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Directorate-General for Health and Food Safety
Opinion on the results of the Risk Assessment of: METHYL OXIRANE (PROPYLENE OXIDE) - Human health and Environment - CAS N°: 75-56-9 - EINECS N°: 200-879-2 Report version : Final Version, 20 February June 2001 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances1. Opinion expressed at the 24th CSTEE plenary meeting, Brussels, 12 June 2001Opinion on the results of the Risk Assessment of: METHYL OXIRANE (PROPYLENE OXIDE) - Human health and Environment - CAS N°: 75-56-9 - EINECS N°: 200-879- Report version : Final Version, 20 February June 2001 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances. Opinion expressed at the 24th CSTEE plenary meeting, Brussels, 12 June 2001.
Terms of reference
In the context of Regulation 793/93 (Existing Substances Regulation), and on the basis of the examination of the Risk Assessment Report the CSTEE is invited to examine the following issues:
1. Does the CSTEE agree with the conclusions of the Risk Assessment Report?
2. If the CSTEE disagrees with such conclusions, the CSTEE is invited to elaborate on the reasons for this divergence of opinion.
Introduction
PO is produced in the EU by 8 companies and its total usage in the EU is appr. 1,495,000 tonnes. Its main uses are use as a monomer in polymer production, use as an intermediate in the synthesis of other substances and, accounting for only a small proportion, direct applications.
There is a discrepancy in the RAR regarding the number of producing companies that should be resolved (section 2.2. states "8", section 4.1.1.1.1. states "7").
Propylene oxide is currently classified as Cat 2 Carcinogen and is labelled R45- May cause cancer. Hence, it is already subject to stringent risk control measures that reduce exposure to as low a level as is reasonably practicable.
HUMAN HEALTH
General comments
The assessment follows the recommendations of the TGD and is comprehensive and properly written. The CSTEE agrees in general with the overall conclusion of the risk assessment.
The critical health concerns are mutagenicity and carcinogenicity. As it is not currently possible to determine a threshold for mutagenic events and, thus, to identify a threshold for carcinogenicity, conclusion iii) is reached for workers and consumers for these endpoints. The CSTEE supports this conclusion.
In addition the CSTEE notes that as industry develops measures that reduce exposure of workers to as low a level as reasonably practicable, and because consumer exposures are extremely low it is concluded in the RAR that there is no need for the development of a risk reduction strategy at this time (conclusion iii a, being dependent upon the industry continuing to implement new procedures to reduce exposure when possible).
Propylene oxide has not been adequately tested for skin sensitisation and, therefore, there is no evaluation of risks to any human population for this endpoint. Given the high level of control currently exercised and the low level of dermal and inhalation exposure, no further testing on skin and respiratory sensitisation is required.
Specific comments
Exposure assessment
PO is mainly used as an intermediate in the synthesis of other substances, with 7-8 EU producers and an estimated 150-300 user plants. Occupational exposure is between 0-30 ppm 8-hr TWA and it can be controlled to less than 3 ppm.
A worst-case 15 minutes TWA of 33-67 ppm during loading/unloading of road, rail and ship storage tankers has been calculated with the EASE model. Worst case calculated exposures from EASE for sampling were > 33 ppm (15 minutes TWA).
Worst-case dermal exposure is estimated 0 – 0.1 mg/cm²/day with the EASE model based on incidental contacts whilst sampling or touching a wet surface.
Consumer exposure to PO in consumer products is considered to be negligible. Potential exposure through contact with foodstuffs, medicinal products, and hydraulic fluids (brake fluids for cars) is mentioned but no further details are given in the RAR. Propylene, a compound of, for instance, car exhaust and cigarette smoke, is another source of PO exposure not mentioned in the RAR.
Human exposure indirectly via the environment is estimated to range from 3 ng/kg/d to 3.9 ug/kg/d with inhalation contributing mostly to this exposure.
Effects assessment
PO is rapidly absorbed into the tissues and metabolised via conjugation with glutathione and hydrolysis. At high doses saturation of the metabolic process for elimination is assumed. Haemoglobin and DNA adduct formation has been observed in several animal tissues following inhalation exposure, including nasal mucosa, trachea, lung, liver, brain and testes. The RAR text needs modification in that no kidney adducts have been investigated in the inhalation experiments.
PO is harmful by inhalation, oral or dermal routes of exposure.
It may cause local irritation on contact with the skin and eyes. It has demonstrated some potential to cause skin sensitisation and it is plausible that it could bind to tissue proteins and elicit an immunological response. A further case-report has been published (Morris AD et al., 1998).
There is no data available on respiratory sensitisation.
Repeated inhalation exposure produces irritation of the nasal epithelium, with marginal effects at 30 ppm and pronounced epithelial damage at 100 ppm and above. Target tissues are the sites of the initial contact.
Propylene oxide is a direct acting mutagen in a wide variety of standard in vitro test systems and in somatic cells in vivo. There is no evidence for propylene oxide to induced heritable mutations in germ cells from dominant lethal tests in rats and mice. Given that propylene oxide is a direct-acting mutagen that might reach the germ cells, the assessor, however, concludes that the possibility for PO inducing heritable mutations in germ cells cannot be discounted. Further information on genotoxic effects of PO in germ cells of Drosophila has not been included in the RAR (Vogel EW and Nivard MJ, 1998).
PO is a respiratory tract carcinogen in animals. Repeated gavage induced forestomach carcinoma in rats. At present, the relative contribution to the carcinogenic process made by irritation, consequential proliferative response and genotoxicity is unclear.
There is no evidence for reproductive and developmental toxicity at non-maternally toxic dose levels from animal studies.
Risk characterisation
Overall, the critical health concerns are for mutagenicity and carcinogenicity. PO is a direct-acting mutagen and is capable of producing somatic cell mutations in vivo, particularly in the tissues at the site of contact. PO is a respiratory tract carcinogen in animals. Possibly, chronic inflammation is a key influence in the development of cancer, but the carcinogenic mechanisms involved (eg cell turnover, DNA repair) remain unproven. Occupational exposures are an order of magnitude below the levels at which respiratory tract irritation is observed in animals.
The CSTEE, therefore, supports the view that for both mutagenicity and carcinogenicity it is not possible to identify a threshold level of exposure below which there would be no risk to human health and, thus, it is not possible to derive a toxicologically valid margin of safety.
The CSTEE agrees with the conclusions reached for workers, consumers, and indirect exposure via the environment and combined exposure.
References
Vogel EW and Nivard MJ (1998): Genotoxic effects of inhaled ethylene oxide, propylene oxide and butylene oxide on germ cells: sensitivity of genetic endpoints in relation to dose and repair status: Mutat Res 20;405(2):259-71
Morris AD et al. (1998): Allergic Contact Dermatitis from Epoxy Propane: Contact Dermatitis, Vol. 38, No. 1, page 57, 2 references.
ENVIRONMENT
General comments
The environmental part of the RAR is in general of good quality, however, the conclusions related to the environment are not well supported enough on the basis of the available information.
The assessment of the soil and atmospheric compartment is conducted without considering the biocidal activity of this chemical. The chemical is of low acute toxicity for fish, daphnia and algae, but, as stated in the report, is biologically active against other organisms. The conclusion of low risk on the basis of extrapolation from aquatic organisms (soil compartment) or considerations of low concentrations (atmospheric compartment) cannot be accepted for a chemical which is biologically active and used as a biocide. Therefore, the CSTEE considers that conclusion ii) is not acceptable for the terrestrial (soil) and atmospheric compartments. Conclusion i) should be considered and specific toxicity data on terrestrial organisms should be requested.
Specific comments
Emissions and exposure assessment
Taking into account the main use and emission patterns in Europe and the physical-chemical properties of propylene oxide, water and air are the potentially exposed compartments.
It must be highlighted that experimental data are very few for the aquatic environment and completely lacking for other compartments. It is not satisfactory that for such a high production volume chemical, monitoring data are inadequate and assessment should be based only on predicted exposure data.
Effects assessment
Aquatic environment
The effects assessment on the aquatic environment is based on a few reliable toxicity data (mainly short term) on fish, Daphnia and algae. Therefore, a high assessment factor has been used for deriving a PNEC for water.
No data are available on aquatic micro-organisms, but there is evidence for effects on soil bacteria. A PNEC for aquatic micro-organisms has not be calculated.
Terrestrial environment
The report properly states that propylene oxide is used as a fumigant (biocide), and therefore should be considered as a biologically active molecule. Potential targets include micro-organisms and some invertebrates. An specific mode of action must be assumed.
The RAR presents the available information on the fumigant activity and concludes that the information is not enough for PNEC derivation. The CSTEE agrees that the presented information does not allow a proper risk assessment.
Then, the RAR report applies the equilibrium partitioning method for deriving the PNECsoil organisms. The chemical showed low acute toxicity in a set of standard (aquatic) organisms, and these values are extrapolated to the soil. The data set does not include information on taxonomic groups which can be target by the biocidal activity. Therefore, this extrapolation cannot be supported.
Similarly the RAR suggests a low risk for atmospheric exposures of organisms, on the basis of the air concentrations but without toxicity data.
The physical-chemical properties suggests that propylene oxide can reach terrestrial environments on the basis of atmospheric deposition. The potential for volatilisation increase the risk of this phenomena on the basis of repeated processes of volatilisation-deposition during rain events-volatilisation-deposition.
Toxicity data on plants, soil micro-organisms and sensitive soil fauna are required. The CSTEE suggests to request tests mimicking the deposition process (spraying with contaminated water), and perform the risk characterisation on the basis of doses expressed as amount per surface (ug/m2).
Risk characterisation
It is opinion of the CSTEE that for such a high production volume chemical the data available are not enough to exclude the need for more information.
The CSTEE supports conclusion ii) for sediment and secondary poisoning
----------------------------------------
1 Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of those substances if they are produced or imported into the Community in volumes above 10 tonnes per year. The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission Regulation (EC) 1488/94, which is supported by a technical guidance document.
Terms of reference
In the context of Regulation 793/93 (Existing Substances Regulation), and on the basis of the examination of the Risk Assessment Report the CSTEE is invited to examine the following issues:
1. Does the CSTEE agree with the conclusions of the Risk Assessment Report?
2. If the CSTEE disagrees with such conclusions, the CSTEE is invited to elaborate on the reasons for this divergence of opinion.
Introduction
PO is produced in the EU by 8 companies and its total usage in the EU is appr. 1,495,000 tonnes. Its main uses are use as a monomer in polymer production, use as an intermediate in the synthesis of other substances and, accounting for only a small proportion, direct applications.
There is a discrepancy in the RAR regarding the number of producing companies that should be resolved (section 2.2. states "8", section 4.1.1.1.1. states "7").
Propylene oxide is currently classified as Cat 2 Carcinogen and is labelled R45- May cause cancer. Hence, it is already subject to stringent risk control measures that reduce exposure to as low a level as is reasonably practicable.
HUMAN HEALTH
General comments
The assessment follows the recommendations of the TGD and is comprehensive and properly written. The CSTEE agrees in general with the overall conclusion of the risk assessment.
The critical health concerns are mutagenicity and carcinogenicity. As it is not currently possible to determine a threshold for mutagenic events and, thus, to identify a threshold for carcinogenicity, conclusion iii) is reached for workers and consumers for these endpoints. The CSTEE supports this conclusion.
In addition the CSTEE notes that as industry develops measures that reduce exposure of workers to as low a level as reasonably practicable, and because consumer exposures are extremely low it is concluded in the RAR that there is no need for the development of a risk reduction strategy at this time (conclusion iii a, being dependent upon the industry continuing to implement new procedures to reduce exposure when possible).
Propylene oxide has not been adequately tested for skin sensitisation and, therefore, there is no evaluation of risks to any human population for this endpoint. Given the high level of control currently exercised and the low level of dermal and inhalation exposure, no further testing on skin and respiratory sensitisation is required.
Specific comments
Exposure assessment
PO is mainly used as an intermediate in the synthesis of other substances, with 7-8 EU producers and an estimated 150-300 user plants. Occupational exposure is between 0-30 ppm 8-hr TWA and it can be controlled to less than 3 ppm.
A worst-case 15 minutes TWA of 33-67 ppm during loading/unloading of road, rail and ship storage tankers has been calculated with the EASE model. Worst case calculated exposures from EASE for sampling were > 33 ppm (15 minutes TWA).
Worst-case dermal exposure is estimated 0 – 0.1 mg/cm²/day with the EASE model based on incidental contacts whilst sampling or touching a wet surface.
Consumer exposure to PO in consumer products is considered to be negligible. Potential exposure through contact with foodstuffs, medicinal products, and hydraulic fluids (brake fluids for cars) is mentioned but no further details are given in the RAR. Propylene, a compound of, for instance, car exhaust and cigarette smoke, is another source of PO exposure not mentioned in the RAR.
Human exposure indirectly via the environment is estimated to range from 3 ng/kg/d to 3.9 ug/kg/d with inhalation contributing mostly to this exposure.
Effects assessment
PO is rapidly absorbed into the tissues and metabolised via conjugation with glutathione and hydrolysis. At high doses saturation of the metabolic process for elimination is assumed. Haemoglobin and DNA adduct formation has been observed in several animal tissues following inhalation exposure, including nasal mucosa, trachea, lung, liver, brain and testes. The RAR text needs modification in that no kidney adducts have been investigated in the inhalation experiments.
PO is harmful by inhalation, oral or dermal routes of exposure.
It may cause local irritation on contact with the skin and eyes. It has demonstrated some potential to cause skin sensitisation and it is plausible that it could bind to tissue proteins and elicit an immunological response. A further case-report has been published (Morris AD et al., 1998).
There is no data available on respiratory sensitisation.
Repeated inhalation exposure produces irritation of the nasal epithelium, with marginal effects at 30 ppm and pronounced epithelial damage at 100 ppm and above. Target tissues are the sites of the initial contact.
Propylene oxide is a direct acting mutagen in a wide variety of standard in vitro test systems and in somatic cells in vivo. There is no evidence for propylene oxide to induced heritable mutations in germ cells from dominant lethal tests in rats and mice. Given that propylene oxide is a direct-acting mutagen that might reach the germ cells, the assessor, however, concludes that the possibility for PO inducing heritable mutations in germ cells cannot be discounted. Further information on genotoxic effects of PO in germ cells of Drosophila has not been included in the RAR (Vogel EW and Nivard MJ, 1998).
PO is a respiratory tract carcinogen in animals. Repeated gavage induced forestomach carcinoma in rats. At present, the relative contribution to the carcinogenic process made by irritation, consequential proliferative response and genotoxicity is unclear.
There is no evidence for reproductive and developmental toxicity at non-maternally toxic dose levels from animal studies.
Risk characterisation
Overall, the critical health concerns are for mutagenicity and carcinogenicity. PO is a direct-acting mutagen and is capable of producing somatic cell mutations in vivo, particularly in the tissues at the site of contact. PO is a respiratory tract carcinogen in animals. Possibly, chronic inflammation is a key influence in the development of cancer, but the carcinogenic mechanisms involved (eg cell turnover, DNA repair) remain unproven. Occupational exposures are an order of magnitude below the levels at which respiratory tract irritation is observed in animals.
The CSTEE, therefore, supports the view that for both mutagenicity and carcinogenicity it is not possible to identify a threshold level of exposure below which there would be no risk to human health and, thus, it is not possible to derive a toxicologically valid margin of safety.
The CSTEE agrees with the conclusions reached for workers, consumers, and indirect exposure via the environment and combined exposure.
References
Vogel EW and Nivard MJ (1998): Genotoxic effects of inhaled ethylene oxide, propylene oxide and butylene oxide on germ cells: sensitivity of genetic endpoints in relation to dose and repair status: Mutat Res 20;405(2):259-71
Morris AD et al. (1998): Allergic Contact Dermatitis from Epoxy Propane: Contact Dermatitis, Vol. 38, No. 1, page 57, 2 references.
ENVIRONMENT
General comments
The environmental part of the RAR is in general of good quality, however, the conclusions related to the environment are not well supported enough on the basis of the available information.
The assessment of the soil and atmospheric compartment is conducted without considering the biocidal activity of this chemical. The chemical is of low acute toxicity for fish, daphnia and algae, but, as stated in the report, is biologically active against other organisms. The conclusion of low risk on the basis of extrapolation from aquatic organisms (soil compartment) or considerations of low concentrations (atmospheric compartment) cannot be accepted for a chemical which is biologically active and used as a biocide. Therefore, the CSTEE considers that conclusion ii) is not acceptable for the terrestrial (soil) and atmospheric compartments. Conclusion i) should be considered and specific toxicity data on terrestrial organisms should be requested.
Specific comments
Emissions and exposure assessment
Taking into account the main use and emission patterns in Europe and the physical-chemical properties of propylene oxide, water and air are the potentially exposed compartments.
It must be highlighted that experimental data are very few for the aquatic environment and completely lacking for other compartments. It is not satisfactory that for such a high production volume chemical, monitoring data are inadequate and assessment should be based only on predicted exposure data.
Effects assessment
Aquatic environment
The effects assessment on the aquatic environment is based on a few reliable toxicity data (mainly short term) on fish, Daphnia and algae. Therefore, a high assessment factor has been used for deriving a PNEC for water.
No data are available on aquatic micro-organisms, but there is evidence for effects on soil bacteria. A PNEC for aquatic micro-organisms has not be calculated.
Terrestrial environment
The report properly states that propylene oxide is used as a fumigant (biocide), and therefore should be considered as a biologically active molecule. Potential targets include micro-organisms and some invertebrates. An specific mode of action must be assumed.
The RAR presents the available information on the fumigant activity and concludes that the information is not enough for PNEC derivation. The CSTEE agrees that the presented information does not allow a proper risk assessment.
Then, the RAR report applies the equilibrium partitioning method for deriving the PNECsoil organisms. The chemical showed low acute toxicity in a set of standard (aquatic) organisms, and these values are extrapolated to the soil. The data set does not include information on taxonomic groups which can be target by the biocidal activity. Therefore, this extrapolation cannot be supported.
Similarly the RAR suggests a low risk for atmospheric exposures of organisms, on the basis of the air concentrations but without toxicity data.
The physical-chemical properties suggests that propylene oxide can reach terrestrial environments on the basis of atmospheric deposition. The potential for volatilisation increase the risk of this phenomena on the basis of repeated processes of volatilisation-deposition during rain events-volatilisation-deposition.
Toxicity data on plants, soil micro-organisms and sensitive soil fauna are required. The CSTEE suggests to request tests mimicking the deposition process (spraying with contaminated water), and perform the risk characterisation on the basis of doses expressed as amount per surface (ug/m2).
Risk characterisation
It is opinion of the CSTEE that for such a high production volume chemical the data available are not enough to exclude the need for more information.
The CSTEE supports conclusion ii) for sediment and secondary poisoning
----------------------------------------
1 Regulation 793/93 provides a systematic framework for the evaluation of the risks to human health and the environment of those substances if they are produced or imported into the Community in volumes above 10 tonnes per year. The methods for carrying out an in-depth Risk Assessment at Community level are laid down in Commission Regulation (EC) 1488/94, which is supported by a technical guidance document.
