Proposed Special Review Decision PSRD2022-02, Special review of Potassium Dimethyldithiocarbamate and its Associated End-use Products: Proposed Decision for Consultation
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Pest Management Regulatory Agency
7 September 2022
ISSN: 2561-636 (PDF version)
Catalogue number: H113-30/2022-2E-PDF (PDF version)
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To obtain a full copy of Proposed Special Review Decision PSRD2022-02, Special Reviews of Potassium Dimethyldithiocarbamate and Its Associated End-use Products: Proposed Decision for Consultation please contact our publications office.
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Table of contents
- 1.0 Introduction
- 2.0 Uses of potassium dimethyldithiocarbamate in Canada
- 3.0 Aspects of concern that prompted the special review
- 4.0 Evaluation of the aspects of concern that prompted the special review
- 5.0 Proposed special review decision for potassium dimethyldithiocarbamate
- 6.0 Next steps
- 7.0 Other information
The Pest Management Regulatory Agency (PMRA) initiated the special reviews of sodium dimethyldithiocarbamate and potassium dimethyldithiocarbamate in 2018 under subsection 17(1) of the Pest Control Products Act based on the toxicology data submitted under section 12 of the Pest Control Products Act, following the re-evaluation of sodium and potassium dimethyldithiocarbamate salts (PRVD2011-05 and RVD2012-01).
Registrants of the active ingredient sodium dimethyldithiocarbamate voluntarily discontinued registration of all products containing sodium dimethyldithiocarbamate. Therefore, the special review of sodium dimethyldithiocarbamate was closed in May 2022. Consequently, this regulatory proposal only pertains to potassium dimethyldithiocarbamate.
Pursuant to subsection 18(4) of the Pest Control Products Act, Health Canada has evaluated the aspects of concern that prompted the special review of pest control products containing potassium dimethyldithiocarbamate. The aspects of concern for this special review are relevant to human health.
2.0 Uses of potassium dimethyldithiocarbamate in Canada
Potassium dimethyldithiocarbamate is a broad-spectrum biocide registered in Canada for use as a slimicide in industrial fluids and as a material preservative for a variety of substances including metal working fluids and brine solutions. All currently registered pest control products containing potassium dimethyldithiocarbamate (see Appendix I of PSRD2022-02, Special review of Potassium Dimethyldithiocarbamate and its Associated End-use Products: Proposed Decision for Consultation) are considered for the special review.
3.0 Aspects of concern that prompted the special review
Based on the review of the data submitted under Section 12 of the Pest Control Products Act, Health Canada updated the potassium dimethyldithiocarbamate toxicology reference values for health risk assessments (Appendix II of PSRD2022-02). The following aspects of concerns were identified for the special review under subsection 17(1) of the Pest Control Products Act:
- Potential cancer and non-cancer risks from occupational handler and post-application exposure.
4.0 Evaluation of the aspects of concern that prompted the special review
Following the initiation of the special review, Health Canada requested information related to the aspects of concern from provinces and other relevant federal government departments and agencies in accordance with the subsection 18(2) of the Pest Control Products Act. No information was received relating to the aspects of concern.
In order to evaluate the aspects of concern for potassium dimethyldithiocarbamate, Health Canada considered currently available relevant scientific information, which includes information considered for the re-evaluation of potassium dimethyldithiocarbamate (PRVD2011-05 and RVD2012-01), information submitted under section 12 of the Pest Control Products Act following the re-evaluation of potassium dimethyldithiocarbamate, and any relevant information obtained since then.
4.1 Toxicology summary
Health Canada conducted a re-evaluation of potassium and sodium dimethyldithiocarbamate salts with the conclusions published in the proposed re-evaluation decision (PRVD2011-05) and in the re-evaluation decision (RVD2012-01). Health Canada concluded that additional data were required to support the continued registration of these salts, and as such, toxicology data were required under section 12 of the Pest Control Products Act. The required data included combined chronic toxicity/oncogenicity studies in the mouse and rat and a multi-generation reproductive toxicity study in the rat.
In response to the data requirements for potassium and sodium dimethyldithiocarbamate salts, the registrant submitted information on the use pattern, a published report of a chronic toxicity study in rats exposed to ziram (a zinc salt of dimethyldithiocarbamate), a report of a carcinogenicity study in mice and rats dosed with ziram, and the results of computer modelling (Derek Nexus) in 2014. In their response, the registrant indicated that the structural and biological activity of ziram was directly analogous to that of potassium and sodium dimethyldithiocarbamate salts and that data on ziram could be considered for the assessment of the potential toxicity of potassium and sodium dimethyldithiocarbamate salts. Health Canada agreed with the registrant that ziram, and the potassium and sodium dimethyldithiocarbamate salts all appear to be structurally related, and used a read-across approach, which allowed for the examination of all of the available toxicity data for ziram, and the potassium and sodium dimethyldithiocarbamate salts. Based on the different parameters examined, it appeared that ziram and the potassium and sodium dimethyldithiocarbamate salts are of similar toxicity. Some gaps and inconsistencies were noted when the different endpoints from the various toxicity studies were compared; however, for the most part, these differences could be attributed to dose selection. Given the similarity between the different salts, Health Canada concluded that the toxicity studies conducted with ziram could be used for the risk assessment of potassium dimethyldithiocarbamate, and thus took a modified approach for the fulfillment of the Section 12 data requirements for potassium dimethyldithiocarbamate based on the available ziram data.
4.2 Dietary exposure and risk assessment
There are no food or food contact uses associated with the preservative uses of potassium dimethyldithiocarbamate. Residues of potassium dimethyldithiocarbamate in potential drinking water sources are not expected as potassium dimethyldithiocarbamate salts are not stable in water (PMRA# 2773561).
4.3 Occupational and non-occupational risk assessment
Occupational and non-occupational (for example, residential) risk is estimated by comparing potential exposures with the most relevant endpoint from toxicology studies to calculate a margin of exposure (MOE). This is compared to a target MOE incorporating uncertainty factors protective of the most sensitive subpopulation. If the calculated MOE is less than the target MOE, it does not necessarily mean that exposure will result in adverse effects, but mitigation measures to reduce risk would be required.
4.3.1 Toxicology reference values
126.96.36.199 Toxicology reference values for occupational and non-occupational exposure to potassium dimethyldithiocarbamate
As a result of the considerations in Section 4.1, the reference values for potassium dimethyldithiocarbamate were revised from those that were presented in RVD2012-01 to those that were established for ziram and presented in RVD2018-39. In using the read-across methodology supported by the registrant, Health Canada established a q1* of 1.82 × 10-2 (mg/kg bw/day)-1 for use in the cancer risk assessment for potassium dimethyldithiocarbamate based on ziram data. Extension of the read-across approach for non-cancer endpoints supported the use of the ziram reference values for potassium dimethyldithiocarbamate. As such, the long-term dermal and inhalation reference values for the potassium dimethyldithiocarbamate risk assessment were based on the point of departure from the 2-year dietary rat chronic toxicity study conducted with ziram. Revised toxicology reference values based on those for ziram are presented in Appendix II, Table 1 of PSRD2022-02.
No dermal absorption (DA) studies were submitted by the registrants for potassium dimethyldithiocarbamate nor were any available in the literature. Due to this, a DA value of 100% was selected for the special review of potassium dimethyldithiocarbamate.
Refinement of this value using physical/chemical properties such as molecular weight and formulation type was explored; however, they do not suggest that potassium dimethyldithiocarbamate has a low DA potential.
4.3.2 Non-occupational exposure and risk assessment
Non-occupational (residential) risk assessment involves estimating risks to the general population, including adults, youth, children, during or after pesticide application.
188.8.131.52 Residential applicator exposure and risk assessment
A residential applicator assessment for potassium dimethyldithiocarbamate was not required since there are no registered domestic-class pesticide products.
184.108.40.206 Residential post-application exposure and risk assessment
Residential post-application exposure occurs when an individual is exposed through dermal, inhalation and/or incidental oral (non-dietary ingestion) routes as a result of being in a residential environment where a consumer product containing potassium dimethyldithiocarbamate as a material preservative has been used.
Potassium dimethyldithiocarbamate is registered for use as a material preservative in pulp and paper manufacturing, however, all end-use product labels currently contain a statement which prohibits its use in any paper product or food packaging material that would come into contact with food. Considering this, potential food dietary exposure to potassium dimethyldithiocarbamate is expected to be minimal based on a qualitative assessment.
Potassium dimethyldithiocarbamate is registered for use as a material preservative of the brine solutions during the curing of leather products. Exposure may result when coming into contact with leather products made from hides/skins cured in the potassium dimethyldithiocarbamate treated brine solutions. Based on a submitted study (PMRA# 1956512), no detectable levels of potassium dimethyldithiocarbamate are expected to be found in leather made from potassium dimethyldithiocarbamate treated hides. Therefore, exposure to potassium dimethyldithiocarbamate residues in the final leather products, if applied according to the rates prescribed on the current product labels, is expected to be minimal based on a qualitative assessment.
4.3.3 Occupational exposure and risk assessment
There are potential exposures to workers mixing and loading potassium dimethyldithiocarbamate commercial-class end-use products when treating fluids used in industrial facilities and material preservation scenarios.
220.127.116.11 Occupational primary handler exposure and risk assessment
Exposure to potassium dimethyldithiocarbamate is expected to be intermittent (a few minutes daily or once a week) over an intermediate to long-term duration (that is >30 days to several months).
Based on the use pattern, the major scenarios identified are:
- Manual transfer of liquids (conventional container)
- Closed transfer of liquids (assessed qualitatively)
A closed transfer (injection) system has the characteristics where there is no contact of workers with the active ingredient and thus workers are assumed to have no potential for exposure. Due to this, occupational risk (cancer and non-cancer) for closed transfer (injection) systems were assessed qualitatively and risks were determined to be acceptable.
Potassium dimethyldithiocarbamate end-use product labels have both open and closed transfer requirements but do not specify when one or the other is required, therefore, both types of systems were considered in the risk assessment. Occupational risk (cancer and non-cancer) to workers from open transfer activities in small scale facilities were assessed quantitatively. It was assumed that large scale facilities would have closed transfer systems already in place and these scenarios were assessed qualitatively.
No appropriate chemical-specific handler exposure data were available for potassium dimethyldithiocarbamate. Therefore, dermal and inhalation exposures for occupational applicators were estimated using the liquid pour (PMRA# 2296582, 2296584) exposure study submitted by the Antimicrobial Exposure Assessment Task Force II (AEATF II). While there are limitations in the use of generic data, these exposure data represent the most reliable information currently available. Inhalation exposures were based on light inhalation rates (17 L/min).
There is limited information available to estimate the amount of potassium dimethyldithiocarbamate handled in one day by workers for the various Canadian industrial facilities or material preservation scenarios. The United States Environmental Protection Agency (USEPA) "Antimicrobial Division Draft Summary of Amounts Handled or Treated for Occupational Handler Scenarios" (PMRA# 3084493Footnote 1) contains standard values for the majority of industrial processes. As industrial facilities have a range of production capacities, an amount handled per day (AHPD) value of up to 38 L end-use product/day was utilized to address all small scale facilities that would use an open pour method to mix, load, and apply the antimicrobial. Use information submitted to the PMRA indicated that 9.46-18.8 L end-use product/day is handled in brine solutions/brine curing scenarios (PMRA# 2912486). This value is consistent with the open pour value in PMRA# 3084493 1 for leather tanning scenarios (5 gallons end-use product/day) and was used in the occupational risk assessment.
For the cancer risk assessment, it was assumed workers in industrial facilities or material preservation scenarios would handle potassium dimethyldithiocarbamate every work day of the year, except when on vacation (250 days per year). It was also assumed that a worker in a "Technician and Related Support" career would handled potassium dimethyldithiocarbamate each year over the span of their career of 22.2 years (PMRA# 1945742). This value also addresses the years of exposure for the 'Operators, Fabricators, and Laborers' (14.7 years).
The calculated combined MOEs and cancer risks for workers handling potassium dimethyldithiocarbamate showed that risks were not acceptable at single layer personal protection equipment (PPE) (long pants, long-sleeved shirt, chemical-resistant (CR) gloves). Risks could not be mitigated with additional PPE as exposure in the AEATF II study was primarily to the hands and exposure to the remainder of the body was minimal. To mitigate risks, it is proposed that closed transfer systems be used for all commercial-class potassium dimethyldithiocarbamate end-use products. The quantitative cancer and non-cancer long-term occupational handler risk assessment for potassium dimethyldithiocarbamate is presented in Appendix III, Tables 1 and 2 of PSRD2022-02.
18.104.22.168 Occupational secondary handler exposure and risk assessment
Downstream workers in industrial facilities and material preservation scenarios:
There are potential exposures to workers using potassium dimethyldithiocarbamate in industrial facilities and as a material preservative. Downstream workers are not expected to handle potassium dimethyldithiocarbamate treated fluids, however, limited contact may occur (PMRA# 2912486). Exposure is expected to be low given the occupational hygiene standards in these workplaces that require safe work conditions. Workers are expected to be wearing PPE as required by laws related to worker health and safety, which would limit potential exposure. Additionally, as the vapour pressure of potassium dimethyldithiocarbamate is low (not calculated as the melting point is > 300°C; PMRA# 2773561), inhalation exposure of the vapour from volatilization is considered to be minimal. Therefore, the risk assessment for downstream workers in industrial facilities and in material preservation scenarios was considered qualitatively, unless discussed below, and was determined to be acceptable.
Metal working fluids (cutting fluids):
Potassium dimethyldithiocarbamate end-use products are used to preserve metal working fluids. Workers using the treated metal working fluids are expected to be exposed to potassium dimethyldithiocarbamate via dermal contact of the fluids and through inhalation of the mist/aerosol.
An inhalation assessment was conducted following the USEPA Chemical Engineering Branch model which measures oil mist concentrations for metal working operations and measures inhalation exposure to the mists and aerosols. A dermal risk assessment was conducted using the 2-hand immersion model (PMRA# 3354881).
Using the maximum registered rate of 1000 ppm, both cancer and non-cancer risks were identified. To mitigate risk, a lower registered rate of 80 ppm will be proposed as the maximum rate for use in metal working fluids (cutting fluids). At this rate, risks (cancer and non-cancer) are determined to be acceptable. The post-application risk assessment for metal working fluids (cutting fluids) is presented in Appendix III, Table 3 of PSRD2022-02.
Brine solutions/brine curing:
Potassium dimethyldithiocarbamate is registered for use as a material preservative of the brine solutions during the curing of leather products. No model currently exists for assessing risk to downstream workers in the leather industry.
Dermal exposure is considered to be extensive, and to the entire body, for workers handling the treated brine solutions as well as treated leather. Due to this, and the lack of data to assess potential exposures, the use of potassium dimethyldithiocarbamate in brine solutions/brine curing is proposed to be removed from potassium dimethyldithiocarbamate product labels.
4.4 Aggregate risk assessment
Aggregate exposure is the total exposure to a single pesticide that may occur from food, drinking water, residential and other non-occupational sources, and from all known or plausible exposure routes (oral, dermal and inhalation).
In an aggregate risk assessment, the combined potential risk associated with food, drinking water and various residential exposure pathways is assessed. A major consideration is the likelihood of co-occurrence of exposures from the use of products containing potassium dimethyldithiocarbamate as a preservative. Additionally, only exposures from routes that share common toxicological endpoints can be aggregated.
There are no registered potassium dimethyldithiocarbamate food uses, nor is it used in products designed for food packaging materials or in areas where food is stored, handled or processed. Residues of potassium dimethyldithiocarbamate in potential drinking water is not expected as potassium dimethyldithiocarbamate salts are not stable in water (PMRA# 2773561). Incidental oral and dermal exposure to potassium dimethyldithiocarbamate from its use as a material preservative during the leather manufacturing process is not expected as exposure to potassium dimethyldithiocarbamate residues is expected to be minimal.
Therefore, aggregate exposure and risks were considered to be acceptable based on a qualitative assessment.
4.5 Cumulative assessment
The Pest Control Products Act requires that Health Canada consider the cumulative exposure to pest control products with a common mechanism of toxicity. Accordingly, an assessment of potential common mechanism of toxicity with other pesticides was undertaken for potassium dimethyldithiocarbamate. Potassium dimethyldithiocarbamate is a member of the dimethyldithiocarbamate class of pesticides along with sodium dimethyldithiocarbamate, ziram, ferbam, and thiram. Since all agricultural uses of ferbam and ziram were cancelled along with the material preservative uses of ziram and sodium dimethyldithiocarbamate, the only uses for consideration in a cumulative risk assessment are the seed treatment use of thiram and the material preservative use of potassium dimethyldithiocarbamate.
Ziram, which was used to characterize the toxicity of potassium dimethyldithiocarbamate, is structurally related to thiram. Both ziram and thiram inhibit the enzyme acetaldehyde dehydrogenase, and induce some similar toxic effects in mammals, including evidence of neurotoxicity. It is unknown whether a common mode of action underlies these similar toxic effects. However, the anticipated dietary and residential exposure to potassium dimethyldithiocarbamate from the material preservative uses are considered to be minimal, and thus would contribute very little to the cumulative risk from potential co-exposure to thiram and potassium dimethyldithiocarbamate. Therefore, cumulative risk is acceptable.
4.6 Health incident reports
As of 18 February 2022, no incident reports involving potassium dimethyldithiocarbamate salts related to the aspects of concern had been reported to the PMRA.
5.0 Proposed special review decision for potassium dimethyldithiocarbamate
Under the authority of the Pest Control Products Act and based on an evaluation of available relevant scientific information related to the aspects of concern for human health, Health Canada is proposing continued registration of potassium dimethyldithiocarbamate and associated end-use products registered for sale and use in Canada with the risk mitigation measures below.
Risk mitigation measures - Human health
As a result of the special review of potassium dimethyldithiocarbamate salts, the PMRA is proposing further risk-reduction measures on product labels. Additional revisions to the potassium dimethyldithiocarbamate labels are proposed to meet the current labelling standards and for consistency. This includes updating the PPE label statement. Refer to Appendix IV for all proposed label amendments.
The following mitigation measures are proposed to reduce potential exposure to workers using potassium dimethyldithiocarbamate in industrial facilities or in material preservation scenarios:
- The use of a closed loading and transfer system
- For metal working fluid (cutting fluid) uses, a maximum rate of 80 ppm
- Cancellation of the brine curing/brine solutions uses
Additional Scientific Information
- No additional scientific data are required at this time.
This proposed special review decision is a consultation documentFootnote 2. The PMRA will accept written comments on this proposal up to 45 days from the date of publication of this document. Please forward all comments to Publications.
6.0 Next steps
Before making a special review decision on potassium dimethyldithiocarbamate, the PMRA will consider all comments received from the public in response to this consultation document. A science-based approach will be applied in making a final decision on potassium dimethyldithiocarbamate. The PMRA will then publish a special review decision document, which will include the decision, the reasons for it, a summary of the comments received on the proposed decision, and the PMRA's response to these comments.
7.0 Other information
The relevant confidential test data on which the proposed decision is based (see References in PSRD2022-02) are available for public inspection, upon application, in Health Canada's Reading Room. For more information, please contact Health Canada's Pest Management Information Service.
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