Screening Assessment - Canada.ca (2024)

Twenty-three Substances on the Domestic Substances List Used Primarily as Pharmaceuticals
Chemical Abstracts Service Registry Numbers

50-06-6 (Phenobarbital), 81-81-2 (Warfarin), 7481-89-2 (Zalcitabine), 50-18-0 (Cyclophosphamide), 126-07-8 (Griseofulvin), 13010-47-4 (Lomustine), 55-86-7 (Mechlorethamine), 148-82-3 (Melphalan), 18883-66-4 (Streptozocin), 55-98-1 (Busulfan), 154-93-8 (Carmustine), 20830-81-3 (Daunorubicin), 56-75-7 (Chloramphenicol), 305-03-3 (Chlorambucil), 29767-20-2 (Teniposide), 57-41-0 (Phenytoin), 443-48-1 (Metronidazole), 30516-87-1 (Zidovudine), 68-22-4 (Norethindrone), 446-86-6 (Azathioprine), 51264-14-3 (Amsacrine), 71-58-9 (Medroxyprogesterone), 604-75-1 (Oxazepam)

(PDF Format - 440 KB)

• Synopsis
• 1. Introduction
• 2. Summary of Use Information Used as Basis for this Screening Assessment
• 3. Ecological Exposure and Risk Characterization from Industrial Releases and Prescription Use
• 4. Human Health Exposure and Risk Characterization from Indirect Exposure
• 5. Uncertainties
• 6. Proposed Conclusion
• 7. References
• Appendix A: Substance Identity and Human Health and Ecological Classifications for 23 Pharmaceuticals
• Appendix B: Estimated Quantities of 23 Pharmaceuticals Used in Canada for the Years 2007, 2011 and 2012
• Appendix C: Results from Environmental Exposure Modelling for 20 Pharmaceuticals Using Quantity Data from 2012
• Appendix D: Measured Concentrations of 18 Pharmaceuticals in Wastewater Treatment Plant Influent and Effluent, Surface Water, Groundwater and Drinking Water
• Appendix E: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for 18 Pharmaceuticals with Measured Concentrations
• Appendix F: Intake Estimates, Lowest Therapeutic Doses and Calculated Margins of Exposure for Two Substances Based on Modelled Concentrations in Surface Water

Drugs containing these substances as ingredients were previously assessed under the Food and Drugs Act (F&DA) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use.

Entry characterization (how the substances are entering the Canadian environment) was conducted by identifying the potential use of these substances outside of their intended pharmaceutical use. With the exception of warfarin, which is also used as a rodenticide, the only other identified use for these substances was as positive controls in research. Quantities in commerce for the consumption of pharmaceutical products that contain these substances have been estimated using information on amounts purchased by hospitals and pharmacies for 2007, 2011 and 2012.

Given that the main releases of these substances to the environment are through either industrial or down-the-drain consumer releases, the principal potential source of exposure is surface water containing these pharmaceuticals.

In order to estimate exposure in the environment, sales volumes were used as an input into modelling for predicted environmental concentrations (PECs). PECs were generated for water as a result of industrial releases and down-the-drain releases from consumer uses. The PECs from both of these scenarios were then compared with the predicted no-effect concentrations (PNECs), which were based on critical toxicity values identified during the DSL categorization process. For all substances, the predicted environmental concentration (PEC) in water was below the PNEC calculated for aquatic species.

Measured concentrations in different media, including drinking water, surface water, groundwater and wastewater treatment plant effluent, were identified in the literature for a subset of these substances, either internationally or in Canada. Where available, the measured concentrations were also compared with the PNEC for each substance; the resulting risk quotients were all less than 1, which supports and generates confidence in the modelling results.

Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms or the broader integrity of the environment from these substances. It is therefore concluded that the 23 substances do not meet the criteria under paragraph 64(a) or 64(b) of CEPA 1999, as they are 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.

With regard to potential exposure of the general population, upper-bounding estimated intakes from ingestion of drinking water were very low (less than 2.7 ng/kg body weight per day) for all substances. Based on low exposure, risks from exposure to these substances are not expected. To further support this risk characterization, the upper-bounding estimated intakes of the general population were compared with the lowest therapeutic dose identified for each substance. The margins of exposure for these substances were large, ranging from 10 900 to 8×1013.

Based on the adequacy of the margins of exposure, it is concluded that the 23 substances do not meet the criteria under paragraph 64(c) of CEPA 1999, as they are not 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.

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A screening assessment was undertaken on 23 substances on the Domestic Substances List (DSL) that were known or suspected to be used primarily as ingredients in pharmaceuticals and identified during the categorization of substances on the DSL as posing a potential high hazard to human health based on classifications by other national or international agencies for either carcinogenicity or developmental toxicity.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of the Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999). Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution.^Footnote[2]

This screening assessment includes consideration of information on chemical properties, hazards, uses and exposure. Relevant data were identified up to March 2013. Key studies were critically evaluated, along with modelled results, to reach conclusions. When available and relevant, information presented in risk and hazard assessments from other jurisdictions was considered. The screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents the critical studies and lines of evidence most pertinent to the conclusion.

Drugs containing these substances as ingredients are assessed under the Food and Drugs Act (F&DA) (Canada 1985) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use

The 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. Comments on the approach used to assess the substance with respect to human health were received from Warren Foster, McMaster University, Sam Kacew, McLaughlin Centre for Population Health Risk Assessment, and Beate Escher, University of Queensland. While external comments were taken into consideration, the final content and outcome of the screening assessment remain the responsibility of Health Canada and Environment Canada.

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Based on the results from categorization of the DSL, the 23 substances listed in this report have all been identified as posing a potential high hazard to human health based on classifications by other national or international agencies for either carcinogenicity or developmental toxicity. The list of substances, along with their hazard classifications and categorization decisions, can be found in Tables A.1, A.2 and A.3 of Appendix A.

For two of these substances, a survey was conducted by issuing a Notice with respect to selected substances identified as priority for action pursuant to paragraphs 71(1)(a) and 71(1)(b) of CEPA 1999. The Notice was published in Part I of the Canada Gazette on March 4, 2006 (Canada 2006). The substances surveyed were medroxyprogesterone and oxazepam.

For five substances, a survey was conducted by issuing a Notice with respect to inanimate substances (chemicals) on the Domestic Substances List pursuant to paragraphs 71(1)(a) and 71(1)(b) of CEPA 1999. The Notice was published in Part I of the Canada Gazette on October 3, 2009 (Canada 2009).The five substances surveyed were zalcitabine, warfarin, chloramphenicol, zidovudine and phenobarbital.

In response to both of these notices, there were no reports of activity (import or manufacture) with respect to these seven substances in Canada above the reporting threshold of 100 kg for the specified reporting years. Additional sources of information were also considered to verify the commercial status of these substances in Canada.

For all 23 substances, entry characterization was conducted by searching for information on sources and releases of the substances in relevant databases, particularly to identify potential for exposure of the general population from sources other than pharmaceutical use (Canada [1978]; HSDB 1983– ; Household Products Database 1993– ; LNHPD 2008; DPD 2010; EAFUS 2011; NHPID 2011). Based on notifications submitted under the Cosmetic Regulations to Health Canada, these substances are not used in cosmetic products in Canada (2012 email from the Consumer Product Safety Directorate, Health Canada, to the Existing Substance Risk Assessment Bureau, Health Canada; unreferenced). Information available for all of these substances indicates that their uses are limited to human or veterinary pharmaceuticals and positive controls in research, with the exception of warfarin, which is also used as a rodenticide. This use of warfarin as a rodenticide is regulated by Health Canada under the Pest Control Products Act (Canada 2002).

Two of these substances, phenobarbital and oxazepam, are considered to be controlled drugs and are listed under Schedule IV of the Controlled Drugs and Substances Act. As controlled substances, these two drugs are subject to the requirements of the Controlled Drugs and Substances Act and the Food and Drug Regulations (Canada [1978]). The remaining 21 substances are regulated as prescription drugs through the Prescription Drugs List and are subject to the requirements of those regulations (Health Canada 2014; Canada [1978]). Twenty of these substances are listed in the Drug Product Database as active ingredients in products available in Canada for the treatment of a variety of medical conditions (DPD 2014). The other three substances, mechlorethamine, griseofulvin and zalcitabine, were at one time used as active ingredients in prescription pharmaceuticals in Canada. Currently, however, no pharmaceutical products containing these substances as active ingredients are being sold in Canada, as they have been discontinued by the company (DPD 2014). As they are no longer being sold, the use and potential for exposure of or risk to humans or the environment are not further considered in certain aspects of the exposure and risk characterization below.

No information was found regarding additional uses or releases of these substances in Canada based on searches conducted up to March 2013.

When a pharmaceutical is prescribed for use, some of the drug may not be absorbed or metabolized, and even drugs that are metabolized may have active metabolites or may revert to the parent form in environmental media. This may lead to excretion of active drug residues into the wastewater system and release of the wastewater effluent containing these residues into surface water (i.e., lakes, rivers), and this surface water has the potential to be used as drinking water. Therefore, the potential for indirect exposure of the general population to these pharmaceuticals was assessed. Given their potential releases, the main source of indirect exposure to these substances is through water. These pharmaceuticals may be present in water as a result of release from manufacturing or formulation sites and/or release of the substances in feces or urine from consumers directly using these substances. An additional source of the pharmaceuticals in water is from the incorrect disposal of unused drugs into household wastewater. No information was available regarding actual releases of these substances from manufacturing or formulation of the pharmaceuticals. Data, however, were available to estimate the amount of each substance sold to hospitals and pharmacies for prescription across Canada for the years 2007 (McLaughlin and Belknap 2008), 2011 and 2012 (MIDAS 2013) (Appendix B).

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A conservative industrial release scenario was used to determine whether there is a potential ecological risk associated with these 20 substances when released to water via industrial releases (as mentioned above, the three substances no longer registered for use as pharmaceuticals in Canada are not being examined further). This is conducted by comparing the conservative predicted environmental concentration (PEC) in the aquatic environment with a predicted no-effect concentration (PNEC). The result is a risk quotient (RQ) based on an industrial non-site-specific scenario. This simple model represents a point source discharge from an industry, its dilution in a small watercourse and calculation of a risk quotient for that scenario.

A conservative PEC was calculated using the following equation:

PEC_aq = (1000×Q×L)×(1 − R) / (N×F×D)

where:

PEC _aq:

Aquatic concentration resulting from industrial releases (mg/L)

1000:

Conversion factor (g/kg)

Q:

Total substance quantity produced annually at an industrial site (kg/year) (see values for each substance for the most current year, 2012, provided in Appendix B)

L:

Loss to wastewater (fraction) (assumed to be 0.5% of total use for pharmaceuticals)

R:

Wastewater treatment plant removal rate (fraction) (default = 0%)

N:

Number of annual release days (days/year) (assumed to be manufactured in small batches and therefore released 21 days/year)

F:

Wastewater treatment plant effluent flow (m ³/day) (default = 3456 m ³/day)

D:

Receiving water dilution factor (dimensionless) (default = 10)

This PEC_aq value is then used to calculate a risk quotient, as shown in the following equation:

RQ = PEC_aq / (PNEC)

where:

RQ:

Risk quotient (dimensionless)

PEC _aq:

Aquatic concentration resulting from industrial releases (mg/L)

PNEC:

Predicted no-effect concentration (mg/L). The PNECs selected for this assessment were the values identified during the categorization process and are provided in Appendix C; an assessment factor of 100 was used to account for uncertainties in deriving the PNEC.

For two of the substances, daunorubicin and oxazepam, the industrial scenario was further refined to simulate an industrial production site in a large urban area with a wastewater treatment plant flow rate of 285120 m³/day and wastewater treatment plant removal rates ranging from 1.9% to 2.5%.

The calculated RQs for all substances were less than 1 (see full results in Appendix C). Given that the industrial scenario provides a conservative estimate of exposure, these results indicate a low potential for ecological harm to the aquatic environment resulting from local exposure from a point source industrial release.

A down-the-drain release from pharmaceutical use scenario was employed to estimate the potential concentrations in multiple water bodies receiving wastewater treatment plant effluents to which pharmaceutical products containing the substances may have been released based on conservative assumptions regarding the amount of chemical used and released by consumers (Environment Canada 2008b). By default, primary and secondary wastewater treatment plant removal rates are assumed to be 0% for these substances, the fraction released during use is assumed to be 100%, the consumer use of the substance is assumed to occur over 365 days/year and the flow rate used for receiving water bodies at all sites is assumed to be the 10^thpercentile value. These estimates are made for approximately 1000 release sites, which account for most of the major wastewater treatment plants across Canada. Although the default values are recognized to be highly conservative, if indication of risk is low based on these assumptions, further refinement of input values is not required at this time.

In light of uncertainty relating to the identity and environmental stability of the metabolites of these substances, a conservative environmental concentration value was obtained by not considering human metabolism in the derivation of the PECs. RQs were calculated using maximum PECs calculated from down-the-drain releases of these substances from pharmaceutical use and PNECs as identified during the categorization process, derived using an application factor of 100 to account for uncertainties associated with the values. The maximum RQ was less than 1 for all of these substances (see full results in Appendix C), indicating a low potential for ecological harm to the aquatic environment resulting from down-the-drain releases from consumer uses.

Measured data for some of these substances were identified for Canada and/or elsewhere in the world and are shown in Appendix D. Concentrations measured in various media, wastewater effluent, surface water, groundwater and drinking water (including bottled water) were examined, and the information available is consistent with the predicted concentrations from the models. The majority of studies did not detect these substances in the media of interest; however, some were measured at concentrations up to 564 ng/L in wastewater effluent. A comparison of the measured values with the PNECs determined for these substances results in RQs that are all less than 1, contributing to the weight of evidence indicating that there is no significant potential for ecological harm to the aquatic environment from these substances.

Given the lack of exposure to these substances, no further collection or analysis of information relevant to the persistence, bioaccumulation and inherent toxicity to non-human organisms of these substances has been conducted beyond what was done for categorization. Therefore, the decisions made on the hazard properties during categorization remain unchanged in this assessment. Accordingly, none of the substances are considered to meet the criteria for persistence or for bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999 (Canada 2000).

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Drugs containing these substances as ingredients were previously assessed under the Food and Drugs Act (Canada 1985) with respect to their safety, effectiveness and quality. This assessment focused on uses and exposures that were not covered as part of the F&DA assessment, specifically the risks posed by the residues resulting from manufacture, formulation and disposal after use

Only a portion of pharmaceuticals used would be released into the wastewater system. Drug residues released following prescribed use can be further reduced as a result of wastewater treatment, environmental biodegradation and/or drinking water treatment prior to consumption. The concentration in the water source is also significantly reduced via dilution, as the waste is released into waterways.

Measured data for 18 of these substances were identified for Canada and elsewhere and are shown in Appendix D. Concentrations measured in wastewater effluent, surface water, groundwater and drinking water (including bottled water) were examined. Overall, the studies indicated that the concentration of pharmaceutical measured decreases significantly as the substance moves from the wastewater treatment plant effluent into surface water and then the surface water is treated for drinking water purposes. As there is variability in the use of pharmaceuticals in different countries (due to different population levels, prescription preferences, drug registrations, etc.), the measured concentrations in other countries are not necessarily representative of concentrations in Canadian waters. They can, however, account for releases from all potential sources and for potential reductions in drug concentrations resulting from metabolism, environmental degradation, removal via wastewater treatment, removal via drinking water treatment, etc., depending on the source of the sample. For these reasons, in this case, the measured concentrations are preferable to modelled concentrations, even if measurements were made in other countries. Selection of the most relevant data was based on location of the sampling and the relevance of the media to human exposure. Canadian data were given preference over data from other countries, as they are considered to be most representative of potential exposures of Canadians. Drinking water was considered the most relevant medium, followed by surface water or groundwater, wastewater treatment plant effluent and hospital effluent. If multiple relevant concentrations were available for a particular source (e.g., two measurements in Canadian drinking water), as a conservative approach, the maximum concentration was selected from the measured values identified.

For the two substances for which no measured data were identified, conservative assumptions were used when estimating the potential indirect exposure of the general population. For the purposes of modelling, it was assumed for all substances that 100% of the pharmaceutical purchased by hospitals or pharmacies in the most recent year for which data were available (2012) was dispensed, used as prescribed and eventually released into the wastewater system. It was also assumed that none of the pharmaceutical was removed through wastewater treatment or drinking water treatment processes and that there was no environmental degradation of the substance. It is recognized that these assumptions are highly conservative; however, if indication of risk is low based on these assumptions, further refinement would not be required.

Down-the-drain releases to surface water were modelled using the down-the-drain releases from pharmaceutical use scenario, as described in the ecological exposure section, and maximum PECs can be found in Appendix C. This scenario estimates concentrations in approximately 1000 waterways across Canada. The highest values estimated by this model are typically in small waterways with low dilution capacity, which are unlikely sources of drinking water. As a result, this scenario would be expected to overestimate actual concentrations in drinking water.

The estimated upper-bounding intakes of these pharmaceuticals by the general population were represented by formula-fed infants 0–6 months of age, which is estimated to be the most highly exposed age class, on a body weight basis, of those examined. The equation for deriving the estimated intake is given below:

Intake = (PEC_aq ×IR) / bw

where:

Intake:

Estimated intake of the substance from drinking water (mg/kg bw per day)

PEC _aq:

Predicted environmental concentration in receiving water from modelled or measured data (mg/L)

IR:

Ingestion rate of drinking water for formula-fed infants: 0.8 L/day (Health Canada 1998)

bw:

Default body weight for infants 0–6 months of age: 7.5 kg (Health Canada 1998)

The estimated intakes for 18 substances with measured concentrations are presented in Appendix E, and intakes for 2 substances with only modelled concentrations are presented in Appendix F.

Estimated intakes for all substances were low and range from 1.6×10⁻⁷ to 2.7 ng/kg bw per day. Since the majority of the measurements were based on wastewater treatment plant effluent or surface water, it is expected that these estimates provide conservative upper-bounding estimates of possible exposure and that actual exposures would be significantly lower.

Based on low exposure, risks from exposure to these substances are not expected. This determination is further supported by consideration of two additional lines of evidence for evaluation of the potential for harm to human health.

A comparison was made between the range of estimated intake values for this group of 20 substances and the threshold of toxicological concern (TTC) value of 2.5 ng/kg bw per day originally proposed by Kroes et al. (2004). For all 20 substances, estimated intakes are in the range of or below the TTC. Although the TTC may not be applicable to every member of this group, it does provide a reference point against which the range of estimated intakes can be compared. TTC values, which are derived using probabilistic approaches, establish generic human exposure threshold values below which it is expected that the probability of adverse effects is low. A TTC value of 0.15 µg/day (equivalent to 2.5 ng/kg bw per day) has been established for potentially carcinogenic substances with structural alerts for genotoxicity. Additional higher TTC values have been established for substances not containing similar structural alerts (Munro et al. 1996a, b; Kroes et al. 2004; EFSA 2012; Dewhurst and Renwick 2013).

A second comparison was also made to evaluate potential risk. The lowest therapeutic dose (LTD) for each substance was identified, and a margin of exposure (MOE) was calculated to determine the ratio between the upper-bounding estimate of intake by the general population and the dose that would be expected to produce a pharmacological effect. This approach is consistent with methodology described elsewhere (Webb et al. 2003; Schwab et al. 2005; Watts et al. 2007; Bull et al. 2011; WHO 2011). The LTD is the lowest concentration that evokes a desired therapeutic effect among target populations and is equivalent to the lowest dose prescribed or recommended, taking into account the number of doses per day (WHO 2011). These values are derived from an assessment of the balance between safety and efficacy. LTDs were identified for each pharmaceutical by examining the dosage and administration guidelines presented in the product monographs submitted to Health Canada as part of the pre-market drug authorization, which are available from the Health Canada Drug Product Database (DPD 2010).

MOEs were derived using the equation below and are presented in Appendix E or F:

MOE = LTD/Intake

where:

MOE:

Margin of exposure (dimensionless)

LTD:

Lowest therapeutic dose (mg/kg bw per day)

Intake:

Maximum estimated intake for drinking water derived from modelled or measured concentrations (mg/kg bw per day)

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There is uncertainty regarding the estimation of exposure due to the lack of data on concentrations in Canadian surface water or drinking water for many of these substances. However, confidence is high that actual exposures would be lower than the ones presented from the measured data and models used. The uncertainty in both the environmental and human health risk estimates could be reduced by using measured concentration data from Canadian surface water and/or drinking water for these substances. However, it is unlikely that potential exposures were underestimated.

Potential general population exposures to these substances could occur via other sources, such as ingestion of fish or swimming in waters where the pharmaceuticals are present, but these exposures are expected to be much less than the exposure through drinking water and so are not considered in this assessment.

Some of these substances may have additional off-label or veterinary uses that are not considered in this assessment. The quantities of the substances being used for these purposes are unknown, and so estimation of releases is not possible at this time. For the substances which have measured environmental concentrations these releases may be reflected in those measurements,

It is recognized that the LTD represents an exposure level at which a desired pharmacological response is achieved and further that at this exposure level, adverse effects, in addition to intended effects, may occur in some patients. For certain indications and certain classes of drugs, the nature of these unintended effects may be significant. However, the LTD is developed for patients who require treatment for a particular illness and therefore are likely to be more susceptible to potential effects than a healthy individual. Although the use of the LTD provides a tier 1 type of assessment that does not utilize all the toxicity data that may be available for each substance, the highly conservative exposure defaults that have been used lead to significant MOEs between the LTD and the estimated intakes.

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Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms and the broader integrity of the environment from these 23 substances. It is concluded that these 23 substances do not meet the criteria under paragraphs 64(a) or (b) of CEPA 1999 as they are 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.

Based on the information presented in this screening assessment, it is concluded that these 23 substances do not meet the criteria under paragraph 64(c) of CEPA 1999 as they are not 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 concluded that these 23 substances do not meet any of the criteria set out in section 64 of CEPA 1999.

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