Chemical Abstracts Service Registry Number
Table of Contents
- Substance Identity
- Physical and Chemical Properties
- Releases to the Environment
- Environmental Fate
- Persistence and Bioaccumulation Potential
- Potential to Cause Ecological Harm
- Potential to Cause Harm to Human Health
- Appendix 1: Upper Bounding Estimates of Daily Intake of Isoprene by the General Population in Canada (µg/kg-bw per Day by Various Age Groups)
- Appendix 2: Summary of Health Effects Information for Isoprene
Pursuant to section 74 of the Canadian Environmental Protection Act, 1999 (CEPA 1999), the Ministers of the Environment and of Health have conducted a screening assessment of 1,3-butadiene, 2-methyl- (isoprene), Chemical Abstracts Service Registry Number (CAS RN) 78-79-5. This substance was identified in the categorization of the Domestic Substances List as a high priority for action under the Ministerial Challenge. Isoprene was identified as a high priority as it was considered to pose greatest potential for exposure to individuals in Canada (GPE) and had been classified by other agencies on the basis of carcinogenicity and mutagenicity. The substance did not meet the criteria for persistence, bioaccumulation or inherent toxicity to aquatic organisms. Therefore, the focus of this assessment on isoprene relates to human health aspects.
Under information reported pursuant to Section 71 of CEPA 1999, the total quantity of isoprene manufactured in Canada in 2006 exceeded 10 000 000 kg and the total quantity imported ranged from 1 000 000 to 10 000 000 kg. This substance is used mainly as a monomer in the production of polyisoprene, butyl rubber and styrene-isoprene-styrene (SIS) rubber. Polyisoprene is subsequently used in the production of vehicle tires and a wide variety of products including paint resins, footwear, adhesives and molded goods. . Butyl rubber is typically used in the manufacture of inner tubes, while SIS rubber is used in pressure sensitive adhesives. Isoprene is also used in the formulation of viscosity improvers for motor oil and in the production of agrochemicals, pharmaceuticals and other substances.
Isoprene is emitted into the environment from both natural and anthropogenic sources, and the principal route of exposure for the general population will likely be through inhalation of ambient and indoor air. Off-gassing of isoprene from consumer products manufactured from polyisoprene may also contribute to the levels of the substance in indoor air.
Based principally on the weight of evidence-based assessments of several international and national agencies, a critical effect for the characterization of risk to human health is carcinogenicity, based on observation of tumours at multiple organ sites in rats and mice. Isoprene was also genotoxic in several in vivoassays. Therefore, although the mode of action has not been fully elucidated, it cannot be precluded that tumours observed in experimental animals resulted from direct interaction with genetic material.
On the basis of carcinogenicity, for which there may be a probability of harm at any level of exposure, as well as the potential inadequacy of the margin between concentrations of isoprene in indoor air and levels associated with non-cancer effects in the thymus in a subchronic study, it is concluded that isoprene be considered as a substance which may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.
On the basis of low ecological hazard and reported releases of isoprene, it is concluded that this substance is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity, or that constitute or may constitute a danger to the environment on which life depends. As set out in the Persistence and Bioaccumulation Regulations, isoprene does not meet the criteria for persistence in air, water, soil or sediment, nor does it meet the criteria for bioaccumulation potential.
In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment and, where appropriate, the performance of potential control measures identified during the risk management phase.
Based on information available, isoprene meets one or more of the criteria set out in section 64 of the Canadian Environmental Protection Act, 1999.
The Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999) requires the Minister of the Environment and the Minister of Health to conduct screening assessments of substances that have met the categorization criteria set out in the Act to determine whether these substances present or may present a risk to the environment or human health. Based on the results of a screening assessment, the Ministers can propose to take no further action with respect to the substance, to add the substance to the Priority Substances List (PSL) for further assessment, or to recommend that the substance be added to the List of Toxic Substances in Schedule 1 of the Act and, where applicable, the implementation of virtual elimination.
Based on the information obtained through the categorization process, the Ministers identified a number of substances as high priorities for action. These include substances that
- met all of the ecological categorization criteria, including persistence (P), bioaccumulation potential (B) and inherently toxic to aquatic organisms (iT), and were believed to be in commerce or to be of commercial interest in Canada; and/or
- met the categorization criteria for greatest potential for exposure (GPE) or presented an intermediate potential for exposure (IPE), and had been identified as posing a high hazard to human health based on classifications by other national or international agencies for carcinogenicity, genotoxicity, developmental toxicity or reproductive toxicity.
The Ministers therefore published a notice of intent in the Canada Gazette, Part I, on December 9, 2006 (Canada 2006), that challenged industry and other interested stakeholders to submit, within specified timelines, specific information that may be used to inform risk assessment, and to develop and benchmark best practices for the risk management and product stewardship of those substances identified as high priorities.
The substance 1,3-butadiene, 2-methyl- (isoprene) was identified as a high priority for assessment of human health risk because it was considered to present GPE and had been classified by other agencies on the basis of carcinogenicity and genotoxicity. The Challenge for isoprene was published in the Canada Gazetteon May 12, 2007 (Canada 2007). A Substance Profile was released at the same time. The substance profile presented the technical information available prior to December 2005 that formed the basis for categorization of this substance. As a result of the Challenge, submissions of information were received.
Although isoprene was determined to be a high priority for assessment with respect to human health, it did not meet the criteria for potential for bioaccumulation or inherent toxicity for aquatic organisms. Therefore, this assessment focuses principally on information relevant to the evaluation of risks to human health.
Under CEPA 1999, screening assessments focus on information critical to determining whether a substance meets the criteria for defining a chemical as toxic as set out in section 64 of the Act, where
"64. [...] For the purposes of this Part and Part 6, except where the expression "inherently toxic" appears, a substance is toxic if it is entering or may enter the environment in a quantity or concentration or under conditions that
(a) have or may have an immediate or long-term harmful effect on the environment or its biological diversity;
(b) constitute or may constitute a danger to the environment on which life depends; or
(c) constitute or may constitute a danger in Canada to human life or health"
Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution.
This screening assessment includes consideration of information on chemical properties, hazards, uses and exposure, including the additional information submitted under the Challenge. Data relevant to the screening assessment of this substance were identified in original literature, review and assessment documents, stakeholder research reports and from recent literature searches, up to February 2008 and June 2008 for information on health effects and human exposure, respectively. Key studies were critically evaluated; modelling results may have been used to reach conclusions. Evaluation of risk to human health involves consideration of data relevant to estimation of exposure (non-occupational) of the general population, as well as information on health hazards (based principally on the weight of evidence based assessments of other agencies that were used for prioritization of the substance). Decisions for human health are based on the nature of the critical effect and/or margins between conservative effect levels and estimates of exposure, taking into account confidence in the completeness of the identified databases on both exposure and effects, within a screening context. The screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents a summary of the critical information upon which the conculsion is based.
This screening assessment was prepared by staff in the Existing Substances Programs at Health Canada and Environment Canada and incorporates input from other programs within these departments. This assessment has undergone external written peer review/consultation. Comments on the technical portions relevant to human health were received from scientific experts selected and directed by Toxicology Excellence for Risk Assessment (TERA), including John Christopher (California Department of Toxic Substances Control), Michael Jayjock (The LifeLine Group) and Wendy Heiger-Bernays (The Science Collaborative and Boston University). While external comments were taken into consideration, the final content and outcome of the screening risk assessment remain the responsibility of Health Canada and Environment Canada. Additionally, the draft of this screening assessment was subject to a 60-day public comment period. The critical information and considerations upon which the assessment is based are summarized below.
For the purposes of this document, this substance will be referred to as isoprene.
Table 1. Substance identity
|Chemical Abstracts Service Registry Number (CAS RN)||78-79-5|
|Domestic Substances List (DSL) name||1,3-butadiene, 2-methyl-|
|National Chemical Inventory (NCI) names||1,3-butadiene, 2-methyl- (TSCA, ENCS, AICS, SWISS, PICCS, ASIA-PAC, NZIoC)|
isoprene (EINECS, PICCS)
BUTA-1,3-DIENE, 2-METHYL- (PICCS)
|Other names||ß-methylbivinyl; 2-methylbutadiene; 3-methyl-1,3-butadiene; isopentadiene|
|Chemical group (DSL stream)||Organics|
|Simplified Molecular Input Line Entry (SMILES)||C(C=C)(C)=C|
|Molecular mass||68.12 g/mol|
A summary of key physical chemical properties for isoprene is presented in Table 2. At room temperature, isoprene is a clear, colourless liquid. It is flammable and highly reactive and is capable of polymerizing explosively when heated.
Table 2. Physical and chemical properties for isoprene
(g/ml at 20°C)
|73 327||Very high||HSDB 2008|
|Henry's Law constant|
|0.077;||Very high||HSDB 2008|
Isoprene is a biogenic volatile organic compound that is naturally emitted to the atmosphere from various plant and tree species (Zimmer et al. 2000). Indoor house plants may also be a source of exposure, although no relevant data have been identified. The substance is also formed endogenously in humans and is generally the major hydrocarbon present in exhaled breath (Gelmont et al. 1981). Anthropogenic releases occur during the manufacture of synthetic rubber and other elastomers (Lewis 1997). Isoprene may also be released to the environment through rubber abrasion (Graedel 1986).
Further releases occur during wood pulping operations and from oil fires, wood-burning stoves, fireplaces and other biomass combustion processes. Isoprene is also found in gasoline, cigarette smoke and exhaust gases from turbines and automobiles (HSDB 2008).
Under information reported pursuant to the CEPA 1999 section 71 notice with respect to isoprene, Canadian companies reported manufacturing the substance in a quantity greater than 10 000 000 kg and importing a quantity in the range of 1 000 000 kg to 10 000 000 kg for the 2006 calendar year. However, greater than 10 000 000 kg was exported during the same calendar year. (Environment Canada 2007a).
According to submissions made under section 71 of CEPA 1999 Challenge questionnaire submissions, other voluntarily submitted data and available scientific and technical literature, isoprene is used mainly as a monomer in the production of polyisoprene (cis-1,4-polyisoprene), butyl rubber (isobutene-isoprene copolymer), thermoplastic and elastomeric co-block polymers (e.g., styrene-isoprene-styrene rubber). Polyisoprene is used mostly in the production of vehicle tires and in the manufacture of a wide variety of products including medical equipment, toys, shoe soles, elastic films and threads for textiles and golf balls, adhesives and paints and coatings, while butyl rubber is typically used in the manufacture of inner tubes and styrene-isoprene-styrene rubber is used in pressure sensitive adhesives (Environment Canada 2007a; IARC 1999; OECD 2005). Isoprene may also be used in the formulation of viscosity improvers and in the production of agrochemicals, pharmaceuticals and other chemicals (Shell 2008).
In Canada, a large number of cosmetic products are available that are formulated with polyisoprene or various isoprene copolymers (e.g., styrene/isoprene, isoprene/pentadiene), but no information on the amount of unreacted isoprene in these products is available (as per email from Cosmetic Products Branch, dated June 9, 2008). Butyl rubber is also used in can sealants for food containers and crown corks used on bottles, coatings for plastic films and seam end tops used in packaging in accordance with good manufacturing practice (GMP) where any contact with the food is expected to be incidental (as per email from Health Products and Food Branch, dated Feb 15 2008).
Isoprene is a naturally occurring substance that is continually emitted to the atmosphere by agricultural crops, trees and other vegetation. It is also the basic structural unit in many natural products, including terpenes and vitamins A and K (IARC 1994). It has been estimated that global emissions of the substance range from 1.75 to 5.03 x 1011 kg C per year and represent approximately 44-51% of the total global natural volatile organic compound emissions (Guenther et al. 1995).
Anthropogenic releases of isoprene occurring during ethylene production by the cracking of naphtha and from other industrial operations involving the use of isoprene (e.g., manufacture of polyisoprene) are much smaller in comparison to natural releases. The National Pollutant Release Inventory (NPRI) reports the releases of isoprene to air from industrial facilities in Canada have been reduced from 54 900 kg in 2000 to 14 500 kg in 2006. No releases to water or land have been reported (NPRI 2006). Recent information gathered under CEPA 1999 through a section 71 notice with respect to isoprene included reports of releases to air in 2006 in a quantity greater than 10 000 kg (Environment Canada 2007a).
Isoprene having a very high vapour pressure of 73 327 Pa and a low boiling point of 34°C, is expected to exist solely as a vapour in the atmosphere, where it will be degraded by reaction with photochemically-produced hydroxyl radicals, ozone molecules and nitrate radicals. The half-lives for the reaction in air with hydroxyl radicals and ozone molecules are estimated to be four and 19 hours, respectively (HSDB 2008).
If released to water, isoprene is expected to volatilize from the water surface, based on its very high Henry's Law constant. Volatilization half-lives for a model river and a model lake are estimated to be one and 78 hours, respectively (HSDB 2008). If released to soil, isoprene is expected to have moderate mobility, based upon an estimated log Koc of 2.69. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.077 atm-cu m/mole. The estimated Koc indicates that isoprene is not expected to adsorb to suspended solids and sediment (HSDB 2008).
Once released into the environment , isoprene is likely to degrade significantly in all environmental compartments. Experimental half-life values of 0.11 days for photodegradation and 0.8 days for ozone reaction in air (Atkinson 1989) indicate that isoprene degrades relatively rapidly; therefore, the substance does not meet the persistence criterion for air (half-life of ≥ 2 days) set out in the Persistence and Bioaccumulation Regulations. (Canada 2000a).
A quantitative structure-activity relationship (QSAR)-based weight of evidence approach (Environment Canada 2007b) was applied to predict the persistence in water (Table 3). Based on the predicted half-lives and biodegradation value in water, it can be concluded that isoprene does not persist in water (half-life ≥ 182 days). The predicted biodegradation half-life of 15 days in water was further used to predict the half-life of this chemical in soil and sediment by applying Boethling's extrapolation factors (t1/2water : t1/2 soil : t1/2 sediment = 1: 1:4) (Boethling et al. 1995). According to these values, it is concluded that this chemical does not meet the persistence criteria for water and soil (half-life ≥ 182 days) or sediment (half-life ≥ 365 days) set out in the Persistence and Bioaccumulation Regulations (Canada 2000a).
Table 3. Modelled data for persistence of isoprene in water
|Medium||Fate process||Degradation value||Degradation endpoint||Reference|
|Water||Biodegradation||0.67||Probability||BIOWIN 2000, MITI Non-linear Probability|
|Water||Biodegradation||0.54||Probability||BIOWIN 2000, MITI Linear Probability|
|Water||Hydrolysis||n/a||Half-life (days)||HYDROWIN 2000|
Potential for Bioaccumulation
Experimental and modelled log Kow values of 2.42 and 2.58, respectively, indicate that the potential for bioaccumulation is likely to be low. Experimental bioconcentration (BCF) values for fish range from 9.5 to 12.9 L/kg (MITI 1992) and modelled predictions for bioaccumulation and bioconcentration factors range from 6.3 L/kg to 117 L/kg (Table 4). Therefore, isoprene does not meet the bioaccumulation criterion (BCF, BAF ≥ 5000) as set out in the Persistence and Bioaccumulation Regulations(Canada 2000a).
Table 4. Modelled data for bioaccumulation of isoprene
|Test organism||Endpoint||Value wet weight|
|Fish||BAF||6.3 L/kg||Gobas BAF T2MTL|
(Arnot and Gobas 2003)
|Fish||BCF||5.9 L/Kg||Gobas BCF T2LTL|
(Arnot and Gobas 2003)
|Fish||BCF||117 L/kg||OASIS Forecast 2005|
|Fish||BCF||14.6 L/kg||BCFWIN 2000|
 Bioconcentration factor
As indicated earlier, isoprene does not meet the criteria for persistence in air, water, soil or sediment, nor does it meet the criterion for bioaccumulation potential as set out in thePersistence and Bioaccumulation Regulations( Canada 2000a).
Experimental ecotoxicological data (ECOTOX database) indicate that isoprene does not cause significant harm to aquatic organisms at low concentrations. For four species of fish, acute LC50 values vary within a range of 42.54 to 240 mg/L.
The NPRI reports the releases of isoprene to air from industrial facilities in Canada have been reduced from 54 900 kg in 2000 to 14 500 kg in 2006. No releases to water or land have been reported (NPRI 2006). In recent information gathered through a section 71 notice under CEPA 1999 (Environment Canada 2007a), companies reported the release of isoprene in 2006 in a quantity greater than 10 000 kg, exclusively to air. Given the quantity and nature of these releases, they are deemed unlikely to result in significant exposure of organisms in the environment.
Based on the information available, the conclusion has been reached that it is unlikely that isoprene is causing ecological harm in Canada .
Appendix 1 presents the upper bounding estimates of intake of isoprene for each age group in the general population of Canada, based on the maximum concentrations of the substance measured in indoor and outdoor air and data for one type of beverage. These upper bounding estimates of intake range from 5.6 µg/kg-bw per day (seniors, 60+ years) to 16.8 µg/kg-bw per day (children, 0.5-4 years). These estimates indicate that indoor air is the most important source of environmental exposure to isoprene for all age groups of the general population of Canada, typically comprising approximately 95% of total exposure. Ambient air is the next highest source of exposure, while only limited data for beverages were available to estimate intake from food. No data on concentrations of isoprene in drinking water and soil were identified, although contribution from these media is expected to be negligible in comparison to that from air, based on information on the physical/chemical properties, use patterns and releases of the substance.
Isoprene is the predominant unsaturated hydrocarbon present in sidestream cigarette smoke, and average yields of 3100 µg/cigarette have been measured in a test chamber (Lofroth et al. 1989). Health Canada, which has been monitoring tobacco smoke of cigarettes sold in Canada for over 30 years, reports that the emission data of cigarettes sold in Canada in 2004 show that the level of isoprene in Canadian cigarette smoke under ISO standard smoking conditions in mainstream smoke is 30-397 µg/cigarette and 395-864 µg/cigarette under modified smoking conditions. Furthermore, the level of isoprene found in sidestream smoke is 90-3194 µg/cigarette (as per email from Tobacco Control Directorate, July 29, 2008). In another study, it has been reported that isoprene comprised 16.7% of C2-C8 hydrocarbons present in the indoor air of a smoky café in Sweden (Barrefors and Petersson 1993). Also, in a monitoring study conducted in homes and workplaces in the Philadelphia, PA area, mean concentrations of isoprene in personal air samples ranged from 4.65 µg/m3 in non-smoking homes to 18.2 µg/m3 in homes with smokers, and from 5.29 µg/m3 in non-smoking workplaces to 22.8 µg/m3 in workplaces with smokers. The approximate four-fold increases in levels of isoprene in environments where smoking occurs compared to environments without smoking were considered highly significant (Heavner et al. 1996). Thus, smoking is expected to be the primary source of isoprene in the indoor air of homes and other environments where smokers are present.
Consumer products containing polymer derived from polyisoprene such as paint resins, footwear, adhesives, moulded goods and motor oil viscosity improvers may contain residual levels of unreacted isoprene and contribute to levels in indoor air as well as to consumer exposure. For example, 17 of 19 samples of polyisoprene analyzed for residual monomer had no detectable levels of isoprene (detection limit 0.02 ppm) while the remaining two samples contained amounts that ranged between 0.02 and 0.04 ppm (OECD 2005). No attempt was made to quantify exposure from this source because of the lack of adequate information needed to complete an exposure estimate (e.g., release rate of unreacted monomer from polyisoprene). However, based on the very low levels identified, off-gassing of isoprene from polyisoprene products would likely be only a minor contributor to overall indoor air levels. Furthermore, because of the very high vapour pressure and low log Kowfor isoprene, emissions are expected to partition directly to air and dermal uptake of isoprene from handling polyisoprene products would likely be negligible.
Isoprene is endogenously produced in the human body, possibly as a by-product of isoprenoid biosynthesis or as an end product of isoprenoid degradation, typically comprising from 30-70% of the total hydrocarbons exhaled, with an estimated quantity exhaled ranging from 2-4 mg/day. This quantity did not appear to vary with age, sex, ethnicity, diet, life style or fasting/non-fasting state (Gelmont et al.1981). Furthermore, based on extrapolations from data in mice and rats, it has been reported that the average quantities of endogenously produced isoprene formed in the body ranged from 264-332 pmol/ml of tissue (Hartmann 1994). Several other studies also report on the levels of endogenously produced isoprene found in humans, including a range of 15-70 nmol/L (1.0-4.8 µg/L) in blood (Cailleux et al. 1992) and a production rate of 0.15 µmol/kg/h (about 17 mg/day for a 70 kg adult) (Taalman 1996). In another study, it was clearly shown that levels of isoprene in classrooms were much higher following occupation by children than background levels in unoccupied classrooms, and the authors concluded that the substance can be regarded as a measureable index of contaminants from human origin (Cailleux et al. 1993). Thus, endogenous production of isoprene may contribute to observed indoor air levels of the substance. However, it was also reported that while isoprene is formed endogenously, 90% will be metabolized within the body and only about 10% exhaled unchanged (Filser et al. 1996). Phillips et al (1994) reported that concentrations of isoprene were greater in alveolar air than in inspired air, consistent with an exogenous origin and uptake and catabolism in vivo or excretion via an extrapulmonary pathway.
Confidence in the upper bounding estimate of intake of isoprene through environmental media is considered to be high, since recent Canadian monitoring data were available for the most relevant media of exposure (i.e., indoor and ambient air). Although no data were available for drinking water and soil and only limited data for food, it is expected that these media are not major sources of exposure.
Health Effects Assessment
An overview of the toxicological database for isoprene is presented in Appendix 2.
On the basis of investigations in experimental animals, isoprene has been classified by the International Agency for Research on Cancer (IARC) as Group 2B (Possibly carcinogenic to humans) (IARC 1999) and by the European Commission as Category 2 (Regarded as if they are carcinogenic to man; May cause cancer) (ESIS [date unknown]; European Commission 2004). As well, the U.S. National Toxicology Program (NTP) has classified isoprene as being ". . . reasonably anticipated to be a human carcinogen . . ." (NTP 2004). These classifications were based on increased incidences of neoplastic effects at multiple sites in both mice and rats exposed to isoprene via inhalation, as described below.
In a stop-exposure bioassay in male B6C3F 1 mice exposed via inhalation to up to 19 530 mg/m3of isoprene for 26 weeks and observed for an additional 26 weeks, increased incidences of tumours in several tissues were observed, including alveolar/bronchiolar adenoma or carcinoma, Harderian gland adenoma, hepatocellular adenoma or carcinoma and forestomach squamous-cell papilloma or carcinoma (NTP 1995, Melnick et al. 1994). In an additional study in B6C3F 1 mice, males were exposed via inhalation to concentrations of up to 6138 mg/m3of isoprene for 20, 40 or 80 weeks and were observed until 96 or 104 weeks, while female mice were exposed via inhalation to concentrations of up to 195 mg/m3for 80 weeks and observed until 104 weeks. Male mice had significantly increased incidences of tumours of the lung, liver, and Harderian gland in addition to histiocytic sarcomas. As well, non-significantly increased incidences of heart and spleen haemangiosarcomas were observed in males. Increased incidences of Harderian gland and pituitary adenomas (significant) were observed in female mice exposed to the highest concentration (Placke et al. 1996).
Male and female F344/N rats were exposed to concentrations of up to 19 530 mg/m3of isoprene for 104 weeks. There were increased incidences of mammary fibroadenoma in males and females, as well as renal tubule adenomas or carcinomas and interstitial-cell adenoma of the testis in males (NTP 1999a). A slight increase in the incidence of interstitial-cell adenoma of the testis was also observed in male F344/N rats in a stop exposure study, where animals were exposed via inhalation to concentrations up to 19 530 mg/m3of isoprene for 26 weeks, and were observed for a further 26 weeks (Melnick et al. 1994, 1996; NTP 1995). However, an IARC Working Group noted that spontaneous incidence of this tumour type is high in two-year studies, and that the duration was not adequate for evaluation of carcinogenic potential (NTP 1994a; IARC 1994), although it is noteworthy that the incidence increased after only 26 weeks of exposure.
The European Commission has also classified isoprene as Category 3 regarding its mutagenicity (Substances which cause concern for man owing to possible mutagenic effects; Possible risk of irreversible effects) (ESIS [date unknown]; European Commission 2004). Isoprene was genotoxic in in vivo assays as positive results were observed for sister chromatid exchanges and micronuclei induction in bone-marrow cells in mice exposed via inhalation (IARC 1999). However, negative results were observed in some assays conducted in vitro, specifically tests for mutations in bacteria, and sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells (IARC 1999). A positive result was observed for the Comet assay in blood cellsin vitro (Fabiani et al. 2007). According to IARC (1994), the genotoxic activity of isoprene in vivo may be due to a metabolite of isoprene, 2-methyl-1,2:3,4-diepoxybutane.
Although thorough analyses of the potential mode of action for induction of tumours by isoprene is considered to be beyond the scope of this screening assessment, the NTP has postulated that reactive alkylating metabolites of isoprene may be involved, but it is also noted that other mechanisms should be considered (NTP 1999b).
Exposure to isoprene via inhalation, the predominant route of exposure for the general population, also induced a variety of non-cancer effects in experimental animals, often at the lowest concentration tested. In addition, hyperplasia occurred at sites at which tumours were also observed (lungs, forestomach, kidneys and testis). The lowest lowest-observed-effect-concentration (LOEC) for exposure to isoprene is 11 mg/m3, which was associated with an increase in proliferative activity of the thymus of Wistar rats exposed for four months, followed by one month of observation (Mamedov 1979). At a higher concentration, a variety of effects such as changes in thymus weight, mitotic index and cellularity of the thymus were observed to be reversible during exposure or recovery, but at the lower concentration, the increased proliferation of the thymus was noted during the recovery period. As well, a short-term LOEC of 98 mg/m3was identified for increased proliferative activity in the thymus in male Wistar rats exposed for 30 days (Mamedov 1979). As in the subchronic study, reversible changes were observed in the thymus as well as in the spleen, but the proliferative changes remained at the end of the study. Although both studies are limited in the scope of organs and biological systems investigated, in other studies which involved more comprehensive gross and histopathology analyses, effects were also noted in the thymus (change in thymus weight, thymic atrophy) as well as the spleen (change in spleen weight) of rats and mice exposed to higher concentrations of isoprene for 2, 13 or 26 weeks (NTP 1995). In addition, splenic fibrosis was observed in rats exposed for 105 weeks to 1953 mg/m3and above (NTP 1999a). The next lowest LOEC of approximately 28 mg/m3was identified for a non-significant decrease in ovarian weight in female mice exposed to up to 195 mg/m3of isoprene for 80 weeks (Placke et al. 1996). (It is noteworthy that ovarian atrophy was induced at low concentrations in mice after exposure to 1,3-butadiene, a structural analogue of isoprene [NTP 1984, 1993; Bevan et al. 1996].) Additional effects observed on the female reproductive system, including increased estrous cycle length and decreased gravid uterine weight were observed in female mice exposed to higher concentrations for shorter durations (Melnick et al. 1994; NTP 1995).
The confidence in the toxicity database in experimental animals is considered to be moderate to high, as data were identified for acute, repeat-dose, reproductive and developmental toxicity, carcinogencity and genotoxicity; however, the level of detail reported in some of the repeat dose studies is limited and no sufficient human epidemiology data were available. There is also uncertainty regarding the mode of induction of tumours.
Characterization of Risk to Human Health
Based principally on the weight of evidence based assessments of several international and national agencies (IARC 1999, NTP 2004, NTP 1999b, European Commission 2004), a critical effect for characterization of risk to human health for isoprene is carcinogenicity. In chronic bioassays, isoprene consistently induced tumours at multiple sites in both mice and rats. This substance was also genotoxic in in vivo assays in mice. Thus, in light of these data, a mode of induction for tumours involving direct interaction with genetic material cannot be precluded. Although epidemiological data are inadequate for evaluation, isoprene is a structural analogue of 1,3-butadiene, which has been associated in lymphohaematopoietic cancer in exposed workers.
With respect to consideration of critical non-cancer effects in a screening context, comparison of the conservatively selected lowest identified inhalation effect level (11 mg/m3 or 11 000 µg/m3) from a subchronic study, with the highest identified concentration of isoprene (30.5 µg/m3) reported in indoor air in Canada in 2006, the principal source of exposure for the general population, results in a margin of exposure of approximately 360. Comparison of this effect level with the highest identified concentration of 9.48 µg/m3 reported in ambient air in an urban area in Canada yields a margin of exposure of approximately 1160. While it is recognized that endogenous production and natural sources of isoprene contribute to overall exposure in addition to anthropogenic sources, it is not possible to separate the relative contribution of each of these sources in the scope of a screening level assessment. In addition, data indicate that cigarette smoking results in higher concentrations of isoprene in indoor air; therefore, the margin of exposure may be smaller in the homes of smokers. Thus, in light of the uncertainties in the databases, including those relating to the mode of induction of tumours, it is considered that these margins of exposure may not be adequately protective of human health.
Uncertainties in Evaluation of Risk to Human Health
The scope of this screening assessment of isoprene does not take into account variability across the general population or differences between humans and experimental animals with respect to differences in sensitivity of induction of effects, particularly in light of the lack of sufficient epidemiological studies. However, the metabolic pathway of isoprene is qualitatively similar between experimental animals and humans, although there may be slight quantitative differences (Gervasi and Longo 1990; Csanady and Filser 2001, Peter et al. 1987). In addition, the available data support a similar profile of health effects as that for 1,3-butadiene, which has been associated with cancer in humans. Although isoprene induced tumours at multiple sites in multiple experimental animal species, the method of tumour induction has not been fully elucidated. However, there are indications that metabolites of the substance could play a role, potentially through interaction with genetic material. In addition, the critical study for non-cancer effects was limited in the range of organs and biological systems investigated.
There are also significant uncertainties regarding the relative contribution of biogenic sources of isoprene, such as trees and other plants, and endogenous production of the substance in humans. While it is not possible to distinguish between the relative contributions of exogenous and endogenous sources of isoprene reaching target tissues, exposure to exogenous isoprene induced tumours in rodents, which also produce the substance endogenously. However, there is considerable variation in reported rates of endogenous production for different species. Quantitative comparison of kinetics and dynamics of isoprene between humans and experimental species could elucidate differences in sensitivities to external sources in terms of tumourgenicity, but such analyses are beyond the scope of this screening assessment.
In addition, the contribution of emissions from consumer products manufactured from polyisoprene, butyl rubber and SIS rubber to population exposure to isoprene is unknown, although likely to be insignificant in comparison to other anthropogenic or natural sources.
Based on the available information, it is concluded that isoprene is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity, or that constitute or may constitute a danger to the environment on which life depends. Additionally, isoprene does not meet the criterion for persistence or for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations.
On the basis of the carcinogenicity of isoprene, for which there may be a probability of harm at any level of exposure, as well as the potential inadequacy of the margins of exposure for non-cancer effects, it is concluded that isoprene be considered as a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.
It is therefore concluded that isoprene does not meet the criteria in paragraph 64a and 64b of CEPA 1999, but that it does meet the criteria in paragraph 64c of CEPA 1999.
Arnot JA, Gobas FAPC. 2003. A Generic QSAR for Assessing the Bioaccumulation Potential of Organic Chemicals in Aquatic Food Webs. QSAR Comb Sci 22(3): 337-345.
Atkinson R. 1989. Kinetics and mechanisms of the gas phase reactions of the hydroxyl radical with organic compounds. J Phys Chem Ref Data. Monograph No. 1.
Barrefors G, Petersson G. 1993 Assessment of ambient volatile hydrocarbons from tobacco smoke and from vehicle emissions, J. Chromatog., 643: 71-76.
Bayer AG. (Institute fur Toxikologie). 1972. Isopren - Akute Toxizitatsuntersuchungen. Unpublished Report No. 3733. [Cited in BG Chemie 2000].
[BG Chemie] Berufsgenossenschaft der chemischen industrie (DE). Toxicological evaluation: Isoprene CAS No. 78-79-5 [Internet]. 2000. Heidelberg : Berufsgenossenschaft der chemischen industrie. Report No.: 105. [cited 12 March 2007 ].
Bevan C, Stadler JC, Elliott GS, Frame SR, Baldwin JK, Leung H-W, Moran E, Panepinto AS. 1996. Subchronic toxicity of 4-vinylcyclohexene in rats and mice by inhalation exposure. Fundam Appl Toxicol 32: 1-10. [Cited in Canada 2000b].
[BCFWIN] BioConcentration Factor Program for Windows [Estimation Model]. 2000. Version 2.15. Washington (DC): U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. [cited 2007 Apr 30]. Exposure Assessment Tools and Models.
[BIOWIN] Biodegradation Probability Program for Windows [Estimation Model]. 2000. Version 4.02. Washington (DC): U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. Exposure Assessment Tools and Models..
Bohmann, J.J., 1984. Bestimmung und alterungsverhalten des bieres. Monatsschridft fur Brauwissenschaft. Heft 10: 436-441.
Boethling RS, Howard PH, Beauman JA, Larosche ME. 1995. Factors for intermedia extrapolations in biodegradability assessment. Chemosphere. 30 (4), 741-752
Bond JA, Bechtold WE, Birnbaum LS, Dahl AR, Medinsky MA, Sun JD, Henderson RF. 1991. Disposition of inhaled isoprene in B6C3F1 mice. Toxicol Appl Pharmacol 107(3):494-503. [Cited in BG Chemie 2000, IARC 1999].
Cailleux A, Cogny M, Allain P. 1992. Blood Isoprene Concentrations in Humans and in Some Animal Species, Biochem Med Metab Biol 47: 157-160.
Cailleux A, Turcant A, Premel-Cabic A, Allain P. 1993. Volatile organic compounds in indoor air and in expired air as markers of activities. Chromatographia: 37, 1/2: 57-59.
Canada. 1999. Canadian Environmental Protection Act, 1999.S.C., 1999, c. 33. Canada Gazette, Part III, Vol. 22, No. 3 (accessed August 3, 2007).
Canada. 2000a. Canadian Environmental Protection Act: Persistence and Bioaccumulation Regulations. P.C. 2000-348, 23 March, 2000, SOR/2000-107. Canada Gazette, Part II, Vol. 134, No. 7.
Canada. 2000b. 1,3-Butadiene. Ottawa (ON): Environment Canada ; Health Canada. (Priority substances list assessment report).
Canada, Dept. of the Environment, Dept. of Health. 2006.Canadian Environmental Protection Act, 1999: Notice of intent to develop and implement measures to assess and manage the risks posed by certain substances to the health of Canadians and their environment. Canada Gazette, Part I, Vol. 140, No. 49.
Canada, Dept. of Environment. 2007. Canadian Environmental Protection Act, 1999: Notice with respect to certain Batch 2 substances. Canada Gazette, Part I, Vol. 141. No. 19.
Csanady GA, Filser JG. 2001. Toxicokinetics of inhaled and endogenous isoprene in mice, rats and humans. Chem Biol Ineract 135-136: 679-685.
Dahl AR, Birnbaum LS, Bond JA, Gervasi PG, Henderson RF. 1987. The fate of isoprene inhaled by rats: comparison to butadiene. Toxicol Appl Pharmacol 89: 237-248. [cited in BG Chemie 2000; IARC 1994].
de Meester C, Mercier M, Poncelet F. 1981. Mutagenic activity of butadiene, hexachlorobutadiene and isoprene. In: Gut I, Cikrt M, Plaa GL, eds. Industrial and Environmental Xenobiotics. Berlin : Springer, pp 195-203. [cited in IARC 1999; OECD 2005 (dossier)].
Del Monte M, Citti L, Gervasi PG. 1985. Isoprene metabolism by liver microsomal monooxygenases. Xenobiotica 15: 591-597. [cited in BG Chemie 2000].
Doerr JK, Hooser SB, Smith BJ, Sipes IG. 1995. Ovarian toxicity of 4-vinylcyclohexene and related olefins in B6C3F 1 mice: role of diepoxides. Chem Res Toxicol 8: 963-969. [cited in IARC 1999].
Environment Canada 2006, unpublished data from Tom Dann, Pollution Measurement Division, Environmental Technology Centre, River Road, Ottawa, Ont.
Environment Canada. 2007a. Data for Batch 2 substances collected under the Canadian Envrionmental Protection Act, 1999, Section 71: Notice with respect to certain Batch 2 Challenge substances. Data prepared by: Environment Canada, Existing Substances Program.
Environment Canada. 2007b. QSARs: Reviewed Draft Working Document, Science Resource Technical Series, Guidance for Conducting Ecological Assessments under CEPA 1999. Existing Substances Division, Environment Canada, Gatineau (QC). Internal draft document available on request.
[ESIS] European Chemical Substances Information System [database on the internet]. [date unknown]. Version 5. European Chemicals Bureau. [cited 2008 Jan 7].
European Commission. 2004. Isoprene (stabilized).Commission Directive 2004/73/EC of 29 April 2004. Annex 1B. Official Journal of the European Union 16.6.2004. L216:27. European Commission. 29th ATP.
Fabiani R, Rosignoli P, De Bartolomeo A, Fuccelli R, Morozzi G. 2007. DNA-damaging ability of isoprene and isoprene mono-epoxide (EPOX I) in human cells evaluated with the comet assay. Mutat Res 629: 7-13.
Faustov AS. 1972. Toxic and hygiene characteristics of the gas factor in the production of certain types of general purpose synthetic rubber. Trud Voron Med Inst. 87: 10-16. [cited in BG Chemie 2000].
Faustov AS, Lobeeva NV. 1970. Action of some chemical substances on the protein content of serum and bone marrow. Chem Abstr 73: Abstr 118648c. [cited in BG Chemie 2000].
Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, Kessler W, Kreuzer PE, Putz C, Shen JH, Stei P. 1996. Toxicokinetics of isoprene in rodents and humans. Toxicology 113:278-287.
Gage JC. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br J Ind Med 27: 1-18. [cited in BG Chemie 2000].
Galloway S, Armstrong M, Reuben C, Colman S, Brown B, Cannon C, Bloom A, Nakamura F, Ahmed M, Duk S and others. 1987. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: evaluations of 108 chemicals. Environ Mol Mutagen 10: 1-175. [cited in OECD 2005].
Gelmont D, Stein RA, Mead JF. 1981 Isoprene - The Main Hydrocarbon in Human Breath Biochem Biophys Res Commun 99(4):1456-1650
Gervasi PG, Longo V. 1990. Metabolism and mutagenicity of isoprene. Environ Health Perspect 86: 85-87.
Gostinskii VD. 1965. Toxicity of isoprene and maximal safe concentration of the vapor in air. Fed Proc Transl Suppl. 24(6):1123-6. [Cited in OECD 2005, BG Chemie 2000].
Graedel TE. 1986. Atmospheric Chemical Compounds. Orlando, FL : Academic Press p. 145 [Cited in HSDB 2008]
Guenther A, C. Hewitt, D. Erickson, R. Fall, C. Geron, T. Graedel, P. Harley, et al. 1995. A Global Model of Natural Volatile Organic Compound Emissions. J Geophys Res 100: 8873-8892.
Hartmann M 1994. Pharmakokinetik und endogene production von isoprene beim menschen. GSF Report 21/94. [cited in BG Chemie 2000].
Health Canada. 1998. Exposure factors for assessing total daily intake of priority substances by the general population of Canada. Unpublished report. Ottawa (ON): Health Canada, Environmental Health Directorate.
Health Canada 2008. Windsor Ontario Exposure Assessment Study 2005, 2006: VOC Sampling Data Summary (Draft). Fuels and Exposure Assessment Section, Air Health Sciences Division.
Heavner DL, Morgan WT, Ogden MW. 1996. Determination of volatile organic compounds and respirable suspended particulate matter in New Jersey and Pennsylvania homes and workplaces. Environ Int 22(2): 159-183.
[HSDB] Hazardous Substances Data Bank [database on the Internet]. 1983 -. Bethesda (MD): National Library of Medicine (US). [cited 2008 Jan 3].
Huntingdon Life Sciences. 2003. Ames assay. Huntingdon Life Sciences Ltd., Cambridgeshire, England. [cited in OECD 2005 as Huntingdon Life Sciences 2003a].
[HYDROWIN] Hydrolysis Rates Program for Microsoft Windows [Estimation Model]. 2000. Version 1.67. Washington (DC): U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation [cited 2007 Apr 30]. Exposure Assessment Tools and Models.
[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1994. Some industrial chemicals. Isoprene. IARC Monogr Eval Carcinog Risks Hum. 60: 215-32.
[IARC] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1999. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. Isoprene. IARC Monogr Eval Carcinog Risks Hum. 71(3): 1015-25.
Kimmerle G, Solmecke B. 1972. Isopren-Akute Toxizit, tsuntersuchungen.: Bayer AG. unveroffentlichter Bericht Nr. 3373. [Cited in OECD 2005].
Korbakova AI, Fedorova VI. 1964. Zur toxikologie von isopren. Toksikol. Novykk. Prom. Khim. Veschesto. 6:18-29. [German translation from Russian; Cited in BG Chemie 2000].
Kushi A, Yoshida D, Mizusaki S. 1985. Mutagenicity of gaseous nitrogen oxides and olefins on Salmonella TA 102 and TA 104. Mutat Res 147: 263-264. [cited in OECD 2005 (Dossier)].
Lanxess 2005. Product Specification Sheet for Lanxess Butyl 101-3.
Lewis RJ Sr, 1997; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY : Van Nostrand Reinhold Co., p. 631 [Cited in HSDB 2008]
Lofroth G, Burton RM, Forehand L, Hammond SK, Seila RL, Zweidinger RB, Lewtas J. 1989. Characterization of Environmental Tobacco Smoke, Environ Sci Technol, 23: 610-614.
Madhusree B, Goto S, Ohkubo T, Tian H, Ando F, Fukuhara M, Tohkin M, Watanabe I. 2002. Mutagenicity testing of 1,3-butadiene, 1,4-pentadiene-3-ol, isoprene, 2,4-hexadiene, cis - andtrans -piperlylene. J Health Sci 48(1):73-8.
Mamedov AM. 1979. [Lymphoid tissue reaction and several integral indices following isoprene inhalation]. Gig Tr Prof Zabol. (6):35-7.
Mast TJ, Evanoff JJ, Stoney KH, Westerberg RB, Rommereim RL. 1989. Inhalation Developmental Toxicology Studies: Teratology Study of Isoprene in Mice and Rats: Final Report. Govt. Rep. Announce. Index. Issue 14:255. [Abstract No. 9393174; Cited in IARC 1994].
Mast TJ, Rommereim RL, Weigel RJ, Stoney KH, Schwetz BA, Morrissey RE. 1990. Inhalation developmental toxicity of isoprene in mice and rats. Toxicologist 10(1):42. [Abstract No. 165; Cited in IARC 1994].
Melnick RL, Roycroft JH, Chou BJ, Ragan HA, Miller RA. 1990. Inhalation toxicology of isoprene in F344 rats and B6C3F1 mice following two-week exposure. Environ Health Perspect 86: 93-98. [cited in IARC 1999; OECD 2005].
Melnick RL, Sills RC, Roycroft JH, Chou BJ, Ragan HA, Miller RA. 1994. Isoprene, an endogenous hydrocarbon and industrial chemical, induces multiple organ neoplasia in rodents after 26 weeks of inhalation exposure. Cancer Res 54(20):5333-9. [Cited in OECD 2005, BG Chemie 2000, IARC 1999, NTP 1999b].
Melnick RL, Sills RC, Roycroft JH, Chou BJ, Ragan HA, Miller RA. 1996. Inhalation toxicity and carcinogenicity of isoprene in rats and mice: comparisons with 1,3-butadiene. Toxicology 113(1-3):247-52. [Cited in IARC 1999, OECD 2005, BG Chemie 2000].
The Merck Index. 1996. An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ : Merck and Co., Inc., p. 887
[MITI] Ministry of International Trade & Industry (Jpn). 1992. Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Chemical Products Safety Division Basic Industries Bureau, Ministry of International Trade & Industry, Edited by Chemicals Inspection & Testing Institute, Japan.
Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger E. 1986. Salmonella mutagenicity tests: II: Results from the testing of 270 chemicals. Environ Mutagen 8(Suppl 7): 1-119. [cited in IARC 1999; OECD 2005].
MITI (Ministry of International Trade & Industry). 1992. Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Chemical Products Safety Division Basic Industries Bureau, Ministry of International Trade & Industry, Edited by Chemicals Inspection & Testing Institute, Japan.
[NCI] National Chemical Inventories [database on CD-ROM]. 2007. Issue 1. Columbus (Ohio): American Chemical Society, Chemical Abstracts Service. [cited 2007 Oct]. National Chemical Inventory (NCI) System Requirements.
[NHW] Department of National Health and Welfare (CA). 1990. Present patterns and trends in infant feeding in Canada. Ottawa (ON): Department of National Health and Welfare. NHW Cat. No. H39-199/1990E. [Cited in Health Canada 1998]
[NPRI] National Pollutant Release Inventory [database on the Internet]. 2006. Gatineau (QC): Environment Canada. [cited 2008 Jan].
[NTP] National Toxicology Program (US). 1984. NTP technical report on the toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. Report No.: Technical Report No. 288. [Cited in Canada 2000b].
[NTP] National Toxicology Program (US). 1989. Inhalation developmental toxicology studies: teratology study of isoprene in mice and rats. Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. Report No.: TER88045, NTIS#DE89008095. [Cited in OECD 2005].
[NTP] National Toxicology Program (US). 1993. NTP technical report on the toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. Technical Report No. 434 [Cited in Canada 2000b].
[NTP] National Toxicology Program (US). 1994a. NTP technical report on toxicity studies of isoprene (CAS No. 78-79-5); administered by inhalation to F344/N rats and B6C3F1 mice (NIH Publication 94-3354). Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. [Cited in IARC 1994 as US National Toxicology Program 1994; Draft version of NTP 1995].
[NTP] National Toxiciology Program (US). 1994b. Intraperitoneal administration of isoprene to B6C3F1 mice and urinary metabolites of isoprene in F-344 rats and B6C3F1 mice. [unpublished study cited in BG Chemie 2000].
[NTP] National Toxicology Program (US). 1995. NTP technical report on toxicity studies of isoprene (CAS No. 78-79-5) administered by inhalation to F344/N rats and B6C3F1 mice. NIH Publication No. 95-3354 [Internet]. Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. Report No.: Toxicity Report Series Number 31.
[NTP] National Toxicology Program (US). 1999a. NTP technical report on toxicology and carcinogenesis studies of isoprene (CAS No. 78-79-5) in F344/N rats (Inhalation studies) [Internet]. Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. Report No.: NTP TR 486.
[NTP] National Toxicology Program (US). 1999b. NTP report on carcinogens background document for isoprene [Internet]. Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program. [cited 10 January 2008 ].
[NTP] National Toxicology Program (US). 2004. Substance profiles: isoprene CAS No. 78-79-5 [Internet]. Research Triangle Park (NC): U.S. Department of Health and Human Services, National Toxicology Program [page last updated 26 Aug 2005 ; cited 3 April 2007 ].
[OASIS Forecast] Optimized Approach based on Structural Indices Set [Internet]. 2005. Version 1.20. Bourgas (BG): Bourgas Prof. Asses Zlatarov University, Laboratory of Mathematical Chemistry. OASIS Software.
[OECD] Organization for Economic Cooperation and Development. 2005. Isoprene CAS No. 78-79-5 [Internet]. United Nations Environment Program (UNEP) Publications. [Cited 21 March 2007 ].
Peter H, Wiegand HJ, Bolt HM, Greim H, Walter G, Berg M, Filser JG. 1987. Pharmacokinetics of isoprene in mice and rats. Toxicol Lett 36: 9-14.
Phillips M., Greenberg J, Awad J. 1994. Metabolic and environmental origins of volatile organic compounds in breath. J Clin Pathol, 47: 1052-1053.
Placke ME, Griffis L, Bird M, Bus J, Persing RL, Cox LA Jr. 1996. Chronic inhalation oncogenicity study of isoprene in B6C3F1 mice. Toxicology 113(1-3):253-62.
Repina EF. 1988. Untersuchung der selektiven gonadotoxischen Aktivität von isoprene und piperylen im akuten versuch. Gig Proizv Okruzh Sredy, Okhrana Zdorov'ya Rab v Neftegazodobyv i Neftekhim, Prom-sit M: 96-99. [German translation from Russian; cited in BG Chemie 2000].
Rhone-Poulenc, Inc. 1971. Initial submission: acute inhalation toxicity of isoprene, isoprene hydrochloride and allyl chloride in rats with cover letter dated 09/04/92. Submitted (1992) to U.S. Environmental Protection Agency (Microfiche No. OTS 0555961; Document No. 88-920010693).
Rohr AC, Wilkins CK, Clausen PA, Hammer M, Nielsen GD, Wolkoff P, Spengler JD. 2002. Upper airway and pulmonary effects of oxidation products of (+)-alpha-pinene, d-limonene, and isoprene in BALB/c mice. Inhal Toxicol 14(7):663-84.
Samedov IG, Mamedov AM, Mamedova LN, Bekesev IA. 1978. Immunologische indices als mögliche kriterien zur bewertung der einwirkung von chemischen faktorn mit geringer intensität auf den organismus. Azerb Med Zh 55: 58-61 [German translation from Russian; cited in BG Chemie 2000].
[Shell] Shell Chemical Company, 2008 Product Overview [Internet]. Shell Chemical Company [Cited 2008, Jan].
Shugaev BB. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch Environ Health 18(6):878-82. [Cited in BG Chemie 2000, OECD SIDS 2005].
Sun JD, Dahl AR, Bond JA, Birnbaum LS, Henderson RF. 1989. Characterization of haemoglobin adduct formation in mice and rats after administration of [14C]butadiene or [14C]isoprene. Toxicol Appl Pharmacol 100: 86-95. [cited in IARC 1999; BG Chemie 2000].
Taalman R. 1996. Isoprene: background and issues. Toxicology 113: 242 - 246.
Tareke E, Golding BT, Small RD, Tornqvist M. 1998. Haemoglobin adducts from isoprene and isoprene monoepoxides. Xenobiotica 28(7):663-72.
Tice RR, Boucher R, Luke CA, Paquette DE, Melnick RL, Shelby MD. 1988. Chloroprene and isoprene: cytogenetic studies in mice. Mutagenesis 3: 141-146. [cited in IARC 1999].
Tsutsumi S, Yamaguchi T, Komatsu S, Tamura S. 1969. On the teratogenic effects of vitamin A-like substances. Proc Congenital Anomalies Res Assoc, Ann Rep No. 9: 27 [cited in BG Chemie 2000; OECD 2005 (Dossier)].
Von Oettingen WF. 1940. Toxicity and portenial dangers of aliphatic and aromatic hydrocarbons. Publ Health Bull No. 255: 26-28. [cited in BG Chemie 2000].
Wilkins CK, Clausen PA, Wolkoff P, Larsen ST, Hammer M, Larsen K, Hansen V, Nielsen GD. 2001. Formation of strong airway irritants in mixtures of isoprene/ozone and isoprene/ozone/nitrogen dioxide. Environ Health Perspect 109(9): 937-941.
Zimmer W, Bruggemann N, Emeis S, Giersch C, Lehning A, Steinbrecher R, Schnitzler JP. 2000. Process-based modelling of Isoprene emission by oak leaves. Plant Cell Environ 23: 585-595.
Appendix 1: Upper Bounding Estimates of Daily Intake of Isoprene by the General Population in Canada (µg/kg-bw per Day by Various Age Groups)
|Route of exposure||0-6 months, , ||0.5-4 yr||5-11 yr||12-19 yr||20-59 yr||60 + yr|
|Breast fed||Formula fed||Not formula fed|
|Food and beverages||na||na||na||0.03||0.06||0.04|
 Assumed to weigh 7.5 kg, to breathe 2.1 m3of air per day, drink 0.8 L/day of water (formula fed) or 0.3 L/day (not formula fed) or 0.74 L/day of breast milk and ingest 30 mg of soil per day (Health Canada 1998). Breast-fed and formula-fed infants are assumed to consume no other foods.
 For exclusively formula-fed infants, intake from water is synonymous with intake from food. The concentration of isoprene in water used to reconstitute formula was based on available water data. No data on concentrations of isoprene in formula were identified for Canada. Approximately 50% of infants are introduced to solid foods by four months of age and 90% by six months of age (NHW, 1990 [cited in Health Canada 1998]).
 Assumed to weigh 15.5 kg, to breathe 9.3 m3of air per day, drink 0.7 L/day of water and ingest 100 mg/day of soil (Health Canada 1998).
 Assumed to weigh 31.0 kg, to breathe 14.5 m3/day of air, drink 1.1 L/day of water and ingest 65 mg/day of soil (Health Canada, 1998).
 Assumed to weigh 59.4 kg, to breathe 15.8 m3/day of air, to drink 1.2 L/day of water and ingest 30 mg/day of soil (Health Canada 1998).
 Assumed to weigh 70.9 kg, to breathe 16.2 m3/day of air, drink 1.5L/day of water and ingest 30 mg/day of soil (Health Canada 1998).
 Assumed to weigh 72.0 kg, to breathe 14.3 m3/day of air, drink 1.6 L/day of water and ingest 30 mg/day of soil (Health Canada 1998).
 The highest concentration of isoprene (9.48 µg/m3) identified in ambient air samples collected from one of 15 sites across Canada (Environment Canada 2006) was used to calculate the upper bounding estimate of exposure. It is assumed that Canadians spend 3 hours/day outdoors (Health Canada 1998). The critical data were selected from a dataset of Canadian studies of ambient air (Health Canada 2008).
 The highest concentration of isoprene (30.5 µg/m3) identified in indoor air samples collected from randomly selected non-smoking homes in Windsor, Ontario (Health Canada 2008) was used to calculate the upper bounding estimate of exposure. It is assumed that Canadians spend 21 hours/day indoors (Health Canada 1998).
 No reported concentrations of isoprene in tap water in Canada or elsewhere were identified.
 Not available
 The only available information on concentration of isoprene in food and beverages was a single study from Germany showing that it it was present at 4 µg/kg in beer (Bohmann, 1984). This value was used to calculate isoprene intake from food and beverages for the relevant age groups (12-19 yrs, 20-59 yrs, 60+ yrs). However, isoprene may be used to manufacture an isobutylene-isoprene copolymer (butyl rubber) that is used a chewing gum base, and it is possible that residual amounts of the monomers may be ingested while chewing gum. While the maximum allowable level of isoprene in the copolymer is 10 ppm (Lanxess, 2005), recent surveys by the industry failed to detect the presence of either isoprene or isobutylene in samples of gum base or finished chewing gum using a detection limit of 1 ppm. The non-detection is probably due to volatization and dilution of the unreacted monomers during the production of gum base and finished chewing gum (as per email from Health Products and Food Branch, June 20 2008). Thus, the contribution to the overall intake of isoprene from this potential source will likely be insignificant.
 No reported concentrations were identified of isoprene in soil in Canada or elsewhere.
|Endpoint||Lowest effect levels[a] / Results|
Lowest oral LD50 = 2043-2210 mg/kg in rats (Kimmerle and Solmecke 1972)
Additional studies: N/A
Lowest inhalation LC50 = 139 000 mg/m3 in male mice (Gostinskii 1965)
Additional studies: Shugaev 1969; Mamedov 1979; Korbakova and Fedorova 1964; LC50 values expressed as "greater than": Kimmerle and Solmecke 1972; Bayer 1972; Rhone-Poulenc, Inc. 1971
Lowest inhalation LO(A)EC = 20 ppm or 46 mg/m3 in B6C3F 1 mice after a 6-hour exposure for respiratory effects such as depressed breathing frequency (0, 46, 460, 4600 mg/m3) (Bond et al. 1991)
Additional studies: Mamedov 1979; Korbakova and Fedorova 1964; Von Oettingen 1940; Gostinskii 1965; Rohr et al. 2002; Wilkins et al. 2001; Dahl et al. 1987
Lowest dermal LD50 > 681 mg/kg bw in rats (Bayer 1972)
Additional studies: Kimmerle and Solmecke 1972
|Short-term repeated-dose toxicity|
Lowest oral LOEL = N/A
Additional studies: Del Monte et al. 1985
Lowest inhalation LOEC = 0.098 mg/L or 98 mg/m3 (lowest concentration tested) in rats for effects observed on the thymus (increased mitotic index) after exposure by inhalation (0, 98, 1016 mg/m3 for 4 hours per day for 30 days) (Mamedov 1979).
Additional studies: LOEL = 438 ppm b or 1220 mg/m3(lowest concentration tested) for lesion formation in the liver, forestomach; changes in haematology and organ weights (liver, thymus) of mice exposed to up to 19 530 mg/m3for 6 hours/day for 5 days/weeKover 2 weeks (Melnick et al. 1990; NTP 1995); Von Oettingen 1940; Melnick et al. 1990; NTP 1995; Gage 1970; Bayer 1972
Lowest inhalation LOEC = 0.0108 mg/L or 11 mg/m3 (lowest concentration tested) in Wistar rat exposed to up to 116 mg/m3for 4 months for effects observed in the thymus (increased proliferative activity) after one month of recovery (0, 11, 116 mg/m3for 4 hours/day for 4 months) (Mamedov 1979).
Additional studies: LOEL = 70 ppm b or 195 mg/m3(lowest concentration tested) in B6C3F 1 mice due to spinal cord degeneration after 26 weeks of exposure and 26 weeks of recovery by inhalation at exposure levels of up to 19 530 mg/m3(0, 195, 614, 1953, 6138, 19 530 mg/m3for 6 hours/day, 5 days/week for 26 weeks with an additional 26 weeks of observation); changes in haematology, muscle strength, organ weights (liver, spleen, brain) and histology (lesions in forestomach, liver, harderian gland, lungs, nose) observed at higher exposure levels in mice (Melnick et al. 1994, 1996; NTP 1995).
Placke et al. 1996; Melnick et al. 1994; Gostinskii 1965 (range of levels); Faustov 1972; Samedov et al. 1978; Faustov and Lobeeva 1970 (single level studies)
|Chronic toxicity / carcinogenicity|
Lowest inhalation LOEC = 70 ppm [b] or 195 mg/m3 for significant mild metaplasia of the olfactory epithelium in the nose of female mice exposed to up to 195 mg/m3 for 80 weeks. Due to study exposure protocol for male mice and the reporting of results, it is difficult to select an effect level for male mice in this study (Placke et al. 1996); also LOEC = 70 ppm or 195 mg/m3 for spinal cord degeneration in mice exposed for 26 weeks and observed until 52 weeks (NTP 1995; Melnick et al. 1994). According to the NTP, "A NOAEL was not achieved for spinal cord degeneration.. ." (NTP 1995).
Additional studies: (NTP 1999a)
Bioassasys in mice
Male B6C3F 1 mice were exposed to 0, 10, 70, 140, 280, 700 or 2200 ppm (0, 28, 195, 391, 781, 1953 or 6138 mg/m3) by inhalation for 4 or 8 hours/day, 5 days/weeKover 20, 40 or 80 weeks. Female B6C3F 1 mice were exposed to 0, 10 or 70 ppm (0, 28, 195 mg/m3) for 80 weeks. Post-exposure observation lasted until week 96 or 104. Male mice had a significant increase in incidence of alveolar/bronchiolar adenoma and carcinoma (at 1953 mg/m3and above), hepatocellular adenoma and carcinoma or Harderian gland adenoma (at 391 mg/m3and above), as well as histiocytic sarcomas (found in kidney, lung, lymph nodes, bone marrow and spleen) (at 391 mg/m3and above). Alveolar and forestomach hyperplasia was noted at the higher concentrations (not specified). Non-significant increases in incidence of heart and spleen haemangiosarcoma were observed. Female mice had a significantly increased incidence of Harderian gland adenoma (0, 28, 195 mg/m3: 2/49, 3/49, 8/49), and pituitary adenomas (0, 28, 195 mg/m3: 1/49, 6/46, 9/49) at 195 mg/m3. Metaplasia of the nasal cavity was noted in males at 391 mg/m3and in females at 195 mg/m3. Haematopoietic cell proliferation in the spleen and myeloid hyperplasia of the bone marrow was slightly increased in all exposed groups (significance not reported). Due to study exposure protocol for male mice and the reporting of results, it is difficult to select an effect level for male mice exposed for 20, 40 and 80 weeks to levels up to 6138 mg/m3(Placke et al. 1996).
Bioassays in rats
Groups of male F344/N rats were exposed via inhalation to concentrations of isoprene of 0, 70, 220, 700, 2200, or 7000 ppm (0, 195, 614, 1953, 6138 or 19 530 mg/m3) for 6 hours/day, 5 days/week for 26 weeks, and were observed for a further 26 weeks; 10 rats exposed to the highest concentration were sacrificed after cessation of exposure. An increase was observed in the incidence of interstitial-cell adenoma (non-significant, but slightly greater) of the testis in male rats (0, 195, 614, 1953, 6138, 19 530 mg/m3: 3/30, 3/30, 4/30, 7/30, 8/29, 9/30). Interstitial cell hyperplasia was observed in the testes of rats examined at the end of the exposure period. (Melnick et al. 1994, 1996; NTP 1995). An International Agency for Research on Cancer Working Group noted that spontaneous incidence of this tumour type is high in two-year studies, and that the duration was not adequate for cancer evaluation (IARC 1994) It was also noted that the 26-week study in F344/N rats provided no conclusion regarding carcinogenic activity (NTP 1999a)
No studies conducted with isoprene specifically designed for reproductive endpoints.
Lowest inhalation LOEC = 10 ppm or 28 mg/m3 (lowest concentration tested) in female mice for ovarian effects (non-significantly reduced ovarian weight) observed after 80 weeks of exposure to up to 195 mg/m3 in female B6C3F 1 mice (Placke et al. 1996). (N.B.: No data provided regarding incidence of effect.)
Additional studies: Repina 1988; Melnick et al. 1994; NTP 1995;Doerr et al. 1995 (intraperitoneal injection) shows effects in ovarian follicles of mice.
Lowest fetal inhalation LOEC = 280 ppm or 781 mg/m3 (lowest concentration tested) in Swiss mice due to decreased fetal body weight in female pups, where maternal mice were exposed to isoprene concentrations up to 19 530 mg/m3 for 6 hours/day, 7 days/weeKover gestational days 6-17 (Mast, Evanoff et al. 1989; Mast, Rommereim et al. 1990; NTP 1989, 1995). (According to the NTP, "A NOAEL was not achieved for. .. developmental toxicity.. " [NTP 1995].)
Lowest maternal inhalation LOEC = 7000 ppm or 19 530 mg/m3 in Swiss mice due to a significant reduction in uterine weight and maternal body weight (Mast, Evanoff et al. 1989; Mast, Rommereim et al. 1990; NTP 1989; NTP 1995)
Additional studies: Mast, Evanoff et al. 1989; Mast, Rommereim et al. 1990; NTP 1989, 1995
Lowest oral LOEL = 1895 mg/kg body weight as no embryotoxicity or teratogenicity observed after treatment of Wistar rat on gd 9-12; although slightly reduced ossification of the sternebrae and occipital bone observed in fetus (Tsutsumi et al. 1969).
|Genotoxicity and related endpoints: in vivo|
Sister Chromatid Exchange
Covalent Binding/Adduct formation
Additional study: NTP 1994b (no details reported in BG Chemie  regarding hemoglobin adduct quantity formed)
|Genotoxicity and related endpoints: in vitro|
Sister chromatid exchange
[b] Conversion factor: 1 ppm = 2.79 mg/m3at 25°C (IARC 1999)
- Date Modified: