Summary of public comments received on the screening assessment report for chlorhexidine and its salts

Official title: Summary of public comments received on the screening assessment report for chlorhexidine and its salts

Comments on the draft Screening Assessment Report for chlorhexidine and its salts to be addressed as part of the Chemicals Management Plan (CMP) were provided by 3M Canada Company, Canadian Consumer Specialty Products Association (CCSPA), L’ORÉAL CANADA Inc., and Ostrem Chemical Co. Ltd.

1. New information & data

Summarized comment Summarized response
Information was provided regarding use of chlorhexidine as a disinfectant in dairy/farm applications and as an antiseptic in clinical settings for skin use and oral health. Additional information was considered and found to support the analysis in the screening assessment.
Information was provided on the general efficacy of chlorhexidine-based products. The efficacy of substances used in specific applications is not considered in screening assessments. However, efficacy can be considered as a socio-economic factor during identification of risk management measures.

2. Methodology

Summarized comment Summarized response
The point-of-departure (POD) value selected for algae was the lowest of the two values identified (0.0062 and 0.021 mg/L). Selecting the lowest value is conservative, particularly when considering the cumulative uncertainty factor applied to this POD. The risk quotient (RQ) based on this value should not be used in the screening assessment. The critical toxicity value (CTV) is typically the lowest value chosen from an adjusted data set. The value of 0.0062 mg/L was chosen as the CTV after the data points were adjusted to represent comparable long-term, low to no effect values. This considered exposure duration, severity of the endpoint, and median compared to low or no-effects. The assessment factor of 30 accounted for the endpoint type, species variation in the dataset and a potential reactive mode of action, and took the extent of available data into consideration.
The sediment parameter only had a single study upon which the assessment was based. This should be supplemented with additional data, to increase robustness such as bridging approaches to utilize read-across data. The risk quotient based on this value should not be used in the screening assessment. Suitable analogues and associated data are considered, when they are available; however, in the case of this assessment, none were found that met our CMP risk assessment acceptability criteria. The limited data available on sediment parameters are acknowledged in the uncertainties section).
The Predicted Ecological Concentrations (PEC) are based entirely on modelling estimates and not confirmed by empirical sampling data. This represents a significant uncertainty in the screening assessment.

Ecological PECs are based on modelled estimates using information from industrial processes and quantities of chlorhexidine used by facilities in Canada; however, monitoring data was collected and used to validate and refine some of the parameters used in the modelling estimates.

Note that the ecological PECs account for non-continuous releases. Empirical results from sampling may not reflect non-continuous releases that could occur during manufacture of chlorhexidine-based products when sampling is being done. This may account for measured concentrations that do not reflect peak exposure levels.

3. Uses

Summarized comment Summarized response
Across the continuum of patient care, chlorhexidine gluconate (CHG) is a critical antimicrobial and an essential tool for healthcare providers. Unlike alternative antimicrobials that demonstrate decreasing effectiveness, CHG provides broad spectrum efficacy, prolonged effectiveness minimal resistance in a clinical setting, and is generally well tolerated by patients. Noted.
Chlorhexidine is effective against Gram-positive bacteria, Gram-negative bacteria, and fungi. Chlorhexidine inactivates microorganisms with a broader spectrum than alternative antimicrobials and with a quicker kill rate. Depending on its concentration, chlorhexidine has both bacteriostatic and bactericidal mechanisms of action and works by disrupting the cell membrane. Since chlorhexidine formulations can kill most categories of microbes, there is limited risk for the development of opportunistic infections. Chlorhexidine resistance has not been observed in a clinical setting despite its use in healthcare for almost 60 years. Noted.

4. Sources and releases

Summarized comment Summarized response
Disposal of manufacturing waste is conducted according to regional disposal regulations by an external firm specialized in waste handling. Noted.
Drums containing residual CHG are decontaminated and reconditioned or incinerated by external specialty waste handlers. Noted.

5. Risk characterization

Summarized comment Summarized response
A site-specific ecological exposure scenario for the industrial formulation of products containing chlorhexidine noted that the releases from a facility are not expected to pose a risk to aquatic and benthic organisms. Risk assessments for substances under CEPA are based on best available data to represent a range of potential exposure scenarios in Canada. This includes information associated with many different sites, rather than a single source. The screening assessment conclusion is based on estimates of exposure that are protective of the Canadian environment. The submitted calculations of the PEC for aquatic and sediment media are consistent with those that we used during the assessment; however, they do not account for the fact that multiple facilities can be releasing to the environment through the same discharge point.  
Chlorhexidine has a long duration of action and a low toxicity to humans. In topical applications, chlorhexidine binds to the proteins in human tissues such as skin with limited systemic or bodily absorption. Protein bound chlorhexidine releases slowly leading to prolonged activity. Based on product efficacy data, CHG (0.05-4%) suppresses regrowth of bacteria for at least 72h. Noted.

6. Risk management

Summarized comment Summarized response
Chlorhexidine is already approved for use in antiseptic products and is therefore subject to various standards and guidelines for infection prevention, such as those published by the Centre for Disease Control (CDC), the Infusion Nurses Society (INS), Safer Healthcare Now!, Prevent Surgical Site Infections, World Health Organization (WHO), and Operating Room Nurses Association of Canada (ORNAC. Optimal and prudent use of products containing CHG, and product instructions are well defined. Noted.
Address the risk management information gaps to develop effective mitigation measures, particularly to address point source releases from facilities, such as the presence of chlorhexidine and its salts in wastewater. Monitoring to determine the quantity of chlorhexidine that is released to the environment has taken place and additional analyses are planned. As analytical results become available, they will inform risk management decision-making regarding chlorhexidine and its salts, and may help establish a baseline for the quantity of chlorhexidine that is released to the environment.
Manufacturing processes that blend the CHG solution comply with good manufacturing practices and maintain process standards for compounding, packaging, and clean up. Noted.

7. Alternatives & chemical substitution

Summarized comment Summarized response
Restricting the production and/or use of chlorhexidine-based products would negatively impact patient care and the dairy/farm industry because alternatives are not as effective and are more expensive. Risk management instruments are being considered to prevent or minimize environmental releases of chlorhexidine from industrial sources. This includes ways to apply informed substitution to support chemicals management (Combined government discussion paper and science committee report on informed substitution. Publication date: 2018-08-28).
The only suitable alternative to chlorhexidine and its salts is an iodine treatment, which is significantly more expensive because of limited supplies of iodine/iodophors. While the iodine alternative exists, the dairy and farm industry must be made aware that the best prevention of infection/mastitis is a combination of disinfection treatments to reduce the probability of bacteria resistant strains that could result from using only one type of disinfectant. Additionally, the increased cost to the farm and dairy industry should be examined in full. Alternative chemicals or processes are not considered in CMP screening assessments. However, when adequate and relevant information is available on the economic, social and environmental implications for Canada, alternatives may be considered during the risk management phase. Risk Management Scope and Approach documents include a section on alternatives.
Extensive lab development work, clinical studies, time, and financial investment would be required to replace CHG in the antiseptic product family essential to the continuum of patient care. No equivalent alternatives have been identified that match the benefits of chlorhexidine. Separate development, clinical studies, and registrations for each concentration and dosage form would be required, should an alternative be obligatory. Noted.
Healthcare products containing CHG include critical antiseptics for use in surgical preparation, patient care, and infection prevention. Restriction of CHX/CHG-containing products would most certainly negatively impact patient outcomes based on the overwhelming literature-based evidence identifying chlorhexidine as the standard of care. Noted.
Alternative approaches to wastewater handling, such as neutralizing CHG before disposal, require engagement with industry experts and further study. Noted.
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