Renewable hydrocarbons of vegetable oil and/or animal fat origin (LPG type fraction)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

2.21 mg/m³

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

23.4 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

Acute/short term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

Additional information - workers

Dermal and oral studies are not technically feasible as they are gases at room temperature. The main components of Other Petroleum Gases show very low toxicity via the inhalation route. There was an absence of adverse effects relevant to humans in the acute, repeat dose and chronic toxicity studies. However, Other Petroleum Gases may contain small quantities of benzene (>0.1% but <0.3%), 1,3 butadiene (>0.1% but <1%), carbon monoxide (<1%) and hydrogen sulphide (<1%). Therefore the DN(M)EL for the Other Petroleum Gases category is defined by these substance (see Section 5.11.2 of the CSR). Demonstration of “safe use” for inhalation hazards associated with the presence of <1% 1,3-butadiene will also provide adequate protection against inhalation hazards arising from benzene, carbon monoxide and hydrogen sulphide. Benzene is the only marker substance that contributes dermal hazard to the stream (remaining markers are gases).

 

The long-term inhalation DN(M)EL for 1,3 butadiene (2.21 mg/m3) and the long-term dermal DN(M)EL for benzene (23.4 mg/kg bwt/d) will therefore be used for worker risk characterization.

Compositional information:

These hydrocarbon streams meet the regulatory definition of UVCB substances, with inherent variations in composition present due to differences in manufacturing history. This variability is documented in the Category Justification, which lists the chemical marker substances present along with an indicative concentration range for each e.g.

 

·        Benzene:some streams >0.1% but <0.3%

·        1,3-Butadiene:some streams >0.1% but <5%

·        Propylene: up to 100%

·        Carbon monoxide: up to 1%

 

Other minor components such as hydrogen, nitrogen and hydrogen sulphide may be present as impurities, however no information is available on their concentration.

 

For the purposes of risk characterisation, it has been assumed that hazards associated with hydrogen and C1-C4 alkanes will be controlled by qualitative risk management measures designed to address flammability. Indicative inhalation DN(M)ELs have been developed for carbon monoxide and hydrogen sulphide based on a maximum concentration of 1%.

 

Uses:

These hydrocarbon streams are used as intermediates and monomers, hence risk characterization will focus on workers only. (The presence of >0.1% butadiene and >0.1% benzene precludes their supply to the general population.)

 

Intrinsic hazards of marker substances and associated DN(M)ELs:

The following hazard information and DN(M)ELs are available for marker substances present in this Category.

 

Benzene

Benzene causes adverse effects on the haematopoietic system of animals and in humans after repeated dose exposure via oral or inhalation routes. Long term experimental carcinogenicity bioassays have shown that it is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia). Human epidemiological studiesprovide clear and consistent evidence of a causal association between benzene exposure and acute myelogenous (non-lymphocytic) leukemia (or ANLL). An effect on bone marrow leading to subsequent changes in human blood cell populations is believed underpin this response.

 

In accordance with REACH guidance, a science-based Binding Occupational Exposure Limit value (BOELV) can be used in place of a formal DN(M)EL providing no new scientific information exists which challenges the validity of the BOELV. While some information regarding a NOAEC for effects of benzene on human bone marrow (NOAEC = 11.18 mg/m^3 [a]) post-date the BOELV, a DNEL based on these bone marrow findings would be higher (and hence offer less protection) than the BOELV. The BOELV will therefore be used as the basis of the DN(M)EL for long-term systemic effects associated with benzene, including carcinogenicity.

 

Worker – long-term systemic inhalation DN(M)EL
The BOELV will be used with no further modification

 

DN(M)EL_{l-t inhalation}       =3.25 mg/m³

 

 

Worker - long-term systemic dermal DN(M)EL
The dermal DN(M)EL for benzene is based on the internal dose achieved by a worker undertaking light work and exposed to the BOELV for 8 hr,assuming 50% uptake by the lung and 1% by skin for benzene uptake from petroleum streams. The value of 1% is based on experiments with compromised skin and with repeated exposure (Blank and McAuliffe, 1985; Maibach and Anjo, 1981) as well as the general observation that vehicle effects may alter the dermal penetration of aromatic compounds through the skin (Tsuruta et al, 1996).

 

As the BOELV is based on worker life-time cancer risk estimates no assessment factor is needed.

 

Dermal NOAEL       = BOELV xwRV_8-hour[b] x [ABS_inhal-human/ABS_dermal-human]

                                   = 3.25 x 0.144 x [50 / 1]

DN(M)EL_{l-t dermal}          = 23.4mg/kg bw/d

In summary, the following DN(M)ELs apply to benzene:

	Worker
	Inhalation	Dermal
	DN(M)EL mg/m^3	DN(M)EL mg/kg bw/d
benzene	3.25	23.4

 

 

1,3-Butadiene

1,3-Butadiene is a multi-species carcinogen. In the mouse, it is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours. In the rat, fewer tumour types, mostly benign develop at exposure concentrations of 100 to1000-times higher than in the mouse. In humans, 1,3-butadiene is a recognised carcinogen. A positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia). Various models have established a dose response-relationship for cumulative exposure to 1,3-butadiene, especially concentrations above 100 ppm. The estimates for occupational and population human risk are based on these models.

 

Worker – long-term systemic inhalation DN(M)EL

The association between 1,3-butadiene exposure and leukemia has been extensively modeled using Cox and Poisson regression models and the excess risk of leukemia determined. The preferred model for workers is the Cox continuous model (Cheng et al, 2007) as employed by Sielken et al (2008), using the exposure metric that excluded exposure that occurred more than 40 years ago or excluded the 5% of workers with the highest cumulative 1,3-butadiene exposures and included as covariate, the cumulative number of exposures to 1,3-butadiene concentrations > 100 ppm (the number of High Intensity Tasks [HITs]). This model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. The estimate of the excess risk of death from leukemia as a result of exposure to a DMEL of 2.21 mg/m³(1 ppm) is 0.33 x 10^-4(with an upper bound of 0.66 x 10^-4based on a one-sided 95% upper confidence limit for the regression parameter).

 

This estimate is less than 0.4 x 10^-4, which has been proposed as a future limit for acceptable occupational risk (, 2008). Regression coefficients from other Cox regression models reported by Cheng et al (2007) and TCEQ (2008), and estimates from Poisson regression models, indicate that other risk estimates are generally close to 0.4 x 10^-4, even if based on regression models that do not adjust for 1,3-butadiene HITs. All of the estimates are considerably lower than the current limit for acceptable occupational risk of 4 x 10^-4that has recently been proposed (,2008).

 

 

Acute effects, local effects and other routes

1,3-Butadiene is a gas at room temperature and therefore exposure by the dermal route is not relevant.

 

In summary, the following DN(M)EL applies to 1,3-butadiene:

 

	Worker Inhalation
	DN(M)EL mg/m^3
1,3-Butadiene	2.21

 

 

Carbon monoxide

 

An IOELV has not been established for carbon monoxide. However, the toxicology and human health hazard has been comprehensively assessed by WHO (1999) and presented in the 2^ndedition of the air quality guidelines. The guidance values recommended (see table below), considered as equivalent to the long-term inhalation values required by REACH, are designed to ensure that a carboxy-haemoglobin (COHb) level of 2.5% is not exceeded, even when a normal subject engages in light or moderate exercise (equivalent to worker exposure).

 

 

 

	Worker
	Inhalation	Dermal
	DN(M)EL mg/m^3	DN(M)EL mg/kg bw/d
Carbon monoxide	8 h: 10 mg/m^3	na
na = Carbon monoxide is a gas, hence dermal DMEL not quantifiable

Hydrogen Sulphide

 

An IOELV has been established for hydrogen sulphide at 7 mg/m³(8-hour time weighted average (TWA) (EU, 2009) .

 

	Worker
	Inhalation	Dermal
	DN(M)EL mg/m^3	DN(M)EL mg/kg bw/d
Hydrogen sulphide	8 h: 7 mg/m3	na
na = Hydrogen sulphide is a gas, hence dermal DMEL not quantifiable

 

Substance selection for risk characterization

Risk characterization will be based on the premise that a marker substance with a low DN(M)EL present at high concentration in a stream will possess a greater relative hazard potential than a marker substance with a higher DN(M)EL present at the same or lower concentration. It will also focus on the potential of the markers to cause serious long-term health effects rather than on short-term or irritation-related changes.

 

In the case of this stream, the hazardous marker substances present are ranked as follows:

 

Marker substance	Indicative concentration     (%)	Inhalation		Dermal
		DN(M)EL       mg/m^3	Relative hazard potential   (max % ÷ DN(M)EL)	DN(M)EL       mg/kg bwt/d	Relative hazard potential   (max % ÷ DN(M)EL)
1,3-Butadiene	>0.1% - 5%	2.21	2.26	na	na
Benzene	>0.1% - <0.3%	3.25	0.09	23.4	<0.01
Carbon monoxide	<1%	10	0.10	na	na
Hydrogen sulphide	<1%	7	0.14	na	na
na = substance is a gas, hence dermal DN(M)EL not quantifiable

 

 

For workers: Based on this analysis, demonstration of “safe use” for inhalation hazards associated with the presence of<5% 1,3-butadiene will also provide adequate protection against inhalation hazards arising from benzene, carbon monoxide and hydrogen sulphide. Benzene is the only marker substance that contributes dermal hazard to the stream (remaining markers are gases).

 

The long-term inhalation DN(M)EL for 1,3 butadiene and the long-term dermal DN(M)EL for benzene will therefore be used for worker risk characterization.

 

 

References

 

Blank IH, McAuliffe DJ (1985). Penetration of benzene through human skin. J. Invest. Dermatol. 85, 522–526.

Committee on Hazardous Substances (). (2008). Guide for the quantification of cancer risk figures after exposure to carcinogenic hazardous substances for establishing limit values at the workplace. 1. Edition.: Bundesanstalt für Arbeitsschutz und Arbeitsmedizin. Availablehttp://www.baua.de/nn_21712/en/Publications/Expert-Papers/Gd34,xv=vt.pdf
Cheng H, Sathiakumar N, Graff J, Matthews R, Delzell E (2007). 1,3-Butadiene and leukemia among synthetic rubber industry workers: exposure-response relationships. Chem Biol Interact, 166,15-24.

EU (1993). Occupational exposure limits: Criteria document for benzene. Report EUR 14491 en, ISSN 1018-5593, Commission of the European Communities, pp126.
EU (1999). Council Directive 1999/38/EC of 29 April 1999 amending for the second time Directive 90/394/on the protection of workers from the risks related to exposure to carcinogens at work and extending it to mutagens. Official Journal of the European Communities, L138, 66-69,.
EU (2006) Directive 2006/15/EC of 7 February 2006 establishing a second list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directives 91/322/and 2000/39/EC. Official Journal of the European Union, l 38, 36-39.
EU (2009) Directive 2009/161/EU ofestablishing a third list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC and amending Directive 2000/39/EC. Official Journal of the European Union, 338/87 19 December 2009

Maibach HI, Anjo DM (1981). Percutaneous penetration of benzene and benzene contained in solvents used in the rubber industry. Arch. Environ. Health 36, 256–260.

Sielken RL, Valdez-Flores C, Gargas ML, Kirman CR, Teta MJ, Delzell E (2007). Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective. Chem Biol Interact 166, 140-149.
Sielken RL, Valdez-Flores C, Delzell E (2008). Quantitative Risk Assessment of Exposures to Butadiene in European Union Occupational Settings Based on the University of Alabama at Birmingham Epidemiological Study: All Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, and Chronic Myelogenous Leukemia. Unpublished report to Lower Olefins Sector Group,,.
TexasCommission on Environmental Quality (TCEQ) (2008). Development Support Document. 1,3-Butadiene. Chief Engineer’s Office.Available:http://tceq.com/assets/public/implementation/tox/dsd/final/butadiene,_1-3-_106-99-0_final.pdf

Tsuruta H (1996). Skin absorption of solvent mixtures-effect of vehicle on skin absorption of toluene. Ind. Health 34, 369–378.

World Health Organisation (1999). Environmental Health Criteria 213 (Carbon Monoxide, second edition) 1999, updated 2004

[a]       Data reported as 3.5 ppm, and converted to mg/m³using tool available fromhttp://www.cdc.gov/niosh/docs/2004-101/calc.htm

[b]worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of
0.2 L/min/kg bw (wRV_8-hour= (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m³/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

Value:

0.066 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Overall assessment factor (AF):

1

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

Acute/short term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

Acute/short term exposure

Hazard assessment conclusion:

no data available: testing technically not feasible

DNEL related information

Additional information - General Population

The main use of hydrocarbon streams are as intermediates and monomers, hence no exposure of the general population is likely. The presence of >0.1% butadiene and >0.1% benzene precludes the supply of these streams to the general population, however general population DN(M)ELs have been determined in case of exposure.

 

The analysis for workers demonstrated that“safe use” for inhalation hazards associated with the presence of<5% 1,3-butadiene will also provide adequate protection against inhalation hazards arising from benzene, carbon monoxide and hydrogen sulphide. Benzene is the only marker substance that contributes dermal hazard to the stream (remaining markers are gases) but this is not relevant for general population exposure. Oral exposure is also not relevant as these streams are gases at room temperature. No acute effects or local effects have been identified.

 

 

1,3-Butadiene: General Population – long-term systemic inhalation DN(M)EL

 

1,3-Butadiene is a multi-species carcinogen. In the mouse, it is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours. In the rat, fewer tumour types, mostly benign develop at exposure concentrations of 100 to1000-times higher than in the mouse. In humans, 1,3-butadiene is a recognised carcinogen. A positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia). Various models have established a dose response-relationship for cumulative exposure to 1,3-butadiene, especially concentrations above 100 ppm. The estimates for occupational and population human risk are based on these models.

 

The association between 1,3-butadiene exposure and leukemia has been extensively modeled using Cox and Poisson regression models and the excess risk of leukemia determined. Three possible models using Cox regression (Sielken 2008, Cheng 2007) were considered appropriate for determining the risk for populations, these are Cox log-linear ppm-years continuous, Cox log-linear ppm-years mean-scored deciles and Cox log-linear (restricted to lower 95% of exposure range) ppm-years continuous. These models incorporate dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required.

 

 TCEQ (2008) based their risk analysis on the Cox regression model for continuous cumulative 1,3-butadiene exposure restricted to the lower 95% of exposure range, but there does not seem to be any good reason to give this model any more weight than the other two models, and the mean scored deciles model may be a better approach to assess the impact of data in the upper part of the cumulative 1,3-butadiene exposure range. An estimate of the concentration of 1,3-butadiene giving an excess risk of death from leukemia of 1 in 10⁵was determined for all three models. The geometric mean of the three estimates derived from the models without adjustment for 1,3-butadiene concentrations > 100 ppm (the number of High Intensity Tasks [HITs]) is 28.9 ppb (30.1 ppb without use of the additional age-adjustment factor to reflect higher potential risk at early ages). The geometric mean of the three estimates derived from models that did adjust for HITs is 44.5 ppb (no estimates available without use of the age-adjustment factor).

 

The models that did not include HITs as covariate were considered to be more appropriate for population exposure as1,3-butadiene ppm years and number of HITs may be correlated and it may not be appropriate to include both of them in the same model..The geometric mean of the three estimates that did not include HITs as covariate (30 ppb, 0.0664 mg/m³) is therefore proposed as the DMEL.

 

Estimates based on the Poisson linear regression model with mean scored deciles (Sielken et al., 2007) behaved similarly to the Cox log-linear model with mean scored deciles. However, the range of air concentrations giving a 1 in 10⁵risk was much wider than for the equivalent Cox regression model; 14.33 ppb (age only) to 127.4 ppb (age & number of HITs > 100 ppm). 

Discussion

The long-term inhalation DN(M)EL for 1,3 butadiene (0.0664 mg/m³) will therefore be used for general population risk characterization.