Screening Assessment for the Challenge

2-Pyrrolidinone, 1-ethenyl-
(1-Vinyl-2-pyrrolidone)

Chemical Abstracts Service Registry Number
88-12-0

Environment Canada
Health Canada

September 2010

(PDF Version - 407 KB)

Table of Contents

• Synopsis
• Introduction
• Substance Identity
• Physical and Chemical Properties
• Sources
• Uses
• Releases to the Environment
• Environmental Fate
• Persistence and Bioaccumulation Potential
• Potential to Cause Ecological Harm
• Potential to Cause Harm to Human Health
• Conclusion
• References
• Appendix 1a: Upper-bounding estimates of daily intake of NVP by the general population in Canada
• Appendix 1b: Upper-bounding estimates of chronic and acute intake of NVP from personal care products
• Appendix 1c: Parameters used to predict exposure to NVP from personal care products
• Appendix 2: Summary of health effects information for NVP

Synopsis

The Ministers of the Environment and of Health have conducted a screening assessment of 2-pyrrolidinone, 1-ethenyl- (1-vinyl-2-pyrrolidone, abbreviated as NVP), Chemical Abstracts Service Registry Number 88-12-0. This substance was identified as a high priority for screening assessment and included in the Challenge. NVP was identified as a high priority as it was classified by the European Commission on the basis of carcinogenicity. The substance did not meet the ecological categorization criteria for persistence, bioaccumulation potential or inherent toxicity to aquatic organisms. Therefore, the focus of this assessment of NVP relates primarily to human health risks.

According to information submitted under section 71 of theCanadian Environmental Protection Act, 1999 (CEPA 1999), NVP was not manufactured above the 100 kg reporting threshold by any company in Canada .n the calendar year 2006. However, approximately 10 000–100 000 kg of the substance was imported in 2006. The major use of NVP is in the industrial manufacturing of NVP-derived polymers, which are used in the personal care products industry. The polymers function as thickeners, dispersing agents and binders in cosmetics and as stiffeners in hair grooming products. Polymerized NVP has many uses in the pharmaceutical industry. It is used as a binding agent for tablets and in film coatings of capsules to aid ingestion. NVP-derived polymers function as stabilizers for enzymes and heat-sensitive drugs as well as crystallization inhibitors in liquid medications. Industrial uses of NVP include the manufacturing of ultraviolet curable inks and coatings. NVP is used as a formulant in 11 pesticides registered for commercial use in Canada .

The principal source of exposure of the general population in Canada .s thought to be through personal care products (cosmetics). Chronic exposure to NVP from pharmaceuticals is lower than exposure from personal care products.

As NVP was classified on the basis of carcinogenicity by other national and international agencies, carcinogenicity was a key focus for this screening assessment. In a chronic/carcinogenicity study, rats exposed to NVP by inhalation showed dose-related increased incidences of hepatocellular carcinomas and nasal cavity adenomas and adenocarcinomas as well as increased incidences of squamous carcinomas of the larynx at the highest dose tested. Neoplastic changes were also seen in female rats exposed to NVP by inhalation for 3 months followed by 21 months of recovery. However, no long-term study investigating exposure to NVP in other species or via the oral or dermal route of exposure was identified. Consideration of the available information regarding genotoxicity and the conclusions of other agencies indicates that NVP is not likely to be mutagenic. Accordingly, a threshold approach is used to assess risk to human health.

Non-neoplastic effects based on inhalation exposure in repeated-dose studies were observed at the same critical effect level as the neoplastic effects, and the liver and respiratory tract of rats and mice were identified as the target organs. The margins between upper-bounding estimates of exposure from acute and chronic exposure to personal care products and the critical effect level are considered to be adequately protective to account for data gaps and uncertainties in the human health assessment for both cancer and non-cancer effects.

Based on the available information on the potential to cause harm to human health and the resulting margins of exposure, it is concluded that NVP is a substance that is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada .o human life or health.

On the basis of its low ecological hazard and reported releases of NVP to the environment, it is concluded that the 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. NVP does not meet the criteria for persistence or bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999.

Based on the information available, it is concluded that NVP does not meet any of the criteria set out in section 64 of CEPA 1999.

This substance will be considered for inclusion in the DSL inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

Introduction

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 to human health.

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 inherent toxicity to aquatic organisms (iT), and were believed to be in commerce 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 theCanada Gazette, Part I, on December 9, 2006 (Canada 2006), which 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-ethenyl-2-pyrrolidinone (1-vinyl-2-pyrrolidone, abbreviated as NVP) was identified as a high priority for assessment of human health risk because it was considered to present IPE and had been classified by other agencies on the basis of carcinogenicity. The Challenge for this substance was published in the Canada Gazette on March 14, 2009 (Canada 2009). 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 pertaining to the substance were received.

Although NVP was determined to be a high priority for assessment with respect to human health, it did not meet the ecological criteria for persistence, bioaccumulation potential or inherent toxicity to aquatic organisms.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of CEPA 1999. Screening assessments examine scientific information and develop conclusions by incorporating a weight of evidence approach and precaution^Footnote 1.

This final 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 and stakeholder research reports and from recent literature searches, up to July 2009 for the human health and ecological sections of the document. 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 (non-occupational) exposure of the general population, as well as information on health hazards (based principally on the weight of evidence 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 final 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 conclusion is based.

This final screening assessment was prepared by staff in the existing substances programs at Health Canada .nd Environment Canada and incorporates input from other programs within these departments. The ecological and human health portions of this assessment have undergone external written peer review/consultation. Comments on the technical portions relevant to human health were received from Dr. Bernard Gadagbui, Toxicology Excellence for Risk Assessment; Dr. Michael Jayjock, The LifeLine Group; and Dr. Bob Benson, US Environmental Protection Agency.

Additionally, the draft of this screening assessment was subject to a 60-day public comment period. 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. Approaches used in the screening assessments under the Challenge have been reviewed by an independent Challenge Advisory Panel.

The critical information and considerations upon which the final assessment is based are summarized below.

Substance Identity

For the purposes of this document, this substance will be referred to as 1-vinyl-2-pyrrolidone (NVP), based on the European Inventory of Existing Commercial Chemical Substances name and as listed on the Domestic Substances List (DSL). NVP is a monomer and therefore may be present at residual levels when polymerized to polyvinyl pyrrolidone (PVP or povidone) or other NVP-derived polymers. Information on the identity of the monomer, NVP, is summarized in Table 1.

Table 1. Substance identity

CAS RN	88-12-0
DSL name	2-Pyrrolidone, 1-vinyl-
NCI names	1-Ethenyl-2-pyrrolidinone (ECL) 2-Pyrrolidinone, 1-ethenyl (PICCS) 2-Pyrrolidinone, 1-ethenyl- (AICS, ASIA-PAC, NZIoC, PICCS, SWISS, TSCA) Pyrrolid-2-one, 1-vinyl- (PICCS) N-Vinyl-2-pyrrolidine (PICCS) N-Vinyl-2-pyrrolidon (SWISS) 1-Vinyl-2-pyrrolidone (EINECS) N-Vinyl-2-pyrrolidone (ENCS) Vinylpyrrolidone (PICCS)
Other names	Aronix M 150 NSC 10222 NSC 683040 N-V 2RC N-VP NVP 300 V-Pyrol V-Pyrol RC 1-Vinyl-2-pyrrolidinone N-Vinyl-2-pyrrolidinon. Vinylbutyrolactam N-Vinylpyrrolin-2-on.
Chemical group (DSL stream)	Discrete organics
Major chemical class or use	Aliphatic amines; tertiary amines
Major chemical subclass	Not available
Chemical formula	C6H9NO
Chemical structure
SMILES	O=C(N(C=C)CC1)C1
Molecular mass	111.14 g/mol

Physical and Chemical Properties

A summary of key physical and chemical properties of NVP that are relevant to its environmental fate is presented in Table 2.

Sources

NVP is not known to occur as a natural product. NVP is a monomer used alone or in combination with other monomers to produce a number of polymers (EURAR 2003).

Global production of NVP has been identified in Germany and the United States (Chemical Information Services 1995; NICNAS 2000; EURAR 2003).

NVP was not manufactured in Canada .n 2006 above the reporting threshold of 100 kg (Environment Canada 2009a). However, the reported aggregate quantity of NVP imported into Canada .n 2006 was 10 000–100 000 kg, based on data submitted under section 71 of CEPA 1999 (Environment Canada 2009a).

International trade data from Statistics Canada (CIMT 2009) reveal that NVP importation into Canada .as been in decline since 1988, when 228 445 kg was imported. From 1995 to 2006, the average amount of NVP imported into Canada .as 23 449 kg annually (CIMT 2009). However, NVP may be entering Canada .n the form of a residual monomer or co-monomer in formulated consumer products that may not be captured in section 71 submissions or international trade data from Statistics Canada.

Uses

NVP is used for the industrial synthesis of the homopolymer, polyvinyl pyrrolidone (PVP), or with other monomers to produce copolymers for use in formulations of industrial or consumer products. There are no direct consumer end use products containing NVP itself, but NVP may be found in consumer products as a residual monomer from the polymerization process (NICNAS 2000; EURAR 2003).

Major global uses of NVP include its use in formulants for personal care products (PCPs), pharmaceuticals, ultraviolet (UV) curable printing inks and UV stain topcoats (Moore 1983; ECB 2000; NICNAS 2000; Kricheldorf et al. 2005; HSDB 2009).

Internationally, PVP and its copolymers are widely used in the personal care products industry (Moore 1983; Gmahl and Ruess 1993; Hössel et al. 2000; EURAR 2003). PVP functions as a thickener, dispersing agent and binder in cosmetics and as a stiffener in hair grooming products (EURAR 2003). In Canada . PVP and its copolymers are reported in formulations of more than 1500 PCPs, of which 85% are composed of hair care products (2009 personal communication from Risk Management Bureau, Health Canada . to Risk Assessment Bureau, Health Canada . unreferenced).

PVP has a wide range of applications in the pharmaceutical industry. The polymer becomes sticky when wetted and is used as a binder for tablets. It is also used in film coatings to aid oral ingestion of tablets, vitamins and minerals, and it functions as a stabilizer for enzymes and heat-sensitive drugs as well as a crystallization inhibitor in liquid medicines (EURAR 2003).

in Canada . PVP is listed in the Health Canada Drug Product Database (DPD) as a non-medicinal ingredient present in final pharmaceutical products (DPD 2009). Although NVP does not appear in the DPD, it may be present in pharmaceutical products as an impurity (2009 personal communication from Therapeutic Products Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced). PVP has similar use in veterinary drugs available in Canada .2009 personal communication from Veterinary Drugs Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced).

PVP is listed in the Natural Health Products Ingredients Database (NHPID) as an acceptable non-medicinal ingredient in natural health products, with an acceptable daily intake of 50.0 mg/kg body weight (kg-bw) (adopted from FAO/WHO 1986) (NHPID 2009). PVP is listed in the Licensed Natural Health Products Database (LNHPD); thus, it is used in current licensed natural health products available in Canada .LNHPD 2009). Therefore, NVP may be present in licensed natural health products at residual levels (2009 personal communication from Natural Health Products Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced).

in Canada .nd elsewhere, NVP is used as a reactive diluent in UV curable inks and coatings (BASF 1997; Environment Canada 2009a). Global demand for NVP for use in UV curable products has been in decline (Henriks-Eckerman and Kanerva 1997; NICNAS 2000; EURAR 2003), which may account for the significant decrease in NVP importation into Canada .ver the past 20 years. in Canada . it was reported that 78% of NVP was used in the formulation of UV stains, whereas 21% was utilized in the manufacturing of UV curable inks (Environment Canada 2009a). In response to a section 71 notice, UV curable stain and ink products were identified as industrial products that were not intended for sale to the general public (Environment Canada 2009a).

In Europe, PVP may have limited use in the brewing industry as a clarifier in processing bottled or canned beer and wine (EURAR 2003; Kricheldorf et al. 2005). In Canada . there are two known uses of PVP in food product packaging (2009 personal communication from Food Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced).

In Canada, NVP was also identified as an unintended residual in the manufacturing of polyurethane spray foam insulation (Environment Canada 2009a) and as a formulant in 11 commercial pesticides with food uses at a maximum concentration of 50 ppm (2009 personal communication from Pest Management Regulatory Agency, Health Canada, to Risk Assessment Bureau, Health Canada; unreferenced).

As NVP is on the Ingredient Disclosure List (concentration, 1% by weight) of the Hazardous Products Act (Canada 1988), there may be a number of products containing residual levels of NVP that have not been identified as being in commerce in Canada.

Products identified elsewhere, but not confirmed in Canada . include gas-permeable contact lenses (Bohnert et al. 1988; Garrett and Milthorpe 1996; Cai and Gupta 2005), powders for clothes washing, adhesive glue sticks, denture fixatives to anchor false teeth and wettable gums for postage stamps and envelopes (EURAR 2003).

Historically, PVP was used as a blood plasma substitute, but this use is no longer apparent (Wood 1970; Lorenz 1971; Kricheldorf et al. 2005), although PVP continues to be used as an ingredient in cryo-protectants for organ transplantation (O’Neil et al. 2001). A copolymer composed of NVP and polymethacrylates has a historical use as a viscosity improver in automobile crankcase oils; however, this application was identified as being very limited and not considered in the risk characterization of NVP by the European Union (EURAR 2003). Recent information to support the risk characterization for this application was not found during the preparation of this assessment.

Releases to the Environment

In response to a notice issued under section 71 of CEPA 1999, one release of less than 100 kg of NVP to the atmosphere was reported in the 2006 calendar year (Environment Canada 2009a). In the same calendar year, it was reported that less than 100 kg of NVP was transferred to hazardous waste facilities (Environment Canada 2009a). NVP does not appear on either the National Pollutant Release Inventory substance list (NPRI 2006) or the US Toxics Release Inventory Program list of reportable substances (TRI 2009).

Environmental Fate

Based on its physical and chemical properties (see Table 2 above), the results of Level III fugacity modelling (Table 3) suggest that NVP will reside predominantly in water or soil, depending on the compartment of release.

Persistence and Bioaccumulation Potential

Environmental Persistence

Table 4a presents empirical biodegradation data for NVP. In one study by BASF (1979a), 100% biodegradation of NVP was observed over 14 days using the Zahn-Wellens test. In another study (BASF 1995), the biodegradability in active sludge from laboratory sewage plants was measured using the reduction in dissolved organic carbon (DOC), as described in Organisation for Economic Co-operation and Development (OECD) Guideline 301 A (BASF 1995) for ready biodegradability. The substance was found to be readily biodegradable, with >70% degraded within 10 days and 100% decomposed after 28 days. These tests indicate that the ultimate degradation half-life in water is likely to be much shorter than 182 days (6 months) and that the substance is therefore likely to not persist in that environmental compartment.

Since few experimental data on the degradation of NVP are available, a quantitative structure–activity relationship (QSAR)–based weight of evidence approach (Environment Canada 2007) was also applied using the degradation models shown in Table 4b. Given the ecological importance of the water compartment, the fact that most of the available models apply to water and the fact that NVP is expected to be released to this compartment, primarily biodegradation in water was examined. NVP does not contain functional groups expected to undergo hydrolysis (no results were generated from HYDROWIN (2008). Table 4b summarizes the results of available QSAR models for degradation in water and air..

In air, a predicted atmospheric oxidation half-life of 0.29 day (see Table 4b) demonstrates that this substance is likely to be rapidly oxidized. The substance is expected to react with other photo-oxidative species in the atmosphere, such as ozone, but at a much slower rate. It is unlikely to degrade via direct photolysis. Therefore, it is expected that reactions with hydroxyl radicals will be the most important fate process in the atmosphere for NVP. With an estimated half-life of 0.29 day via reactions with hydroxyl radicals, NVP is considered not to be persistent in air.

In water, a predicted hydrolysis half-life for NVP could not be calculated by EPIsuite, as no hydrolysable groups are present. Other fate processes in water therefore need to be considered to determine the persistence in this medium.

There are conflicting model results for biodegradation. All BIOWIN (2008) primary and ultimate biodegradation models suggest that biodegradation may be fast and that the half-life in water would be <182 days, whereas the predictions for TOPKAT (2004) and CATABOL (©2004–2008) suggest a half-life of ≥ 182 days. The predictions for CATABOL (©2004–2008) and TOPKAT (2004) are in the domains of both models, and both are in principle considered reliable. CATABOL (©2004–2008) is close to the threshold and suggests a slow rate of biodegradation (a result of <20% suggests relatively low ultimate biodegradation potential), and TOPKAT (2004) indicates that biodegradation may be very slow or non-existent (≤ 0.3 suggests low ultimate biodegradation potential.

Although the model results are conflicting, both empirical results indicate that NVP degrades rapidly in water (Table 4a). Considering the empirical data, although highly variable are the most reliable, and taking into consideration the fact that the substance has structural features that are associated with chemicals that are easily biodegraded. i.e., amides, cyclic chemicals consisting only of carbon, oxygen, nitrogen and hydrogen), it is concluded that the biodegradation half-life of NVP is likely to be no more than a few weeks, and certainly much less than 182 days, in water.

Using an extrapolation ratio of 1:1:4 for water:soil:sediment biodegradation half-lives (Boethling et al. 1995), the half-life in soil is also <182 days and the half-life in sediments is <365 days. This indicates that NVP is not expected to be persistent in soil or sediment.

Based on the empirical and modelled data (see Tables 4a and 4b), NVP does not meet the persistence criteria for air, water, soil or sediment (half-life in air ≥ 2 days, half-lives in soil and water ≥ 182 days and half-life in sediment ≥ 365 days) as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999 (Canada 2000).

Potential for Bioaccumulation

Experimental and modelled octanol–water partition coefficients (log K_ow values) for NVP suggest that this chemical has low potential to bioaccumulate in biota (see Table 2).

Since no experimental bioaccumulation factor (BAF) or bioconcentration factor (BCF) data for NVP were available, a predictive approach was applied using available BAF and BCF models, as shown in Table 5. The results of these models are expected to be reliable, as this substance is within the domains of their training sets.

According to the Persistence and Bioaccumulation Regulations (Canada 2000), a substance is bioaccumulative if its BCF or BAF ≥ 5000; however, measures of BAF are the preferred metric for assessing the bioaccumulation potential of substances. This is because BCF may not adequately account for the bioaccumulation potential of substances via the diet, which predominates for substances with log K_ow >~4.0 (Arnot and Gobas 2003). Kinetic mass balance modelling is in principle considered to be the most reliable prediction method for determining the bioaccumulation potential, because it can allow for competing rates of uptake and elimination, such as metabolic biotransformation.

Metabolic biotransformation information for this substance was not available, nor was it necessary to consider it in the Arnot and Gobas (2003) BAF and BCF models, because, based on the log K_ow of 0.40, gill elimination is expected to be a much greater loss process than biotransformation for the bioaccumulation of NVP in aquatic organisms.

The available evidence (Table 5) suggests that NVP will have low bioaccumulation potential due to its physical and chemical properties (i.e., very high water solubility and low log K_ow). The Arnot and Gobas (2003) BAF middle trophic level model for fish predicted a BAF of 1.03 L/kg, indicating that NVP does not have the potential to bioaccumulate in fish and biomagnify in food webs. The results of BCF model calculations provide additional evidence to support the low bioconcentration potential of this substance. Based on the available empirical log K_ow and kinetic-based bioaccumulation model values, NVP does not meet the bioaccumulation criteria (BAF or BCF ≥ 5000) as set out in the Persistence and Bioaccumulation Regulations(Canada 2000).

Potential to Cause Ecological Harm

The approach taken in this assessment was to examine the available scientific information and develop conclusions based on a weight of evidence approach and using precaution as required under CEPA 1999. Lines of evidence considered include results from a conservative risk quotient calculation as well as information on the persistence, bioaccumulation, toxicity, sources and fate of the substance.

As described previously, NVP is not expected to be persistent in air, water, soil or sediment. It is also expected to have a low bioaccumulation potential. However, the importation volumes of NVP into Canada . along with information on its uses, indicate potential for widespread release into the Canadian environment. Experimental and modelled effects data are summarized in Tables 6a and 6b, respectively.

Empirical acute ecotoxicity studies are available for fish,Daphnia, and algae, the results are from unpublished studies documented in the European Union risk assessment report (EURAR 2003; see Table 6a). Ecotoxicity values reported were 45 mg/L for a 48-hour Daphnia immobilization study and 913 mg/L for a 96-hour LC₅₀ and 976 mg/L for a 72-hour LC₅₀ for Oncorhynchus mykiss. The effect of NVP on reproduction and growth rate for Scenedesmus subspicatus was investigated, and the 72- to 96-hour EC₅₀s for inhibition of reproduction and inhibition of growth rate were 770 mg/L and >1000 mg/L, respectively. EC₁₀ values for Scenedesmus subspicatus, which correspond to No-Observed-Effect Concentrations (NOEC), range from 115 to 125 mg/L for 72 and 96 hours, respectively, and indicate that algae are likely not sensitive to NVP

Modelled results for acute effects for fish, daphnids and algae (Table 6a) are consistent with empirical results, although one of two models appear to overestimate toxicity to green algae (EC₅₀ = 0.75 mg/L) (ECOSAR 2008). Chronic modelled values indicate a higher toxicity than the acute modelled results and are suspect.

The experimental toxicity values are considered to indicate a low to moderate level of acute toxicity; thus, NVP is generally not expected to cause acute harm to aquatic organisms at low concentrations (<1 mg/L). However, some model results (excluding ECOSAR estimates in algae) suggest the possibility of chronic effects at relatively low exposure concentrations. These data suggest that NVP has the potential to be moderately to highly hazardous to more sensitive aquatic organisms exposed for long periods of time.

A conservative predicted no-effect concentration (PNEC) was derived from the lowest empirical toxicity value identified: an acute EC₅₀ for Daphnia magna of 45 mg/L. This value was selected as the critical toxicity value and divided by an assessment factor of 100 to account for uncertainties related to interspecies and intraspecies variabilities in sensitivity, and extrapolation from a laboratory EC₅₀ to a no-effect value in the field. This calculation resulted in a conservative PNEC of 0.45 mg/L.

No ecological effects studies were found for this compound in media other than water.

A – Industrial Release

The aquatic exposure of NVP is expected if the substance is released from industrial use to a wastewater treatment plant and the treatment plant discharges its effluent to a receiving water body. The concentration of the substance in the receiving water near the discharge point of the wastewater treatment plant is used as the predicted environmental concentration (PEC) in evaluating the aquatic risk of the substance. It can be calculated using the equation

C_water-ind = [1000 × Q × L × (1 - R)] / [N × F × D]

where

C_water-ind: aquatic concentration resulting from industrial releases, mg/L
Q: total substance quantity used annually at an industrial site, kg/yr
L: loss to wastewater, fraction
R: wastewater treatment plant removal rate, fraction
N: number of annual release days, d/yr
F: wastewater treatment plant effluent flow, m³/d
D: receiving water dilution factor, dimensionless

A site-specific exposure analysis was conducted for the aquatic compartment at a total of three sites where NVP was used in high quantities. The quantity of the substance used at each site (Q) was in the range of 10 000 to 100 000 kg/yr. The fraction lost to wastewater (L) from the facility at each site was conservatively estimated at 5% resulting from the cleaning of chemical containers and process treatment. It was also conservatively assumed that there was no on-site wastewater treatment. The wastewater containing the substance was further assumed to be released to sewer and subsequently treated by the local sewage treatment plant (STP). The STP at each site was identified as a secondary system and its removal rate was predicted as 62% (R) by a computer model ASTreat system (ASTreat 2006). For the three sites, the STP effluent flow was found in the range of 10 000 to 400 000 m³/d (F) and the receiving water dilution factor was estimated as 10(D). Finally, the release was assumed to occur 250 days per year (N) which is typical for small and medium-sized facilities. Based on the above assumptions and site-specific data, the predicted environmental concentrations ( PECs) estimated for the three sites are in the range of 0.0003 to 0.03 mg/L (Environment Canada 2010). These PEC values represent the level of exposure in the receiving water near the point of the discharge from the municipal sewage treatment plant at each site.

B – Consumer Products Release

As NVP is found in consumer products and can be released to water, Mega Flush, Environment Canada’s spreadsheet tool was employed to estimate the substance concentration in multiple water bodies receiving sewage treatment plant effluents to which consumer products containing the substance may have been released (Environment Canada 2009c). The spreadsheet tool provides these estimates for approximately 1000 release sites across Canada .ased on realistic assumptions.

The equation and inputs used in this scenario are described in Environment Canada (2009d).The maximum PEC of 0.15 mg/L was derived based on a conservative scenario. This conservative scenario assumes that the total release across the about 1000 sites from consumer products is at the maximum quantity of 100 000 kg/yr imported in Canada and the STP removal rate is zero. In addition, standard input values such as the 10^th percentile flow for watercourses and 365 days/yr for release frequency were used in the estimation.

Characterization of Ecological Risk

The approach taken in this ecological screening assessment was to examine the supporting information and develop conclusions based on a weight-of-evidence approach and using precaution as required under CEPA 1999. Lines of evidence considered include results from a conservative risk quotient calculation, as well as information on persistence, bioaccumulation, toxicity, sources and fate of the substance.

Based on the available empirical log K_ow and kinetic-based bioaccumulation model values, NVP does not meet the bioaccumulation criteria (BAF or BCF ≥ 5000) as set out in thePersistence and Bioaccumulation Regulations(Canada 2000).

Based on the empirical and modelled data (see Tables 4a and 4b), NVP does not meet the persistence criteria for air, water, soil or sediment (half-life in air ≥ 2 days, half-lives in soil and water ≥ 182 days and half-life in sediment ≥ 365 days) as set out in the Persistence and Bioaccumulation Regulations of CEPA 1999 (Canada 2000).

A risk quotient analysis, integrating conservative estimates of exposure with toxicity information, was performed for the aquatic medium to determine whether there is potential for ecological harm in Canada . With PEC in the range of 0.0003 to 0.03 mg/L and PNEC of 0.45 mg/L, the resulting risk quotients (PEC/PNEC) estimated for industrial releases ranged from 0.0007 to 0.07, which indicates that exposure values are unlikely to be high enough to cause harm to aquatic organisms.

For exposure resulting from down-the-drain releases through consumer products, the maximum PEC is 0.15 mg/L under a conservative scenario and the maximum risk quotient (PEC/PNEC) is 0.3. This indicates that down-the-drain consumer and industrial releases of NVP are unlikely to harm aquatic organisms.

Overall, the results of the assessment suggest that NVP does not have the potential to cause ecological harm in Canada . This conclusion was made despite the uncertainties from lack of empirical data on environmental concentrations in Canada . Concentrations in water were modelled based on conservative assumptions.

Although there were empirical data for physical-chemical properties, biodegradation and acute ecological effects of NVP, no chronic experimental effects data were available. Modelled data were also used to supplement and confirm the validity of the experimental data. The application factor of 100 was used, in part, to account for the fact that acute toxicity results are available for three trophic levels. In addition, there was no information on bioaccumulation of NVP. The log K_ow of 0.40 suggests that bioaccumulation is not likely to occur to a significant extent, and the modelled bioaccumulation data available for NVP confirm this.

There is some uncertainty in the estimation of the potential for NVP to cause ecological harm using the industrial release and down-the-drain scenarios; however, the conservative assumptions that are made when using the models are intended to ensure that exposure concentrations are not underestimated.

Potential to Cause Harm to Human Health

Exposure Assessment

Environmental Media and Food

Upper-bounding estimates of NVP intake from environmental media for each age group in the general population of Canada .re presented in Appendix 1a. These upper-bounding estimates of intake range from 2 × 10^-6 µg/kg-bw per day (12–19, 20–59, and 60+ years old) to 5 × 10^-6 µg/kg-bw per day (0.5–4 years old). For all age groups, indoor air, based on NVP levels predicted in ambient air, was estimated to be the major contributor to NVP exposure, albeit at very low levels.

Information on the concentration of NVP in the Canadian environment was not found during the preparation of this report, and less than 100 kg of NVP was released to the environment in 2006 (Environment Canada .009a). Therefore, NVP concentrations in air, water and soil were predicted based on environmental modelling estimates (ChemCAN 2003) using a worst-case scenario derived from Canadian import quantities (Environment Canada 2009a) and an estimated emissions release rate of 5%. Based on this scenario, predicted concentrations of NVP in air, water and soil would be very low--8.64 × 10^-6 µg/m³, 3.57 × 10^-6 µg/L and 4.37 × 10^-4 µg/kg, respectively (ChemCAN 2003).

While NVP itself is not a permitted food additive, there are a few food uses of PVP (in which NVP may be present as a residual) for which there are food additive provisions, namely as a fining agent in various alcoholic beverages at a maximum level of 2 ppm in the finished product, as a tablet binder in tabletop sweetener tablets containing aspartame at a maximum use level of 0.3% and as a viscosity reduction agent and stabilizer in colour lake dispersions at a maximum use level consistent with Good Manufacturing Practice (residues of PVP not to exceed 100 ppm in the finished foods) as per Division 16 of the Food and Drug Regulations (Canada .1978]). PVP must meet the specifications of the Food Chemicals Codex (FCC) when used in these food additive applications (Canada [1978]). The FCC monograph for PVP specifies an acceptance criterion for unsaturation (as vinylpyrrolidone) of not more than 0.001% (FCC 2008). Similarly, polyvinylpolypyrrolidone (PVPP) could be used as a fining agent in the manufacture of some alcoholic beverages that are sold in Canada . For PVPP, the FCC has the same acceptance criterion for unsaturation (as vinylpyrrolidone) as it does for PVP (i.e., not more than 0.001%). Although the Food and Drug Regulationsdo not regulate PVPP as a food additive when used in this manner, PVPP is a powder that is insoluble in water, so it is expected that filtering of the beverage would remove PVPP. Consequently, negligible consumer exposure to NVP is expected to occur as a result of the use of PVPP as a fining agent in the manufacture of alcoholic beverages.

in Canada . NVP may be a residual impurity in an ingredient present in adhesives for paper or polyethylene bags with glued ends used to package dry foods. It may also be present in a UV curable ink used on the outside of plastic bottles. Since the adhesive is not in contact with the dry food and the ink is applied to the outside surface, there would be no direct contact with food; thus, exposure is expected to be negligible (2009 personal communication from Food Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced).

Based on the absence of environmental data and insignificant releases of NVP to the Canadian environment (Environment Canada 2009a), it is unlikely that Canadians are exposed to significant concentrations of NVP from the environment. This finding is supported by estimated upper-bounding daily intakes of NVP, assuming that 5% of NVP imported into Canada .Environment Canada 2009a) are released to the atmosphere (Appendix 1a).

In spite of the uncertainty regarding NVP levels in environmental media and food, confidence in the assessment of environmental exposure is moderate, based on the limited uses of NVP in Canada and the low exposure levels estimated from a scenario in which all NVP imported into Canada .s released to the atmosphere.

Consumer Products

NVP-derived polymers are found in a wide range of PCPs, which include hair products, skin moisturizers and cleansers, deodorant, nail polish, shaving cream and makeup. Owing to the widespread use of NVP-derived polymers in PCPs, PCPs are considered the primary source of exposure of Canadian consumers to NVP, even though NVP concentrations are present at trace, residual levels only.

BASF Corporation has identified several polymers--and their corresponding maximum NVP residual levels--that are available in Canada . notably, the homopolymer PVP (100 ppm) and two quaternized NVP copolymers--polyquaternium-16 (100 ppm) and polyquaternium-11 (50 ppm) (BASF 2006). In Europe, the maximum allowable NVP concentration in cosmetic-grade PVP is 1000 ppm, but the analytically determined concentration is consistently found to be no greater than 100 ppm (EURAR 2003). In Australia , the copolymer polyquaternium-44 has a maximum NVP residual of 50 ppm (NICNAS 2001). The level of 100 ppm was chosen as the maximum NVP residual level in Canadian cosmetic-grade polymers, as it was the highest known concentration in Canada .

NVP levels in Canadian PCPs were estimated by assuming a residual NVP concentration of 100 ppm in NVP-derived polymers found in PCPs (Table 7). PCPs and polymer concentrations shown in Table 7 were provided by the Risk Management Bureau, Health Canada (2009 personal communication to Risk Assessment Bureau, Health Canada ; unreferenced).

Concentrations of NVP-derived polymers found in PCPs are grouped by category (e.g. face makeup, nail polish, etc.) and reported as ranges (footnote 1 in Table 7). For 10 of 25 categories presented in Table 7, the upper-limit of the polymer concentration range is 30% or more. However, the polymer concentrations of PCPs comprising the ranges are not equally distributed: 60% of the PCPs in the 10 categories have NVP-derived polymer concentrations at the lower end of the range (≤ 1% concentration, by weight). in Canada less than 3% of PCPs have NVP-derived polymer concentrations above 10%. (2009 communication from Risk Management Bureau, Health Canada , to Risk Assessment Bureau, Health Canada ; unreferenced). Therefore, to be protective of the general population of Canada , NVP intake estimates in this report are based on the 95th percentile of NVP residual levels in PCPs.

Chronic and acute estimates of upper-bounding NVP intake were predicted using consumer product modelling software and are presented in Appendix 1b (ConsExpo 2006). Exposure modelling parameters used to estimate NVP exposure from PCPs are presented in Appendix 1c. PCPs considered to be applied biweekly or more frequently were categorized as chronic NVP exposure sources, while acute exposure sources were defined as PCPs used on a monthly or less frequent basis.

The maximum chronic NVP intake from PCPs ranged from 1.1 to 2.2 µg/kg-bw per day. Adolescents aged 12–19 years had the greatest estimated chronic intake (2.2 µg/kg-bw per day), followed by adults aged 20–59 years and seniors aged 60+ years, with identical intakes of 1.9 µg/kg-bw per day. Children aged 0.5–4 years had the lowest maximal estimates of NVP intake, at 1.1 µg/kg-bw per day.

Acute NVP exposure intakes were 22 and 18 µg/kg-bw per event for adolescents and the remaining adult population, respectively. Acute exposure intakes for infants and toddlers aged 4 years and younger were not determined, as the scenarios involved the application of hair bleach, hair dye or hair wave permanent.

For all age categories, the major route of exposure from PCPs is dermal, although inhalation and oral routes of exposure do exist. Hair spray has an inhalation component but was not considered for this assessment, as hair gel is used for a similar purpose and had a higher predicted total intake estimate. The calculated acute inhalation exposure from hair spray was considered to be negligible at 7.5 × 10^-5 µg/kg-bw per event. Oral exposure to NVP from teeth whitening strips was not considered to be a significant exposure source based on the amount of product applied per use.

When considering NVP intake from PCPs, it is unlikely that a significant part of the population would use every type of PCP that contains PVP on a regular basis. Therefore, some PCPs were excluded from the exposure assessment presented in Appendix 1b. There are several reasons to exclude certain PCPs when determining a maximal daily intake of NVP. When more than one PCP could reasonably be expected to be used for the same or similar function, the product with the greatest NVP concentration (e.g., hair gel vs. hair mousse/spray) or use by the largest percentage of the general population (e.g., bath foam vs. bath salt) was selected to derive an exposure estimate. For tanning preparations insufficient information was available to conduct an exposure assessment. In general, the major source of NVP exposure from PCPs was from leave-on products with high NVP residual levels, such as moisturizers (body and face) and hair gel. Rinse-off products (hair shampoo and conditioner, shaving cream and body wash) had a 10% retention factor applied to exposure assessments.

Information obtained from Canadian businesses reported that 99% of NVP in Canada .as used in the formulation of UV stains and curable inks (Environment Canada .009a). The UV coatings and inks are cured in situ and used to coat rigid or semi-rigid surfaces, such as metal, wood or plastic (EURAR 2003). UV curable stains and ink are not intended for sale to the general public, and, once cured, NVP residual levels for this type of use are below detectable limits (EURAR 2003; Environment Canada 2009a). As discussed previously, UV curable inks in food packaging do not come in contact with food; therefore, consumer exposure to NVP from UV curable inks and coatings is considered to be negligible.

in Canada . PVP is listed on the Health Canada DPD (2009) as a non-medicinal ingredient present in final pharmaceutical products. Thus, NVP may be present in pharmaceutical products as an impurity (2009 personal communication from Therapeutic Products Directorate, Health Canada . to Risk Management Bureau, Health Canada . unreferenced). The European Union, in EURAR (2003), described “a reasonable worst-case scenario” that involved the daily consumption of as many as 30 tablets. Based on this scenario, NVP exposure from pharmaceuticals in Canada .ould be lower than NVP exposure from PCPs. It should also be noted that the potential risks associated with taking any excipient in medication, including NVP, must be considered against the underlying ailment being treated. Therefore, an NVP intake from pharmaceuticals was not estimated.

Confidence in the assessment of NVP exposure from consumer products is moderate, based on the limited amount of Canadian exposure and use data available. Exposure to NVP from PCPs was established using exposure modelling software, but confidence is moderate in the results obtained, because residual NVP levels in polymers were based on recent information from the manufacturer and applied to highly conservative polymer concentrations.

Health Effects Assessment

An overview of key toxicological studies is presented in Appendix 2.

The European Commission has classified NVP as Category 3 for carcinogenicity (causes concern for humans owing to possible carcinogenic effects) with risk phrase R40 (limited evidence of carcinogenic effect), but it is also stated that the available information was not adequate for making a satisfactory assessment (EURAR 2003). A similar classification with respect to carcinogenicity was given by Australia : Category 3 carcinogen (NICNAS 2000). These classifications were based on clear evidence of carcinogenicity in rats exposed by inhalation, the absence of studies investigating the carcinogenic potential of NVP in other experimental animals and humans and the lack of genotoxic activity in a wide range of in vitro and a few in vivoassays. A classification of Group 3 (not classifiable as to its carcinogenicity to humans) was given by the International Agency for Research on Cancer (IARC 1999) based on the same carcinogenicity database, but in the absence of the genotoxicity studies that were not made available to the working group.

Male and female Sprague-Dawley rats were exposed to NVP concentrations of 0, 23, 46 or 92 mg/m³ (0, 7.1, 14.3 and 28.5 mg/kg-bw per day; dose conversion according to Health Canada .994) stabilized with 3 ppm Kerobit for 24 months. In both sexes, there was a clear dose-related increased incidence of hepatocellular carcinomas and nasal cavity adenomas at all doses, a dose-related increased incidence of nasal cavity adenocarcinomas at the middle and highest doses, as well as a higher incidence of squamous carcinomas of the larynx in the highest-dose group. The nasal cavity adenomas and adenocarcinomas were considered to be different tumours, as they arose from different regions (BASF 1992a; Klimisch et al. 1997a). ^Footnote 2 The carcinogenicity of NVP was also examined in a study in which investigations were confined to the liver. Neoplastic changes were seen in female rats exposed to unstabilized NVP at 207 mg/m³ (64.2 mg/kg-bw per day; Health Canada .994) for 3 months followed by a 21-month recovery period; no liver tumours were detected in control animals (BASF 1987b; Klimisch et al. 1997a). This study supported the conclusion that liver tumours observed in the 2-year study were due to NVP and not to the small quantities of Kerobit present.

Several in vitro and a limited number of in vivo genotoxicity studies on NVP were identified. There was no indication of genotoxicity in a wide variety of in vitrotests in both bacterial and mammalian cell systems (BASF 1978a, 1987c; HRC 1978a; Litton Bionetics 1980a, b, c; Simmon and Baden 1980; Knaap et al. 1985), with the exception of a poorly reported study that found slight increases in sister chromatid exchanges in human lymphocyte cultures (Norppa and Tursi 1984).In vivostudies were limited; there was no increase in micronuclei induction in the bone marrow of mice given a gavage dose of up to 600 mg/kg-bw (BASF 1993). In addition, there was no increase in the frequency of lethal heritable mutations in maleDrosophila melanogaster (Knaap et al. 1985), and there was no evidence of protein, deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) binding in the liver of male rats following intraperitoneal injection (IRI 1985). Based on the largely negative genotoxicity results, it is likely that non-genotoxic mechanisms were involved in the development of tumours in the liver, nasal cavity and larynx in the in vivo carcinogenicity studies. The undetermined mode of action underlying the development of NVP vapour–induced tumours necessitates that these tumours be considered relevant for human health (EURAR 2003). NVP carcinogenicity studies investigated by the oral and dermal routes were not identified.

Acute exposure of NVP has been studied in a wide range of species (BASF 1953, 1955, 1963a, b, 1964, 1979b, c, 1996; Kvasov 1972; FDRL 1975; Burnette 1978; HRC 1978b; Schwach and Hofer 1978). The lowest median lethal dose/concentration (LD₅₀/LC₅₀) values identified were the following: 834–1314 mg/kg-bw in rat (oral), 3070 mg/m³(952 mg/kg-bw per day) in rat (inhalation) and 560 mg/kg-bw in rabbits (dermal). A no-observed-adverse-effect level (NOAEL) of 200 mg/kg-bw and a lowest-observed-adverse-effect level (LOAEL) of 375 mg/kg-bw based on mortality for acute exposure by the dermal route were also identified in a study conducted in rabbits (FDRL 1975; Burnette 1978). However, in another study conducted in the same species, no mortality, local irritation or abnormalities were observed at doses of 400 mg/kg-bw (BASF 1979c).

Extensive repeated-dose studies by the inhalation route have been carried out in rodents at doses ranging from 4.6 to 553 mg/m³ using exposure durations up to 2 years (BASF 1986a, b, 1988b, c, d, e, 1992a; Klimisch et al. 1997a, b). NVP doses of 207 and 553 mg/m³ (275.3 and 171.4 mg/kg-bw per day; Health Canada .994) resulted in mortality in mice and rats, respectively (BASF 1986a, 1988e; Klimisch et al. 1997b). Dysproteinemia, increased levels of enzyme markers of liver toxicity and hematological changes suggestive of anemia were consistently observed, and the liver and the respiratory tract were identified as the major target tissues. The severity of the pathological changes depended on both dose and duration of the exposure. In a 3-month study in rats, nasal cavity toxicity, including inflammation, atrophy of olfactory epithelium and basal cell hyperplasia, as well as slight dysproteinemia, were observed at the lowest-observed-adverse-effect concentration (LOAEC) of 23 mg/m³ (7.1 mg/kg-bw per day; Health Canada 1994) (BASF 1986a, b; Klimisch et al. 1997b).

The same LOAEC of 23 mg/m³ was determined for shorter exposures of 7 weeks in mice and rats, at which inflammation, atrophy of the olfactory epithelium and cell hyperplasia in the respiratory epithelium were observed in mice and atrophy of the olfactory epithelium and hepatic centrilobular necrobiosis were observed in one rat (BASF 1988d, e; Klimisch et al. 1997b). This LOAEC was also determined for longer exposures of up to 2 years, at which hepatotoxicity (focal hepatocyte hyperplasia, eosinophilic foci and foci of spongiosis hepatis) and upper respiratory tract irritancy (focal metaplasia of respiratory epithelium, inflammation, atrophy of olfactory epithelium, focal hyperplasia of submucosal glands and focal mucopurulent inflammation in larynx) were detected (BASF 1992a; Klimisch et al. 1997a). At higher doses, degenerative changes in the nucleus, fatty infiltration and glycogen accumulation within hepatocytes and necrobiosis were found in the centrilobular region of the liver (EURAR 2003). The concentration of 23 mg/m³ was the lowest concentration tested in all the inhalation studies identified, with the exception of a 3-month study in rats; no effect was observed at the lowest dose of 4.6 mg/m³ (1.4 mg/kg-bw per day; Health Canada 1994) (BASF 1986a, b; Klimisch et al. 1997b).

In contrast, when NVP was administered repeatedly by the oral route, the respiratory tract was no longer a target tissue, and higher doses (equivalent to inhalation concentrations) were required to elicit liver toxicity. A LOAEL of 40 mg/kg-bw per day was identified in a 3-month gavage study in rats; at this dose, increased water consumption, ?-glutamyltransferase activity (significant only in females) and relative liver weight in females were observed. Foci in the liver morphologically similar to those observed in inhalation studies, however, were evident only at 100 mg/kg-bw per day (BASF 1986c; Klimisch et al. 1997b). Hydrolysis and/or spontaneous polymerization of NVP under the acidic conditions of the stomach prior to absorption have been suggested to reduce oral bioavailability and therefore toxicity of NVP (EURAR 2003). A LOAEL of 4.1–8.3 mg/kg-bw per day (range accounts for decreased dose with time) was established for rats exposed to NVP for 3 months through their drinking water, based on slight reductions in water consumption, dysproteinemia and decreased levels of total proteins, globulins and, in females, albumin (BASF 1986d; Klimisch et al. 1997b). A LOAEL of 5 mg/kg-bw per day was identified when rats were exposed to NVP in their drinking water for a shorter exposure duration of 21 days. At this dose, a dose-dependent decrease in water consumption and reduced body weight gain in females were observed. Repeated-dose dermal toxicity studies for NVP were not identified.

Female Wistar rats were exposed to NVP at 0, 4.6, 23 or 92 mg/m³ (0, 1.4, 7.1 and 28.5 mg/kg-bw per day; Health Canada .994) during gestational days 6–19 to determine the developmental toxicity of NVP. A LOAEC of 92 mg/m³ for fetotoxicity was determined based on reduced fetal body weight, incomplete ossification and wavy ribs, while a LOAEC of 23 mg/m³ was observed for pregnant dams based on decreased body weight gain. The investigators further concluded, according to the European Union risk assessment report (EURAR 2003), that there was some evidence that pregnant rats may be more susceptible than non-pregnant rats to the toxicity of NVP based on the magnitude of reductions in body weight gain (BASF 2001).

Although the potential for NVP to adversely affect fertility has not been specifically investigated in experimental animals, no adverse effects on reproductive organs have been reported in repeated-dose studies. These studies have examined reproductive organs from rats inhaling aerosols of up to 300 mg/m³(93 mg/kg-bw per day; Health Canada 1994) for 4 weeks (FDRL 1976), in rats and mice inhaling up to 207 mg/m³ (64.2 and 275.3 mg/kg-bw per day in rats and mice, respectively; Health Canada 1994) for 7 weeks (BASF 1988d, e), in rats inhaling NVP at 207 or 553 mg/m³ (64.2 and 171.4 mg/kg-bw per day; Health Canada 1994) for 3 months (BASF 1986a), in rats inhaling NVP at 92 mg/m³ (28.5 mg/kg-bw per day; Health Canada 1994) for 2 years (BASF 1992a) and in rats given NVP at 4.1–8.3 mg/kg-bw per day in drinking water for 3 months (BASF 1986d; Klimisch et al. 1997b).

NVP was not found to be a skin irritant in studies conducted in experimental animals (BASF 1963a, b, 1978b, 1979c), nor was it found to be a skin sensitizer (BASF 1996), but, in its liquid form, it caused irreversible corneal opacity, conjunctival chemosis and iris lesions when directly applied to the eyes of rabbits (BASF 1978b; Burnette 1978). The European Union (EURAR 2003) also suggested that NVP would most likely cause respiratory tract irritation based on increased respiration rates and nasal secretions seen in acute inhalation studies and on its ability to severely irritate eyes.

The toxicokinetics of NVP have been extensively characterized in the rat and to a lesser extent in the dog (Digenis and McClanahan 1982; McClanahan et al. 1983, 1984, 1987; Digenis 1990; BASF 1992b). NVP is rapidly absorbed by both the oral and inhalation routes and is expected to have good dermal absorption, according to EURAR (2003), based on its physicochemical characteristics and its structural similarity to N-methyl-2-pyrrolidone. Quantitative absorption data, however, were not available for the inhalation or dermal route of exposure. NVP has a plasma half-life of 3–4 hours in rats but only 20–40 minutes in dogs, the reason for which is unclear. It is widely distributed within the body, with the highest levels in the liver, small intestines and kidneys. Metabolic studies in the rat have found NVP to be extensively metabolized to highly polar compounds; the two major ones were not identified. It is rapidly eliminated in the urine, with much smaller amounts in the feces through the bile and in exhaled air as carbon dioxide.

Only one epidemiological study was identified, but, given the uncertainty about the actual levels of NVP inhaled or the possibility of co-exposure of the workers in a German manufacturing plant to other chemicals, it was not further considered (Zober et al. 1992).

The confidence in the toxicity database in experimental animals is considered to be moderate, as there was some information to address effects that may be of concern based on inhalation and, to some extent, oral exposures. However, there was no chronic/carcinogenic study conducted for the oral route, and the ones conducted by the inhalation route were only in one species, with the mode of action remaining uncharacterized. There was also a lack of dermal studies and human data for most endpoints.

Characterization of Risk to Human Health

Based on a weight of evidence approach, NVP exposure via inhalation leads to carcinogenicity and to toxicity in the liver and respiratory tract. NVP vapour was carcinogenic in rats, resulting in tumours in the liver, nasal cavity and larynx (BASF 1987b, 1992a; Klimisch et al. 1997a). The carcinogenic potential of NVP has, however, not been tested in other experimental animals or by other routes of exposure. The genotoxicity data for NVP appear to indicate a lack of genotoxicity, including mutagenicity, but there were few in vivo studies. Also, hepatocellular tumours have developed after only 3 months of exposure to NVP at 207 mg/m³ (64.2 mg/kg-bw per day) in rats, suggesting that there is early initiation of irreversible changes with high exposure concentrations (BASF 1987b; Klimisch et al. 1997a). Some uncertainties also exist with respect to the mechanisms responsible for the development of nasal and laryngeal tumours. Consequently, in the absence of evidence to the contrary, it must be assumed that these tumours are relevant to human health. Such a conclusion was also reached by the European Union (EURAR 2003). Given that NVP is unlikely to be mutagenic, it is considered a threshold carcinogen with a LOAEC of 23 mg/m³ (7.1 mg/kg-bw per day), based on an increased incidence of hepatocellular carcinomas and nasal cavity adenomas in male and female rats (BASF 1992a; Klimisch et al. 1997a). These tumours were observed at the lowest dose tested in a chronic toxicity/carcinogenicity study. The same critical effect level based on non-neoplastic effects was determined in repeated-dose studies ranging from 7 weeks to 2 years (BASF 1986a, b, 1988d, e, 1992a; Klimisch et al. 1997a, b).

Comparison of the LOAEC for chronic exposure via inhalation (i.e., 7.1 mg/kg-bw per day) with the upper-bounding estimate of daily intake of NVP by the most highly exposed group (12–19 years) via frequently used PCPs in Canada (2.2 × 10^-3mg/kg-bw per day) results in a margin of exposure (MOE) of approximately 3200. This MOE value is also retained for short-term and subchronic exposures to PCPs, and it is considered adequate given the conservatisms used in the upper-bounding estimates of exposure and the use of a dermal absorption rate of 100%.

A LOAEL based on a route of exposure other than inhalation was also considered for repeated-dose studies. In the absence of repeated-dose dermal toxicity studies, a LOAEL range of 4.1–8.3 mg/kg-bw per day (the range accounts for decreased dose with time) was established for rats exposed to NVP for 3 months through their drinking water. This range was based on the level at which slight reductions in water consumption, dysproteinemia and decreased levels of total proteins and globulins in both sexes and decreased levels of albumin in females were observed (BASF 1986d; Klimisch et al. 1997b). The toxicity noted in this study was indicative of dehydration following reduced water consumption (possible due to palatability), and the use of these endpoints for toxicological reference values is considered to be a conservative interpretation of the study. Based on the LOAEL range and the upper-bounding estimate of daily NVP intake from frequently used PCPs in Canada .2.2 × 10^-3 mg/kg-bw per day), the MOE has an estimated range of 1900–3800. This MOE range is considered adequately protective of human health, as the exposure assessment of NVP from PCPs assumed conservative upper-bounding estimates and the use of a dermal absorption rate of 100%.

In the absence of adequate acute dermal toxicity endpoints, a MOE was calculated for the highest no-adverse-effect level in the acute toxicity database. A NOAEL of 200 mg/kg-bw was therefore used for the calculation of an MOE, since the LOAEL of 375 mg/kg-bw was based on mortality (FDRL 1975; Burnette 1978). Confidence in the use of this NOAEL is further strengthened by the absence of local irritation, apparent abnormalities at necropsy and mortality at a dose of 400 mg/kg-bw in another dermal study conducted in the same species (BASF 1979c). Comparison of this critical effect dose level with the upper-bounding estimate of total acute NVP intake from PCPs (0.022 mg/kg per event for the 12–19 years age group) results in an MOE of approximately 9100 and is considered adequately protective of human health.

Uncertainties in Evaluation of Risk to Human Health

There is uncertainty associated with the cancer endpoint, given that the mode of tumour induction has not been analysed or fully elucidated, carcinogenicity studies were done in one species only via one route of exposure and a NOAEL was not identified in the carcinogenicity/chronic studies. To address these uncertainties, it is assumed that the tumours observed in rats are relevant to humans. In addition, there is uncertainty associated with a lack of oral and dermal studies as well as human data for most endpoints. In the majority of studies conducted, a NOAEL was not identified, and the lowest dose tested was the LOAEL. However, the MOE between the critical effect level and the highest estimated intake of NVP is considered adequately protective to address deficiencies in the data set. An experimentally determined dermal absorption value was not available, which would have been particularly relevant given the prevalence of the dermal route of exposure of humans to NVP. In the absence of an experimentally derived dermal absorption value, a value of 100% dermal absorption was used. While this assumption entails a great deal of uncertainty, the use of a 100% dermal absorption value greatly increases the conservatism inherent in the risk characterization.

Lack of recent Canadian data on levels of NVP in environmental media, food and consumer products is a source of uncertainty in the upper-bounding exposure estimates for the general population of Canada . However, concern about this uncertainty is reduced by taking into account the MOE between the critical effect level and the highest estimated intake of NVP. Confidence is moderate that the derived multimedia and consumer product exposure estimates are adequately protective of the general population of Canada . as highly conservative estimates and upper-bounding scenarios were used when recent Canadian data were unavailable.

Conclusions

Based on the information presented in this screening assessment, it is concluded that NVP 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, NVP does not meet the criteria for persistence and bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations (Canada .000).

Based on comparison of the upper-bounding estimated exposures to NVP in Canada .ith the critical effect levels, it is concluded that the resulting MOEs are adequately protective of human health and that NVP is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada .o human life or health.

It is therefore concluded that NVP does not meet any of the criteria under section 64 of CEPA 1999.

This substance will be considered for inclusion in the Domestic Substances List inventory update initiative. In addition and where relevant, research and monitoring will support verification of assumptions used during the screening assessment.

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Appendix 1a: Upper-bounding estimates of daily intake of NVP by the general population in Canada

Appendix 1b: Upper-bounding estimates of chronic and acute intake of NVP from personal care products^Footnote z, ^Footnote aa

Appendix 1c: Parameters used to predict exposure to NVP from personal care products

Appendix 2: Summary of health effects information for NVP

Date modified:

2013-09-30