and lung (alveolar/bronchiolar adenoma and carcinoma).

There was no concordance in carcinogenic response between rats and mice. Elevated rates of kidney tumors were seen in male and female rats. Each of other tumors occurred in one sex and in one species only. Genotoxicity data did not indicate a direct DNA damaging effect.

With reference to the RAR-chapter 4.1.2.7 there is sufficient evidence that kidney tumors in male and female rats are associated with the high strain-specific incidence of chronic progressive nephropathy (CPN) that is unknown for humans. For tumors in the testis, liver and lung high or very high spontaneous rates occur in the mouse and rat strains used. Ethylbenzene may exert its carcinogenic action by enhancement of tumor development in genetically disposed animals or by reduction in latency periods in tumor development.

Although the detailed mechanisms underlying the increases in tumor rates are presently not clarified, it appears likely that the mode of carcinogenic action of ethylbenzene possesses species and strain specificity. Therefore the toxicological significance and relevance to human health of these findings is uncertain. It appears unlikely from the data available that ethylbenzene poses a carcinogenic risk for humans exposed.

Conclusion: ii

Reproductive toxicity
Fertility impairment

No human data are available. In a guideline 2-generation study in rats by inhalation, no effects on reproduction were noted at exposure levels up to and including 500 ppm with minimal parental toxicity at this exposure level (decreased body weight, increased liver weight). In the preceding 1-generation study no effects on reproduction were found up to and including 1 000 ppm. The findings from the functional tests on fertility with the 1- and 2-generation studies are supported with the results from repeated dose toxicity studies without adverse findings by weight and histopathology of reproductive organs, sperm parameters and estrous cyclicity. Thereby no such adverse effects were found in guideline studies after 13 weeks of inhalation at 1 000 ppm, after 2 years of inhalation at 750 ppm (apart from possibly neoplastic related testicular effects) and after 13 weeks of oral gavage application at 750 mg/kg.

Based on the available data, there seems to be no specific risk for fertility effects.

Conclusion: ii

Developmental toxicity

Data from a 2-generation study and prenatal toxicity studies and a developmental neurotoxicity study are available. From the results of these studies there is no indication for substance induced teratogenicity (up to and including 2000 ppm) or developmental toxicity (up to and including 500 ppm). In the presence of maternal toxicity there is indication for slight fetotoxicity (reduced fetal body weight and occasional increases in skeletal variations) with a NOAEC for fetotoxicity and maternal toxicity of 500 ppm.

However, a reduction of postnatal viability and pup survival, respectively weanling body weight gain was found in a 1-generation reproduction toxicity study with Sprague Dawley rats which inhaled 100, 500 and 1 000 ppm (Strump, 2003; Faber et al., 2007, see also RAR-chapter 4.1.2.9). Based on increased postnatal mortality and body weight gain depression in the offspring a NOAEC of 100 ppm (441 mg/m3) was derived for developmental toxicity. This value is used for the quantitative risk assessment of developmental effects after inhalation and also after dermal contact.



Inhalation exposure

The NOAEC of 100 ppm (441 mg/m3) from the rat is (1) multiplied with a factor of 0.45 (for rat absorption percentage of 45%) and divided by a divisor of 0.65 (for human absorption percentage after inhalation of 65%) and (2) multiplied by a factor of 6.7/10 for activity-driven differences of respiratory volumes in workers. Further differences regarding the the experimental inhalation duration and the working conditions are not considered, because there is no detailed information about exposure conditions. The calculation gives an inhalation starting point of 205 mg/m3 (441 • 0.45 / 0.65 • 6.7/10).

The following adjustment factors are applied for the identification of the reference MOS. For (1) interspecies differences the default factor is 2.5 (the factor for allometric scaling is already implicitly applied), for (2) intraspecies differences (workers) the default factor is 5. Thus the reference MOS calculates to 12.5 (2.5 • 5). The critical inhalation exposure level at the workplace is identified as 16.4 mg/m3 (205 / 12.5).

The shift average value for inhalation is reported as 7 mg/m3 for scenario 2 of ethylbenzene. The exposure level in this occupational scenario is higher than the critical inhalation exposure of 16.4 mg/m³. No concern is derived. For corresponding MOS values see table 2.1.D.

Conclusion: ii

Dermal contact and combined exposure

The NOAEC of 100 ppm (441 mg/m3) from the 1-generation rat study is taken for dermal risk assessment (see above).

The NOAEC of 441 mg/m3 corresponds to an external dose of 127 mg/kg/day (441 mg/m3 • default respiratory volume for the rat for 6 hours of 0.288 m3/kg). With a rat adsorption percentage of 45% after inhalation the internal critical exposure level corresponds to 57 mg/kg/day (127 mg/kg/day • 0.45). To get the (external) value for dermal contact the dermal absoption percentage of 50% for humans has to be included. Thus the internal value has to be multiplied with a factor of 2. This gives an external starting point of 114 mg/kg/day (57 mg/kg/day • 2).

The following adjustment factors are applied for the identification of the reference MOS. For (1) interspecies differences the adjustment factor is 4 • 2.5 (factor 4 for allometric scaling and factor 2.5 for remaining interspacies differences), for (2) intraspecies differences (workers) the default factor is 5. Thus the reference MOS calculates to 50 (4 • 2.5 • 5). The critical dermal exposure level at the workplace is identified as 2.3 mg/kg/day (114 / 50). The internal critical exposure level is 1.1 mg/kg/day (57 / 50).

The shift average value for dermal contact is reported as 28.5 mg/kg/day for scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene). The exposure level in this occupational scenario is about 12 fold higher than the critical dermal exposure of 2.3 mg/kg/day. Concern is expressed regarding dermal and combined exposure for this scenario 2. For corresponding MOS values see table 2.1.D.

Conclusion: iii



Table 2.1.D: MOS values regarding developmental effects of ethylbenzene




Inhalation

Dermal

Combined

Starting point for MOS calculation

205 mg/m3

114 mg/kg/day

57 mg/kg/day

Reference MOS

12.5

50

50

Critical exposure level

16.4 mg/m3

2.3 mg/kg/day

1.1 mg/kg/day




Exposure (mg/m3)

MOS

Conclusions

Exposure (mg/kg/d)

MOS

Conclusions

Internal body
burden (mg/kg/d)

MOS

Conclusions

1.

Production and further processing

1.3

158

ii

0.06

1900

ii

0.15

380

ii

2

Use of paints, lacquers, inks (containing 20% ethylbenzene)

7

29

ii

28.5

4

iii

14.95

3.8

iii


Summary of conclusions for the occupational risk assessment

As result of occupational risk assessment for ethylbenzene, concern is expressed and risk reduction measurs have to be initiated. The most important toxicological endpoints are repeated dose toxicity and developmental toxicity. For all other endpoints no concern is expressed. Table 2.1.E indicates the toxicological endpoints of concern for ethylbenzene.

Table 2.1.E indicates the toxicological endpoints of concern for ethylbenzene



Table 2.1.E: Endpoint-specific overall conclusions

Toxicological endpoints

concern for at least one scenario

Acute toxicity

inhalation

ii

dermal

ii

combined

ii

Irritation/ Corrosivity

dermal

ii

eye

ii

acute respiratory tract

ii

Sensitisation

skin

ii

respiratory

ii

Repeated dose toxicity

local, inhalation

ii

local, dermal

ii

systemic, inhalation

ii

systemic, dermal

iii

systemic, combined

iii(1)

Mutagenicity

ii

Carcinogenicity

inhalation

ii

dermal

ii

combined

ii

Fertility impairment

inhalation

ii

dermal

ii

combined

ii

Developmental toxicity

inhalation

ii

dermal

iii

combined

iii(1)

  1. conclusion iii already results from dermal exposure, therefore no specific concern for the combined exposure scenario is indicated

Risk estimation is mainly based on animal inhalation studies. Based on experimental data an adsorption percentage of 45% is taken for the rat inhalation route, whereas for humans an absorption percentage of 65 % is assumed. For the dermal pathway an absorption percentage of 50% is assumed for humans.

The most important toxicological endpoints are repeated dose toxicity and developmental toxicity of ethylbenzene. On the background of the exposure assessment and the proposed critical exposure levels, the according health risks especially after dermal contact have to be reduced.

Conclusion (iii) applies to dermal and combined exposure of scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) after repeated dose toxicity and regarding developmental toxicity. The exposure value of this scenario with a value of 28.6 mg/kg/day is about 17 fold higher than the critical exposure level of 1.7 mg/kg/day (systemic effects after repeated exposure) and about 12 fold higher than the critical exposure level, resulting from developmental toxicity.

For inhalation the critical exposure level of 9.3 mg/m3 results from systemic effects after repeated exposure. The inhalation exposure values of scenario 1 (production and processing) with 1.3 mg/m3 and scenario 2 (use of paints, lacquers, inks containing 20% ethylbenzene) with 7 mg/m3 are below this value, thus reaching no concern.

Consumers

Current Risk Reduction Measures

Classification and labelling

The current classification of ethyl benzene according to Annex I of Directive 67/548/EEC (19. ATP, Index-Nr. 601-023-00-4) is F; R11 (Highly flammable) - Xn; R20 (Harmful by inhalation). Ethyl benzene has to be labelled with F, Xn; R11-20; S(2-)16-24/25-29.

The rapporteur (of the RAR) proposed to add the following classification and labelling:
R 36/37/38 Irritating to eyes, respiratory tract and to skin
R 48/20 Harmful: Danger of serious damage to health by prolonged exposure through inhalation
R 65 Harmful: May cause lung damage if swallowed

This proposal has not yet been discussed in the EU-Working group on classification and labelling of dangerous substances under Directive 67/548/EEC.

Abbreviations:

F

Highly flammable

R11

Highly flammable

Xn

Harmful

R20

Harmful by inhalation

R 36/37/38

Irritating to eyes, respiratory tract and to skin

R 48/20

Harmful: Danger of serious damage to health by prolonged exposure through inhalation

R 65

Harmful: May cause lung damage if swallowed

S(2-)

Keep out of the reach of children

S 16-

Keep away from sources of ignition - No smoking

S 24/25-

Avoid contact with skin and eyes

S 29

Do not empty into drains


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