UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
MEMORANDUM
Date: 23-MAR-2020
SUBJECT: Inorganic Sulfites. Draft Human Health Risk Assessment in Support of Registration Review.
PC Codes: 077601 and 111409 DP Barcode: D455747 Decision No.: 558683 Registration No.: NA Petition Nos.: NA Regulatory Action: Registration Review Risk Assess Type: Single Chemical Aggregate Case No.: NA TXR No.: NA CAS No.: 7681-57-4 and 7446-09-5 MRID No.: NA 40 CFR: § 180.444
. J/.l.11~ FROM: Danette Drew, Chermst w~- "tl. 0 William Donovan, Chemist ~ _ John Liccione, Toxicologist ~ Kelly Lowe, Environmental Scientist ~ ~~ Risk Assessment Branch V Health Effects Division (7509P)
THRU: Michael S. Metzger, Chief Risk Assessment Branch V NII Health Effects Division (7509P)
TO: Matthew B. Khan, Chemical Review Manager Risk Management & Implementation Branch I Pesticide Re-evaluation Division (7508P)
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Table of Contents
1.0 Executive Summary ...... 3 2.0 Established and Recommended Tolerances ...... 6 2.1 International Harmonization ...... 6 3.0 Data Requirements and Label Recommendations ...... 6 4.0 Inorganic Sulfites Formulations and Use Patterns ...... 7 5.0 Hazard Assessment ...... 12 5.1 Absorption, Distribution, Metabolism & Elimination (ADME) ...... 12 5.2 Toxicity of Sulfur Dioxide and Sodium Metabisulfite ...... 12 5.3 Regulatory Values for Sulfur Dioxide and Inorganic Sulfites ...... 15 5.4 FQPA Considerations ...... 16 5.5 Endocrine Disruptor Screening Program ...... 16 6.0 Anticipated Exposure Pathways ...... 17 7.0 Residue Chemistry ...... 17 8.0 Dietary Exposure ...... 19 9.0 Residential Exposure ...... 19 10.0 Aggregate Exposure and Risk Assessment ...... 19 11.0 Non-Occupational Spray Drift Exposure and Risk Estimates ...... 19 12.0 Non-Occupational Ambient Inhalation Exposure and Risk Estimates ...... 20 13.0 Non-Occupational Bystander Exposure and Risk Estimates ...... 20 14.0 Occupational Exposure ...... 30 14.1 Acute and Short-/Intermediate-Term Occupational Handler Exposure ...... 30 14.2 Acute and Short-/Intermediate-Term Occupational Post-Application Exposure ...... 31 14.2.1 Occupational Post-application Dermal Exposure ...... 31 14.2.2 Occupational Post-application Inhalation Exposure ...... 32 15.0 Public Health and Pesticide Epidemiology Data ...... 34 16.0 Environmental Justice ...... 34 17.0 Cumulative Risk Assessment ...... 35 18.0 Human Studies ...... 36 19.0 References ...... 36 Appendix A. Toxicology Database-Sulfur Dioxide Regulatory Limits ...... 38 Appendix B. Chemical Identification/ Physical and Chemical Properties ...... 39 Appendix C. International Residue Limit Status Sheet...... 40
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1.0 Executive Summary
As part of Registration Review, the Pesticide Reevaluation Division (PRD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate the hazard and exposure data and conduct dietary and non-dietary (occupational and residential) exposure assessments, as needed, to estimate the risk to human health that will result from the currently registered uses of pesticides. This memorandum serves as HED’s draft human health risk assessment (DRA) for the currently registered conventional pesticidal uses of the inorganic sulfites [i.e., sulfur dioxide (SO2) and sodium metabisulfite (an SO2 generator)] in support of Registration Review.
There is a registered antimicrobial use of sodium metabisulfite. The registered product is formulated as packaging stickers (containing (18.8% active ingredient), which are placed inside storage and shipment containers containing items such as, footwear, clothing, luggage, handbags, purses, wallets, gloves, hats, belts, leather goods, sporting goods, and other associated materials. The stickers release sulfur dioxide within the containers as they absorb moisture. This use has been assessed by the Antimicrobials Division (AD) in a separate memo (D4554711).
For the conventional uses, sulfur dioxide is used as a postharvest fumigant treatment for grapes held in cold storage in enclosed spaces (e.g. warehouses and transportation vehicles) to control gray mold disease, which is caused by Botrytis cinerea. In addition, sulfur dioxide is used as a fumigant for sanitation of wine corks and barrels. The sodium metabisulfite products are composed of the anhydrous, solid active ingredient contained in semi-sealed pads (or liners) that are used for the fungicidal control of B. cinerea in table grapes. The sodium metabisulfite pads are placed in containers holding grapes for shipping and storage. As the pads absorb ambient moisture, they release sulfur dioxide within the crate.
Humans may be exposed to inorganic sulfites in food, since sulfur dioxide may be applied directly to grapes after harvest. Exposures through drinking water are not expected since residues are not expected in water due to the use pattern. There are no uses resulting in direct residential exposures; however, there is the potential for non-occupational bystander inhalation exposures to sulfur dioxide. Dermal exposures are not expected given the high vapor pressure of sulfur dioxide and based on the labeled delivery systems. Occupational inhalation exposures are possible. Occupational handlers may be exposed while handling the pesticide prior to application and immediately after application and clearance. Occupational post-application inhalation exposures may also occur from activities associated with cold storage of commodities treated with sulfur dioxide.
Hazard Assessment The inorganic sulfites pesticides include sulfur dioxide and sodium metabisulfite. There is a large volume of published data detailing the toxicity of inorganic sulfites, and consequently the toxicity of inorganic sulfites has been well established. EPA’s Office of Air Quality Planning and Standards (OAQPS) has worked extensively on sulfur dioxide, including setting national
1 D455471. Denning, A. 03/23/2020. Registration Review Draft Risk Assessment for the Antimicrobial Use of Sodium Metabisulfite.
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ambient air quality standards (NAAQS) for sulfur dioxide, a gaseous air pollutant. The U.S. Food and Drug Administration (FDA) has also performed an extensive review of sulfiting agents (including sulfur dioxide, sodium metabisulfite, and sodium bisulfite) that have been added to any food or to any ingredient in any food. For this assessment, HED is relying on established OAQPS regulatory values for sulfur dioxide (bystander inhalation assessment) and the established FDA regulatory value for sulfite (dietary assessment). For occupational workers, HED is also relying on various regulatory levels for inhalation exposure to sulfur dioxide. These include the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limit (PEL), the National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) and Short-Term Exposure Limit (STEL), and the American Conference of Governmental Industrial Hygienists (ACGIH) STEL.
Sulfur Dioxide: The primary mechanism of action of sulfur dioxide is that of an irritant, the respiratory system being the primary target. The most sensitive endpoints are increased airway resistance and decreased forced expiratory volume in 1 second. Sulfur dioxide is considered not classifiable (Group 3) as to carcinogenicity by the International Agency for Research on Cancer (IARC; 1992). No reproductive or developmental effects were noted in toxicity studies in the rat.
Sodium Metabisulfite: Stomach effects (irritation, inflammatory changes, and hyperplasia) were observed in rats after long-term exposure to sodium metabisulfite in the diet. No adverse developmental or reproductive effects have been reported in rodent toxicity studies. Sodium metabisulfite is considered not classifiable (Group 3) as to carcinogenicity by IARC (1992).
Residue Chemistry Sulfites are the residues of concern for consumption of treated foods. Tolerances are established in the 40 CFR §180.444 for residues of sulfites expressed as sulfur dioxide in/on grapes and figs. The fig tolerance was for a Section 18 Emergency Exemption that expired 12/31/2014. The tolerance expression should be modified according to the Interim Guidance on Tolerance Expressions (S. Knizner, 05/27/2009). For sulfur dioxide end-use products, a modified use pattern supported by the available residue chemistry data should be submitted.
Dietary Exposure No residues are expected in drinking water. HED is relying on the FDA-established regulatory level of up to 10 ppm sulfite residues in foods. Residues in grapes from sulfur dioxide and sodium metabisulfite applications are expected to be below the 10 ppm level when applied as tested in the grape residue trials; there are no risks of concern for dietary exposures from these uses on grapes.
Residential Exposure There are no uses of sulfur dioxide resulting in direct residential exposures; therefore, residential handler and post-application exposures are not expected.
Aggregate Risk Assessment There are no residential uses of sulfur dioxide; therefore, the aggregate assessment includes only dietary exposures.
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Non-Occupational Bystander Exposure Bystanders who live or work near sites where commodity fumigation occurs are potentially exposed to fumigant emissions that travel off-site. For Registration Review, a revised PERFUM analysis has been completed. This PERFUM analysis has taken into account various fumigation scenarios as allowed by the registered labels (initial fumigation, maintenance fumigation and a 30 ppm maximum release concentration restriction identified on registered labels with warehouse treatments).
During treatment, the PERFUM analysis showed that, in most cases, air concentrations are not of concern at the edge of the application site during treatment except for the smallest (1000 ft3) and largest building sizes (50,000 ft3 and 500,000 ft3) considered at the highest percentiles. For a 5,000 ft3 building (assumed to be most representative of a truck/trailer fumigation), there are no predicted buffer distances during treatment. After treatment and during aeration, the PERFUM analysis did show varying predicted buffer distances depending on treatment concentration, building size, stack height and air exchange rate. When considering a maximum release concentration of 30 ppm (as required on both currently registered labels for warehouse treatments), no buffers were predicted for the no stack scenarios (with either passive or active aeration), and all fixed stack height scenarios (with active aeration). The smaller portable stack scenarios (5ft and 10ft stacks), as well as the horizontal stack scenarios, did result in predicted buffer distances, mostly for the larger building sizes (e.g., 25,000 ft3 and 50,000 ft3) and higher percentiles (e.g., 95th and 99th). With higher portable stack heights (25ft and 50ft), there were no predicted buffer distances considering a maximum release concentration of 30 ppm.
Based on the results of this analysis, it is acknowledged that many different factors can impact the air concentrations, and resulting exposures, in proximity to structures and chambers that are used for commodity treatments with sulfur dioxide. These factors can include building size, type of aeration/air exchange rate, type and height of ventilation stacks, as well as release concentrations.
Occupational Exposure Sulfur Dioxide: For occupational handlers who handle the pesticide prior to and during application and immediately after application and clearance (e.g., forklift drivers), HED anticipates that the current personal protective equipment (PPE) and air monitoring requirements on the registered labels, along with the existing regulatory standards in place, are adequate to ensure that workers are not exposed to sulfur dioxide levels of concern. Based on available post- fumigation air monitoring data following sulfur dioxide fumigation and considering the current label requirements for aeration to reduce sulfur dioxide concentrations to below 2 ppm, HED does not anticipate significant exposure for occupational post-application workers who may be exposed after fumigation from activities associated with the storage of commodities treated with sulfur dioxide.
Sodium Metabisulfite: Based on the submitted air concentration monitoring data and the existing regulatory standards in place for sulfur dioxide, HED does not anticipate that occupational handlers (both those that apply the sodium metabisulfite products and those that work in the treatment facilities) will be exposed to sulfur dioxide levels of concern. Based on the results of air monitoring data following use of the sodium metabisulfite pads, HED does not anticipate
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4.0 Inorganic Sulfites Formulations and Use Patterns
Use information for sulfur dioxide fumigations and sodium metabisulfite pads were compiled from review of currently registered product labels and registrant submissions. For sulfur dioxide fumigations, use information was provided in MRID 50188501 (The Fruit Doctor: Product Use Information of Sulfur Dioxide – Revised. J. Kay. 02/15/2017). For sodium metabisulfite pads, use information was provided in the protocol submitted to satisfy the Special Study requirement (SS-1117; Monitoring data on fumigated commodities) (Measurement of sulfur dioxide emissions as related to worker exposures resulting from table grape packages containing sulfur dioxide-generating paper pads, plastic sheets, or plastic liners that are used to preserve table grapes. S. Walse. 05/22/2015).
Sulfur Dioxide (SO2) There are three registered sulfur dioxide products: The Fruit Doctor (EPA Reg. 11195-1), Sea Fresh 150 (EPA Reg. 67799-3), and Airgas Sulfur Dioxide (EPA Reg. 89867-2). All of these product labels are designated as Restricted Use Pesticides due to corrosive effects during inhalation and to eyes and skin. These products are used as a postharvest treatment for grapes held in cold storage in enclosed spaces (e.g. warehouses and transportation vehicles) to control gray mold disease which is caused by Botrytis cinerea (EPA Reg. 11195-1 and 67799-3). In addition, sulfur dioxide is used as a fumigant in the wine industry for the sanitation of corks and barrels (EPA Reg. 11195-1 and 89867-2).
Grape Fumigation: Based on information provided in MRID 50188501, treatment of grapes typically begins around July 1 and ends by the middle of January. Use directions on registered labels indicate that the number of treatments depend on the variety of the grapes. For seeded varieties of grapes registered labels allow for up to 20 applications on a 7 to 10-day interval. Seedless varieties of grapes may be fumigated up to 15 times (at 7 to 10-day intervals) and Thompson Seedless grapes should not be fumigated more than 12 times (at 7 to 10-day intervals).
There are three distinct types of applications allowed on the labels: initial fumigation, maintenance fumigation, and total utilization. Initial fumigation is typically conducted at a higher concentration than maintenance fumigation. For the initial fumigation, based on label directions, products are applied to the treatment area via a hose system, with a detector tube, at a maximum rate of 1% concentration (10,000 ppm; based on the measured volume of the fumigation chamber). For the maintenance fumigations, sulfur dioxide (SO2) is applied at a lower concentration, up to 0.5% gas concentration (5,000 ppm). While these are the maximum treatment concentrations allowed by the registered labels, the registrant has indicated in MRID 50188501 that typical treatment concentrations tend to be lower as noted below.
Initial Grape Fumigation: Based on information provided in MRID 50188501, table grapes are picked and packaged in the field. Typically, packed boxes are placed on pallets and the pallets are loaded onto trucks and transported to cold storage facilities. Less frequently, table grapes are placed into field tote boxes and transported to cold storage facilities where they are packaged and palletized in the same manner as in the field. At the cold storage facility, the table grapes are typically immediately precooled (i.e., cooled
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very quickly to reduce the temperature of the grapes by circulating refrigerated air to remove field heat) and simultaneously fumigated with sulfur dioxide. Pre-cooling and treatment aregenerally completed within 4-8 hours. The pre-coolers typically range in size from 10,000 to 50,000 ft3. While the maximum label treatment rate is 10,000 ppm, information provided in MRID 50188501 indicates that the typical treatment rate for this application is 400-1,600 ppm. The initial fumigation can also be performed in non- refrigerated fumigation chambers and then followed by pre-cooling. This treatment time is generally restricted to 30 minutes in rooms that can range in size from 5,000 to 20,000 ft3, although the vast majority of the rooms are smaller than 10,000 ft3. Information provided in MRID 50188501 also indicates that the typical rate for this is also 400-1,600 ppm. The initial fumigation, either in fumigation chambers, trucks, or pre-coolers, only occurs once. However, because harvest occurs over a period of time, applications are made to incoming grapes on an almost daily basis until harvest is complete.
Maintenance Grape Fumigation: Based on information provided in MRID 50188501, after the initial fumigation, grapes are moved to a cold storage room. Grapes are typically held 2-3 months in cold storage. As noted above, the label allows for anywhere between 12 to 20 applications depending on grape variety; according to MRID 50188501, grapes are treated with a maintenance fumigation an average of 10 times, which usually occurs on a weekly basis. This may vary depending on the length of storage, the grape variety, and the treatment schedule. The maximum treatment rate for maintenance fumigations on the label is 5,000 ppm; however, information provided in MRID 50188501 indicates that these applications are typically conducted at lower rates– generally 200 to 650 ppm; although they may range up to 3,000 ppm. Cold storage facilities normally range in size from 50,000 to 300,000 ft3. The Fruit Doctor label (EPA Reg. 11195-1) allows for low dose, frequent maintenance fumigations (i.e., three times a week); however, information provided in MRID 50188501 indicates that they have found that this practice was not generally used in the industry and that a once a week application is typically sufficient.
Total Utilization Grape Fumigation: Total utilization fumigation is a method of fumigation that can be used in the initial fumigation and/or the maintenance fumigation stages. Traditional methods of fumigation result in excess sulfur dioxide that must be removed from the treatment room either through venting or scrubbing. Total utilization circulates sulfur dioxide over a longer period of time until it is almost completely absorbed by the fruit, packaging material, room surfaces, and/or ambient moisture. This method uses precise quantities of fumigant, and typically substantially less than for traditional fumigation, in order to ensure an efficacious dose of sulfur dioxide is applied. This approach results in residual air concentrations of sulfur dioxide at the end of the fumigation period that are 2.0 ppm or less.
Total utilization fumigation can only be used in conjunction with precooling for the initial fumigation since grapes that are not precooled during initial fumigation would employ a shorter exposure time (i.e., 30 minutes and then are quickly moved to a cold storage facility). If total utilization fumigation is used in either the initial or maintenance fumigation stage, air is moved throughout the room and boxes to ensure good penetration of the sulfur dioxide. After the fumigation is complete, the rooms are scrubbed to ensure
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the sulfur dioxide concentration is less than 2.0 ppm. The rates used in total utilization are designed to result in a sulfur dioxide concentration at the termination of fumigation of less than 2.0 ppm without venting or scrubbing, but because of varying absorption factors (for example, from the packaging or grape variety), scrubbing is used to remove any potential excess of sulfur dioxide.
Removal of Sulfur Dioxide after Grape Treatment: There are two main methods of removing sulfur dioxide after treatment: venting or scrubbing. Venting can be either passive aeration or mechanical aeration. For sulfur dioxide treatments, information provided in MRID 50188501 indicates that mechanical aeration is typically used. At the completion of fumigation, the rooms are vented to remove excess sulfur dioxide. Scrubbing is another method of removing sulfur dioxide. Most cold storage facilities utilize a wet scrubbing process, whereby efficient refrigeration systems are designed to pass refrigerated air through a water spray, lowering the sulfur dioxide concentration in the room below 2.0 ppm upon completion of the fumigation process. This process does not result in the release of sulfur dioxide into the environment. Labels indicate that venting or scrubbing must draw all SO2 saturated air from the spaces between the fruit within 20-30 minutes following fumigation to avoid excess residue. This requires complete air movement and air replacement in the room at the rate of at least 0.1 to 0.3 of the cubic volume of the room per minute for a duration of 20-30 minutes. If a water scrubber system is used, it is essential that sufficient scrubbing surface is available to remove the SO2 from the recirculating air to equal the rate of removal by direct venting. Both labels with warehouse fumigation treatments (EPA Reg. 11195-1 and 67799-3) also require that when treating grapes in a warehouse fumigation chamber, treated air is not to be released into the atmosphere containing concentrations of sulfur dioxide in excess of 30 ppm.
Cork Treatment: Based on information provided by the registrant, corks are treated at the place of manufacturing/packaging of corks (not at the wineries that use the corks). The application is automated by machinery that injects a measured amount of sulfur dioxide in a bag with a measured amount of corks. After the addition of the sulfur dioxide and corks to the bags, the bags are automatically sealed, then prepared for shipment. According to the registrant, by the time corks are sent to the user, all of the sulfur dioxide has been absorbed by the corks.
Barrel Treatment: Based on information provided by the registrant, barrels used in wine production are also treated with sulfur dioxide. A sulfur dioxide cylinder with a handheld gassing unit is used for the application. During application, a thumb or lever-operated ball valve dispenses the sulfur dioxide directly into the barrel for approximately 3 seconds. This achieves the desired and typical sulfur dioxide concentration. Right after the application, the gassing unit is removed, and the hole is replaced with a stopper. Depending on the winery, some barrels are treated again after 30 days if they are not put into use. However, because barrels are generally in constant use, it is relatively uncommon for barrels to be treated more than once before use. The total number of days of applications can vary depending on the winery, the number of barrels in use, and the rotation schedule. However, treatment could be considered “occasional” in that applications could occur as frequently as monthly lasting anywhere from one to several days, but applications do not occur on a daily basis.
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Personal Protective Equipment: Current sulfur dioxide end-use product labels require various levels of personal protective equipment (PPE) during application and while checking hose connections. EPA Reg. 11195-1 (Fruit Doctor), which is registered for application to grapes in warehouses, cold storage facilities, and transportation vehicles, as well as applications to barrels and corks used in wine production, requires that when workers are conducting activities in enclosed areas, they must wear a long-sleeved shirt and long pants, chemical-resistant gloves and boots, and either a supplied-air respirator with National Institutes of Occupational Safety and Health (NIOSH) approval number prefix TC-19C, OR a self-contained breathing apparatus (SCBA) with NIOSH approval number TC-13F. When making sulfur dioxide gas applications, workers must also wear goggles. EPA Reg. 67799-3 (Sea Fresh 150), which is also registered for application to grapes in warehouses, cold storage facilities, and transportation vehicles, has similar PPE requirements, but also requires that handlers wear coveralls during fumigations. When mixing/loading or cleaning, this label requires workers wear a chemical-resistant apron, and for overhead exposures, chemical-resistant headgear must be worn. For EPA Reg. 89867-2 (Airgas), which is only registered for use on barrels and corks in wine production, PPE requirements include chemical-resistant coveralls over long-sleeved shirt and long pants or chemical-resistant apron and coveralls over long-sleeved shirt and long pants, chemical resistant footwear plus socks, chemical-resistant gloves and a NIOSH approved full face respirator with acid gas or combination organic vapor/acid gas cartridge.
For workers in the fumigation facility (but not working in enclosed areas), the air concentration must be monitored and if the concentration of sulfur dioxide in the worker area, as measured by a pump and appropriate detector tubes, exceeds 2.0 ppm at any time, all persons working in the fumigation area must wear a NIOSH/Mine Safety and Health Administration (MSHA) approved self-contained breathing apparatus (SCBA) or combination air supplied SCBA respirator. If the concentration does not exceed 2.0 ppm, no respiratory protection is required.
After fumigation and aeration, treated areas must be undisturbed until the level of sulfur dioxide is at or below 2.0 ppm as determined by use of a direct detection device. Entry by any person into the treated area is restricted before this time unless provided with a respiratory protection device (SCBA or combination air supplied/SCBA respirator). For fumigations conducted in refrigerated transportation vehicles, the vehicles must be held for 24 hours and SO2 concentrations must be below 2.0 ppm before releasing the shipment.
Sodium Metabisulfite3 There are ten registered sodium metabisulfite products that are used as a preservative for table grapes. As with the SO2 fumigations, the primary purpose for the pads is to provide fungicidal control of B. cinerea. Products which contain sodium metabisulfite as the active ingredient are comprised of the solid, anhydrous active ingredient contained in semi-sealed pads, which are placed in containers holding grapes for shipping and storage. There is also one product, EPA Reg. 83131-1, that is described as a “liner” to be used with grapes in carry bags that are then placed in shipping containers/boxes and sealed. Sodium metabisulfite pads are used in both the import and export of grapes. In each crate, the sodium metabisulfite pads are separated from the
3 Product use information for sodium metabisulfite pads was provided in the protocol from the Sodium Metabisulfite Task Force. Measurement of sulfur dioxide emissions as related to worker exposures resulting from table grape packages containing sulfur dioxide-generating paper pads, plastic sheets, or plastic liners that are used to preserve table grapes. S. Walse. 05/22/2015.
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grapes by a layer of tissue paper and a layer of kraft paper, and then the entire contents are wrapped in a porous polyethylene liner bag before the crate is closed. As the pads absorb ambient moisture, they release sulfur dioxide within the crate.
Imported Grapes: Table grapes are imported into the United States from various countries around the globe, but primarily Chile. In general, grapes are transported from the field to nearby packing sheds where they are first fumigated with sulfur dioxide. Fruit is then sorted, packaged with SO2-releasing products, palletized, cooled to 32°F, and shipped over a 14 to 22 day period at 31 to 33°F. Four days before arrival at port, the palletized fruit is warmed to 40°F in preparation for methyl bromide fumigation on arrival into the United States. Thereafter, the fruit is returned to cold storage at 31 to 33°F and transported to customers at 31 to 33°F. Prior to display, the boxes are de-palletized, and the SO2-releasing products are removed.
Exported Grapes: California-grown table grapes are exported to markets in various countries. Grapes are packaged in the field, transferred to the packing house, and fumigated with SO2 per label instructions until entering the distribution channel. SO2- releasing products are added to boxes of fruit intended for export and prior to palletization; typically, this occurs either in the field or on arrival at the packing house. Storage temperature at a packing house is ideally 31 to 33°F and can last up to 3 weeks. Shipping times range from 1 to 4 weeks with temperature rarely exceeding 34°F. Table grape boxes intended for domestic distribution do not contain SO2-releasing products.
Since the crates are partially open on the sides and top, the free exchange of low levels of sulfur dioxide with the surrounding air occurs continuously. Once the grapes arrive for retail sale, the pads are removed from the crates and discarded. Since the sodium metabisulfite is contained in sealed pads, the likelihood of either oral or dermal exposure to the solid is considered minimal, providing the pads stay intact.
Pads have been developed as both dual release (with both quick and slow release phases) and as single release products. Single release pads are typically associated with exports. They have only one type of containment for the sodium metabisulfite. These pads can have polyethylene coated paper on both pad surfaces and cells or pockets of sodium metabisulfite evenly spaced across the pads, or they may have an even distribution of sodium metabisulfite laminated (glued) between a polypropylene film and polyethylene coated paper. Dual release pads are typically associated with imports. They consist of separate layers containing sodium metabisulfite. These pads can have pockets or cells of sodium metabisulfite contained between polypropylene film and polyethylene coated paper and another layer of sodium metabisulfite contained between the polyethylene coated paper and Kraft paper, or they may have an even distribution of sodium metabisulfite laminated between polypropylene film and polyethylene coated paper and another even distribution of sodium metabisulfite laminated between the polyethylene coated paper and the Kraft paper.
Some product labels (e.g., EPA Reg. 68506-2 and 74787-1) indicate the pads are available as either dual or slow release and in those cases, the product label indicates that slow release pads must be used in conjunction with an initial sulfur dioxide fumigation. If an initial fumigation is
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not possible, the dual release pads are recommended. For product labels that do not specify whether the pads are slow or dual release, the labels do not indicate whether fumigation with sulfur dioxide is allowed. HED recommends inclusion of a statement on these labels that clearly states whether the combined use of pads and sulfur dioxide fumigation is allowed.
Personal Protective Equipment: Current sodium metabisulfite end-use product labels require handlers to wear chemical-resistant gloves made of waterproof material such as polyethylene or polyvinyl chloride.
5.0 Hazard Assessment
The inorganic sulfites include the chemicals sulfur dioxide and sodium metabisulfite. There is a large volume of published data detailing the toxicity of inorganic sulfites, and consequently the toxicity of inorganic sulfites has been well established. EPA’s Office of Air Quality Planning and Standards (OAQPS) has worked extensively on sulfur dioxide (http://www.epa.gov/airquality/sulfurdioxide/), including setting national ambient air quality standards (NAAQS) for sulfur dioxide, a gaseous air pollutant. The FDA has also performed an extensive review of sulfiting agents (including sulfur dioxide, sodium metabisulfite, and sodium bisulfite) that have been added to any food or to any ingredient in any food.
5.1 Absorption, Distribution, Metabolism & Elimination (ADME)
Sulfur dioxide Sulfur dioxide is rapidly absorbed by the mucosa of the nose and upper respiratory tract (ATSDR 1998; CIR 2003). Sulfur dioxide can be hydrolyzed to sulfites which are taken up by the blood and readily distributed throughout the body (ATSDR 1998). Sulfites participate in three important reactions with biomolecules: sulfitolysis (chemical reaction where disulfide bonds in proteins are removed), autooxidation with generation of free radicals, and addition to cytosine (USEPA 2017; ATSDR 1998).
Inorganic sulfite residues Sulfite that enters the body via ingestion or inhalation is metabolized by sulfite oxidase to sulfate, primarily in the liver (ATSDR 1998; CIR 2003). Oral dose studies using dogs and rats and intravenous (IV) dose studies using rabbits, rats, and rhesus monkeys, demonstrated rapid metabolic clearance of sulfite (CIR 2003). Sulfite is cleared almost exclusively by oxidation to sulfate (Gunnison and Palmes 1976). In all species, ≤ 10% of the administered dose was excreted unchanged in the urine (CIR 2003). In clearance studies with injected sulfite, sulfite clearance in rats was more rapid than in the rabbit or rhesus monkeys (Gunnison et al. 1977).
Besides oxidation, sulfites can also react and become associated with disulfide bonds of plasma proteins, resulting in the formation of S-sulfonates (ATSDR 1998).
5.2 Toxicity of Sulfur Dioxide and Sodium Metabisulfite
Sulfur Dioxide
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For occupational workers, HED is also relying on various regulatory levels for inhalation exposure to sulfur dioxide. These include the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limit (PEL), the National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) and Short-Term Exposure Limit (STEL), and the American Conference of Governmental Industrial Hygienists (ACGIH) STEL (see Appendix A. Table A.2.).
5.4 FQPA Considerations
The primary NAAQs provide public health protection, including protecting the health of "sensitive" populations such as asthmatics, children, and the elderly (https://www.epa.gov/criteria-air-pollutants/naaqs-table). Consistent with the factors specified in FFDCA section 408(b)(2)(D), EPA has also reviewed the available scientific data and other relevant information in support of regulations establishing the 10 ppm maximum permissible level for residues of sulfur dioxide (76FR 56644). EPA also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including sulfite sensitive individuals, infants and children. EPA has concluded that there is sufficient toxicological information for sulfur dioxide to address risks to infants and children. In addition, the available information indicated that there is no evidence of increased quantitative or qualitative susceptibility of the offspring after in utero or postnatal exposure. Based on the lack of observed susceptibility, and since current regulatory values for SO2 (75 ppb) and sulfites (10 ppm) take into account the potential for sensitive populations, including infants and children, these regulatory values are considered protective, and no additional FQPA safety factor is required.
5.5 Endocrine Disruptor Screening Program
As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for the inorganic sulfites, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), the inorganic sulfites are subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).
EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a
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chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.
Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 20134 and includes some pesticides scheduled for registration review and chemicals found in water. Neither of these lists should be construed as a list of known or likely endocrine disruptors.
For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website.5
6.0 Anticipated Exposure Pathways
Humans may be exposed to inorganic sulfites in food, since sulfur dioxide may be applied directly to grapes after harvest. Exposures through drinking water are not expected since residues are not expected in water due to the use pattern. Dermal exposures are not expected given the high vapor pressure of sulfur dioxide, and based on the delivery systems (which include pressurized cylinders and/or impregnated pads). There are no uses of sulfur dioxide resulting in direct residential exposures; however, there is the potential for non-occupational bystander inhalation exposures. Occupational acute, short-, and intermediate-term inhalation exposures are possible and have been evaluated for the commodity uses of sulfur dioxide. Occupational handlers may be exposed while handling the pesticide prior to application and immediately after application and clearance (e.g., forklift drivers). Occupational post-application inhalation exposures may also occur from activities associated with cold storage of commodities treated with sulfur dioxide. This risk assessment considers all the aforementioned exposure pathways based on the existing uses of sulfur dioxide.
7.0 Residue Chemistry
The nomenclature, registration numbers, PC Code, and chemical structure of sulfur dioxide and sodium metabisulfite are listed in Appendix B.
The nature of the residue in grapes is adequately understood based on metabolism studies in which grapes were treated with radiolabel sulfur dioxide once per week for 16 weeks (D344469, J.R. Tomerlin, 10/09/2007 and D185546, B. Cropp-Kohlligian, 09/02/1993). Sulfite and sulfate were identified as the main residues in/on grapes treated with sulfur dioxide. Sulfate is a natural
4 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals. 5 http://www.epa.gov/endo/
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constituent in the human body and is necessary for the biosynthesis of sulfur-containing compounds. Based on the ubiquitous nature of sulfate, and its nutrient characteristics, it is not considered a residue of concern.
As stated in the 2007 RED, the FDA required ingredient labels to list sulfite concentrations in excess of 10 ppm in order to protect sulfite sensitive individuals. For the registration of the sodium metabisulfite end-use products for use on grapes imported from Chile, an expedited laboratory analysis program (ELAP) conducted under an FDA-approved protocol and administered under the Chilean exporters association was conducted to monitor all the grapes imported in 1988-1989. For the registration of sulfur dioxide end-use products, controlled experiments were conducted to test sulfite residues in/on grapes exposed to sulfur dioxide (E. T. Haeberer, 02/09/1989 and 05/25/1989). In the 2007 RED, the 10 ppm tolerance for residues of sulfur dioxide in/on grapes was supported.
The sulfur dioxide fumigation field trial studies with grapes provided important insights regarding sulfite residues in grapes following treatment. Most of the trials reflect a minimum time interval between last treatment and sample collection of 72 hours, and residues decline appreciably with time. Seedless grape varieties were found to have higher sulfite residues than seeded varieties. The residue levels in treated grapes increased with the number of applications, with the maximum number of treatments being 17. Decline data demonstrated slower residue decline in grapes that were fumigated with a combination of direct sulfur dioxide gas treatments and with sodium metabisulfite pads.
As noted previously (D411060, I. Negron-Encarnacion, 09/11/2013) current labels allow a high dosage treatment with an initial application at concentrations of 1% followed by up to 12 (Thompson seedless varieties), 15 (other seedless varieties) or 20 (seed varieties) subsequent applications at concentrations of 0.5% in a 7-10 day interval. However, residue data for the high dosage treatment at weekly intervals supports initial application of 0.5% followed by 12 applications of 0.25% (D156294, M. J. Bradley, 09/12/1990). Since residues are likely to decline significantly in one week, HED has no objection to keeping the current 1% initial application rate assuming at least 1 week between that application and marketing of the commodity. However, subsequent applications should be restricted to 0.25% as represented by available residue data since these applications more likely to affect residue levels of grapes reaching the market. Based on information provided by pesticide registrants and their representatives, subsequent applications of 0.25% are standard industry practice (Letter to K. Nguyen dated 05/21/2013). The maximum number of fumigations recommended by HED for the high dosage use is 12.
An analytical enforcement method (see 21 CFR Part 101 Appendix A) is available for enforcement of tolerances for sulfites at 10 ppm in food. The method transforms residues of sulfite to sulfur dioxide, the latter is converted to sulfuric acid and quantified by titration; residues are expressed as sulfur dioxide. While considered acceptable for tolerance enforcement, this method is not ideal for data collection purposes due to its labor-intensive procedures and limited sensitivity/specificity. It is noteworthy that the grape residue data were collected using a headspace gas chromatography (GC) method instead of the optimized Monier-Williams enforcement method and demonstrated adequate recoveries for spiking levels as low as 1 ppm.
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The literature has reports of an improved method for analysis validated by 11 laboratories in the United States and Canada (KS Carlos and LS de Jager, J AOAC Int. 2017, “Determination of Sulfite in Food by Liquid Chromatography (LC) Tandem Mass Spectrometry (MS): Collaborative Study”). This method converts sulfite to the formaldehyde adduct hydroxymethylsulfonate, which is separated from matrix components using a hydrophilic interaction LC analytical column and quantitated using tandem MS. Improved methods, such as that just described, should be considered for any future residue analysis involving sulfites in foods.
Conclusions: The residue chemistry deficiencies/recommendations below should be addressed. • For sulfur dioxide end-use products, modified labels matching the use pattern supported by the residue data are recommended. • Modification of the tolerance expression in the 40 CFR § 180.444 according to HED guidance is recommended. • Modification of the grape tolerance value is recommended for consistency with OECD Rounding Class Practice.
8.0 Dietary Exposure
Sulfites are the residues of concern for consumption of treated grapes. No residues are expected in drinking water. HED is relying on the FDA-established regulatory level of up to 10 ppm sulfite residues in foods. Residues in grapes from sulfur dioxide and sodium metabisulfite applications are expected to be below the 10 ppm level when applied as tested in the grape residue trials; there are no risks of concern for dietary exposures from these uses on grapes.
9.0 Residential Exposure
There are no uses of sulfur dioxide resulting in direct residential exposures; therefore, residential handler and post-application exposures are not expected.
10.0 Aggregate Exposure and Risk Assessment
In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. There are no residential uses of sulfur dioxide and exposure through drinking water are not expected based on the use pattern. Therefore, the aggregate assessment includes only dietary food exposures.
11.0 Non-Occupational Spray Drift Exposure and Risk Estimates
A spray drift assessment was not completed for sulfur dioxide. The application practices for sulfur dioxide are not reflected in the standard spray drift assessment as outlined in the Residential SOP Addenda 1: Consideration of Spray Drift6. Therefore, spray drift exposures have not been quantitatively assessed.
6 https://www regulations.gov/document?D=EPA-HQ-OPP-2013-0676-0003
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12.0 Non-Occupational Ambient Inhalation Exposure and Risk Estimates
There is the potential for inhalation exposure to sulfur dioxide via ambient air. These exposures can be acute as well as longer-term in nature. Ambient air data are typically required for fumigants; however, sulfur dioxide in ambient air comes from numerous, non-pesticidal sources, and is a criteria air pollutant regulated by EPA’s Office of Air Quality Planning and Standards (OAQPS) which has worked extensively on sulfur dioxide7, including setting national sulfur dioxide ambient air quality standards (NAAQS). Therefore, ambient air monitoring data were not required for sulfur dioxide by OPP for its use as a fumigant; rather, OPP defers to OAQPS for regulation of ambient air levels.
13.0 Non-Occupational Bystander Exposure and Risk Estimates
There are no residential uses of sulfur dioxide, but bystanders who live or work near sites where commodity fumigation occurs are potentially exposed to fumigant emissions that travel off-site.
In the 2007 RED for the inorganic sulfites8, a Probabilistic Exposure and Risk Model for Fumigants (PERFUM) analysis was completed. At the time of the RED, the endpoint selected by the Agency for the bystander inhalation risk assessment was 0.25 ppm9 sulfur dioxide, with a 1-hour exposure duration. It was concluded that there was concern for bystander exposure during grape fumigations, which involve the release of high levels of sulfur dioxide during aeration. At the time, the Agency expected sulfur dioxide concentrations following sulfur dioxide treatments to be too high for buffer zones to be a feasible option to address bystander exposure concerns. Therefore, to address the bystander concern, the RED recommended label changes to require a maximum release concentration of 30 ppm for warehouse treatments and 2 ppm for truck/trailer treatments. The maximum release concentration for warehouses was greater than the concentration for trucks/trailers based on the release of treated air following warehouse fumigation at a greater flow rate and a greater height above ground level, thereby reducing the potential for bystander exposure.
Subsequent to the RED, an amendment was published10 which stated that the Agency received additional data regarding the rate of absorption of sulfur dioxide into the fruit and packaging material during treatment. With this additional information, the Agency was able to establish practical buffer zones and provided recommended buffer tables for the product labels.
During Registration Review, HED has noted that the labels with warehouse treatments (EPA Reg. 11195-1 and 67799-3) include the 30 ppm release concentration restriction, but do not contain any buffer tables. Only EPA Reg. 11195-1 contains the 2 ppm maximum release concentration recommended in the RED for truck/trailer fumigations.
7 https://www.epa.gov/so2-pollution 8 Reregistration Eligibility Decision – Inorganic Sulfites. May 2007. https://www regulations.gov/document?D=EPA-HQ-OPP- 2006-0335-0002 9 Based on an ambient air quality standard set by the California Air Resources Board 10 Letter from P. Caulkins, Acting Director, Special Review and Reregistration Division. Amendment to the Inorganic Sulfites RED. April 25, 2007. https://www.regulations.gov/document?D=EPA-HQ-OPP-2006-0335-0003
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For Registration Review, a revised PERFUM analysis has been completed using the latest version of the model, PERFUM 3.0. This PERFUM analysis has taken into account both the initial fumigation and the maintenance fumigation scenarios, as well as the noted label restriction of a maximum release concentration of 30 ppm for warehouse treatments. Separate PERFUM runs were not included for the truck/trailer fumigation scenarios as these are assumed to be covered by those being run for the warehouse treatment, as noted in more detail below. For the treatment of wine barrels and corks, bystander exposure is not anticipated from these types of fumigations. Large scale venting is not utilized; barrels are closed with a stopper after fumigation and corks are sealed in bags after treatment. Fumigations involving total utilization also have not been assessed for bystander exposure since the result of total utilization is that there is no excess sulfur dioxide after fumigation.
PERFUM Inputs:
Meteorological Data: Major commodity uses occur in the coastal regions of Florida and California at ports, and significant levels of commodity production also occurs in these coastal regions; therefore, data from these locations were considered. Meteorological data representing these regions were used in this assessment, and specifically included Ventura, California, and Bradenton, Florida.
Treatment Types & Exposure Scenarios: A series of scenarios have been completed in order to assess the risks associated with the commodity uses of SO2. These factors stipulate the nature of the buildings, chambers, or structures being treated; application rates and treatment durations; and emission rates and factors. The various types of treatment scenarios include:
• Chamber During Treatment: This scenario represents concentrations resulting from potential leaks from a chamber during treatment (also referred to as a fugitive emission) where the desire is to retain SO2 according to the CxT (concentration x time) schedules until a desired level of efficacy is reached.
• Aeration with No Stack: This scenario represents concentrations that are emitted from a chamber after treatment is complete and the desire is to remove remaining SO2 as quickly as possible. Two different aeration scenarios have been assessed. In one scenario, SO2 is purposely vented with high air exchange rates, but there is no stack available to transport emissions further up into the atmosphere. Similarly, in the other scenario, there is no stack available but passive aeration is utilized, such as a door being opened, for aeration. This latter scenario is assumed to be representative of a truck/trailer fumigation.
• Aeration with Vertical Stack: This scenario represents concentrations that are emitted from a chamber after treatment is complete and the desire is to purposely vent remaining SO2 as quickly as possible. In this scenario, SO2 is purposely vented through a stack to transport emissions further up into the atmosphere to reduce buffer distances and enhance dilution. The results are reflective of a warehouse or other structure that is treated and a stack is on the roof for ventilation purposes. The impacts of near building downwash effects are accounted for in this scenario.
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• Aeration with Portable Vertical Stack Not Near Building: This scenario represents a situation where SO2 is vented through portable tubing to a stack in an area adjacent to a treated structure or chamber. The scenario represents concentrations that are emitted from a chamber after treatment is complete and the desire is to purposely vent remaining SO2 as quickly as possible. In this scenario, SO2 is purposely vented through a stack to transport emissions further up into the atmosphere to reduce buffer distances and enhance dilution. The results reflect a warehouse or other structure that is treated and SO2 is transported to a portable stack, typically within 200 feet of the facility for ventilation purposes. The near building downwash effects are minimized because of the placement of the stacks in this scenario.
• Aeration with Mobile Ground Level Source Not Near Building (horizontal stack): This scenario represents a situation where SO2 is vented through portable tubing where the output is laid on the ground in an area adjacent to a treated structure or chamber. The scenario represents concentrations that are emitted from a chamber after treatment is complete and the desire is to purposely vent remaining SO2 as quickly as possible. In this scenario, SO2 is purposely vented through the tubing to transport emissions away from the chamber or facility to reduce buffer distances. The results reflect a warehouse or other structure that is treated and then SO2 is transported through tubing with the output typically within 200 feet of the facility for ventilation purposes. The near building downwash effects are minimized because of the placement of the vent tubes in this scenario.
Treatment Concentrations (maximum concentrations derived from labels): • Initial fumigation: 10,000 ppm (1.63 lb ai/1000 ft3) • Maintenance fumigation: 5,000 ppm (0.82 lb ai/1000 ft3) • Maximum release concentration restriction: 30 ppm (0.005 lb ai/1000 ft3)
In addition to modeling the treatment concentrations noted above, the PERFUM outputs also include predicted buffer distances based on various percentages of the modeled concentrations (from 1% to 100%).
Chamber/Structure Volume: • Initial fumigation and maximum release concentration restriction in a warehouse: 1000, 5000, 10000, 25000, 50000 ft3 • Maintenance fumigation in a warehouse: 50000, 100000, 250000, and 500000 ft3 • For truck/trailer fumigations, it is assumed that the 5,000 ft3 building scenario would represent this type of fumigation. For trailer lengths of 40 – 53 ft, volumes range from approximately 2,400 ft3 to 3,500 ft3.11
Chamber/Structure Height: • 1,000 ft3 = 10 ft tall • 5,000 ft3 = 17 ft tall • 10,000 ft3, 25,000 ft3, and 50,000 ft3 = 25 ft tall
11 https://cerasis.com/wp-content/uploads/2015/08/2015TrailerGuide.pdf
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• 100,000 ft3, 250,000 ft3, and 500,000 ft3 = 75 ft tall
Stack & Release Heights: • All fixed stack heights = 10, 25 and 50 feet above roof of chambers or structures [Note absolute release height (i.e., the height at which release is occuring or building height plus stack height) then varies when added with specific building height] • Portable stack height = 5, 10, 25, and 50 feet
Active Air Exchange Rates: Per the registered labels for warehouse fumigations, air replacement in the room must be at the rate of at least 0.1 to 0.3 of the cubic volume of the room per minute for a duration of 20-30 minutes; therefore, air exchanges of 6, 12 and 18 hr-1 were modeled. For the treatment and passive aeration scenarios, a default air exchange rate of 0.05 hr-1 was modeled.
Stack Diameters: PERFUM can only accommodate a single stack so the diameters are varied in order to achieve the proper cross-sectional ventilation areas for each combination of chamber/structure size and air exchange value. The results for larger chambers or high concentration treatments, therefore, may be based on very large diameter stacks which would not occur in reality to achieve proper ventilation (i.e., 0.2 m to 5 m). Under actual conditions, multiple stacks would be used in order to achieve target air exchange rates. The architecture of PERFUM requires that these analyses be done in this manner. This approach is not expected to be a negative bias in the results. In fact, this approach is likely a conservative method because all emitted sulfur dioxide is forced out at one location making the predicted distances higher.
Treatment Frequency & Emission Profiles: Based on the label requirement that all sulfur dioxide be vented or scrubbed to draw all SO2 saturated air from the spaces between the fruit within 20-30 minutes following fumigation to avoid excess residue, and also based on the toxicity endpoint chosen for the bystander assessment, a 1-hour single emission treatment scenario was modeled. This scenario is based on a single application lasting 30 minutes, and an emission period also lasting 30 minutes. A one- hour emission profile also closely matches the chosen toxicity endpoint which is based on the 99th percentile of 1-hour daily maximum concentrations, averaged over 3 years.
Target Concentrations and Uncertainty Factors: The target concentration used for the sulfur dioxide PERFUM modeling, as noted above, was the U.S. EPA primary (health-based) National Ambient Air Quality Standard of 75 ppb, with an uncertainty factor of 1.
PERFUM Output:
PERFUM calculates outputs based on each day’s worth of meteorological data and the result is illustrated by Figure 1 which shows the distances from the commodity facility (i.e., chamber or building, green square) where airborne concentrations meet a threshold of concern around its perimeter (i.e., the irregularly shaped red line). The solid black concentric circle represents an example 95th percentile distance value around the perimeter (i.e., the distance for that day where
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MOEs are not of concern for 95% of those exposed). The cross-hatch area represents the locations where distances exceed the 95th percentile value (i.e., MOEs are of concern at these distances for 5% of the exposed population).
Figure 1: Example Daily PERFUM Output
PERFUM generates output for each day over a 5-year period (i.e., 1825 days) then summarizes the information by providing two types of results that include the “Maximum Buffer” distance and the “Whole Field Buffer” distance. Each is reported as a distribution.
The “Maximum Buffer” distribution is based on the maximum distance needed in order for the modeled air concentrations calculated using PERFUM for each day to not be of concern (i.e., modeled air concentration is less than the target concentration adjusted by the uncertainty factor) (i.e., a distribution of the farthest single points on the irregular red line from Figure 1 for each day). This results in a distribution that contains 1825 values.
The “Whole Field Buffer” is also based on values from each day, except the distances on which the distribution is based include the points where the entire irregularly shaped red line cross the spokes coming out from each building, not just the farthest point on the line from Figure 1. The number of values in the distributions vary and are based on 1825 days (or more intervals if averaging time is less than 24 hours) multiplied by the number of spokes around the building which relates to the building footprint.
PERFUM Results: Treatment scenario: In addition to considering appropriate buffer distances and other mitigation strategies during the aeration phase in commodity treatments, it is also important to consider how much material may leak from a chamber (or truck/trailer) during the treatment phase. In order to simulate this, low percentage mass release values (1% and 10% mass released) were used to mimic such situations. These estimates were calculated based on a passive aeration scenario
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lowest when considering a maximum release concentration restriction which was recommended by the RED and is already included on the registered labels for warehouse treatments; (2) there does not appear to be a significant difference in the buffer distances when using CA weather data versus FL weather data; (3) when considering higher release concentrations, the air exchange rate can have an impact on the predicted buffer distances for portable and fixed stacks, but does not impact no stack and horizontal stack scenarios, (4) larger building sizes tend to result in larger predicted buffer distances, and (5) higher release heights (i.e., stack heights) tend to result in smaller predicted buffer distances.
14.0 Occupational Exposure
14.1 Acute and Short-/Intermediate-Term Occupational Handler Exposure
Sulfur Dioxide There is potential for occupational handler exposure from the commodity uses of sulfur dioxide. During fumigation, the gas is dispensed from a steel cylinder through a hose into the interior of an enclosed, sealed structure. After treatment, the structure remains closed for a period of time after which aeration begins.
There is the potential for occupational acute, short-, and intermediate-term inhalation exposures; long-term exposures, or continuous exposures for more than 6 months per year, are not expected based on the seasonal nature of sulfur dioxide use. Occupational dermal exposures are not expected given the high vapor pressure of sulfur dioxide and based on the delivery systems used (which include pressurized cylinders). Therefore, dermal exposures have not been quantitatively assessed.
For the commodity uses of sulfur dioxide, occupational handlers include those individuals who handle the pesticide prior to application and immediately after application and clearance (e.g., forklift drivers). Those activities performed immediately after application are still considered occupational handlers because for commodity fumigation, the fumigation job site is under the purview of the fumigator until the fumigation and aeration has been completed and the commodity released.
Various regulatory exposure levels for inhalation exposure to sulfur dioxide exist to protect occupational workers [see Appendix A (Table A.2.2)]. These include the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limit (PEL) of 5 ppm (8-hr TWA) and the National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) of 2 ppm (up to 10-hr TWA). NIOSH and the American Conference of Governmental Industrial Hygienists (ACGIH) also provide a STEL value, or a short-term exposure limit, which is set at 5 ppm for NIOSH and 0.25 ppm for the ACGIH, and are considered the maximum allowable average airborne concentrations over any 15-minute period.
In addition to these regulatory levels, current sulfur dioxide end-use product labels require various levels of PPE for occupational workers during application and while checking hose connections. Workers conducting activities in enclosed areas must wear a long-sleeved shirt and long pants, chemical-resistant gloves and boots, and either a supplied-air respirator with NIOSH
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approval number prefix TC-19C, or a self-contained breathing apparatus (SCBA) with NIOSH approval number TC-13F. When making sulfur dioxide gas applications, workers must also wear goggles and, for the Sea Fresh 150 product, coveralls. The Sea Fresh 150 label also requires that workers wear a chemical-resistant apron when mixing/loading or cleaning, and chemical-resistant headgear for overhead exposures.
Labels also require that for workers in the fumigation facility (but not working in enclosed areas), the air concentration must be measured and if the concentration of sulfur dioxide in the worker area, as measured by a pump and appropriate detector tubes, exceeds 2 ppm at any time, all persons working in the fumigation area must wear a NIOSH/MSHA approved self-contained breathing apparatus (SCBA) or combination air supplied SCBA respirator.
The Agency believes that the current PPE and air monitoring requirements on the registered labels, along with the existing regulatory standards in place, are adequate to ensure that workers (both those that apply the sulfur dioxide products and those that work in the treatment facilities) are not exposed to sulfur dioxide levels of concern.
Sodium Metabisulfite Sodium metabisulfite is registered for post-harvest fumigation of grapes held in cold storage. Sodium metabisulfite is a solid formulation which produces sulfur dioxide gas when it absorbs water or moisture after being exposed to the atmosphere. Occupational dermal exposures are not expected given the high vapor pressure of sulfur dioxide and based on the delivery system (impregnated pads). Therefore, dermal exposures have not been quantitatively assessed.
Occupational handler inhalation exposure is anticipated to be limited due to the use pattern and packaging of the pads. As is described in more detail in Section 14.2.2, results from a submitted 12 study that measured the depuration of SO2 from an 88-box palletized load of table grapes containing sodium metabisulfite pads in a controlled-atmosphere room indicated that all SO2 concentrations were below the limit of detection of 100 ppb. The Agency believes that this information, along with the existing regulatory standards in place for sulfur dioxide, are adequate to ensure that workers (both those that apply the sodium metabisulfite products and those that work in the treatment facilities) are not exposed to sulfur dioxide levels of concern.
14.2 Acute and Short-/Intermediate-Term Occupational Post-Application Exposure
14.2.1 Occupational Post-application Dermal Exposure
Occupational dermal post-application exposures are not expected given the high vapor pressure of sulfur dioxide. Therefore, dermal exposures have not been quantitatively assessed for either the sulfur dioxide gas products or the sodium metabisulfite pad products.
12 Walse, S. 2018. Measurement of Sulfur Dioxide Emissions as Related to Worker Exposures Resulting from Table Grape Packages Containing Sulfur Dioxide-Generating Paper Pads, Plastic Sheets, or Plastic Liners that are used to Preserve Table Grapes. MRID 50971301.
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14.2.2 Occupational Post-application Inhalation Exposure
There is potential for occupational post-application inhalation exposure to sulfur dioxide while handling treated commodities. These exposures can possibly occur because SO2 may continue to volatilize, or off-gas, from treated commodities or the metabisulfite pads might contain residual quantities of SO2. This exposure may be acute, short- and intermediate-term in duration for workers. Exposure data for cold-storage workers and those further down the distribution chain (e.g., supermarket workers who unpack grape pallets) were required in the 2013 scoping document for Registration Review because of these possible exposures13. Emission-rate data for potential exposures due to off-gassing from treated facilities/commodities for workers conducting post-application activities were requested.
As part of Registration Review, the registrants submitted two studies to address the occupational post-application exposure data requirements for sulfur dioxide and sodium metabisulfite. One study was submitted that measured the off-gassing of sulfur dioxide following the fumigation of California table grapes14. The other submitted study measured the off-gassing of sulfur dioxide from different types of SO2-generating products (e.g., sodium metabisulfite pads) used to preserve fresh table grapes15. Both studies were reviewed by HED and found to be acceptable for risk assessment16.
Sulfur Dioxide The study submitted for sulfur dioxide was conducted in three parts: laboratory-scale, pilot- scale, and commercial-scale experiments. For each part, three scenarios were examined: 1. “Initial fumigation – insect control” – This scenario is meant to represent a situation where insect control is needed. A 1% concentration (or 10,000 ppm) was applied to the grapes for 30 min at 60oF, with varying post-aeration times (0.5, 1, 1.5, and 2 hr) followed by cold storage at 32oF. 2. “High Frequency, Low Dosage, Maintenance Fumigation with Total utilization”17 – This scenario involved maintenance fumigation with total utilization @ 400 ppm at 32oF 3x/week for 12 weeks. 3. Initial fumigation-forced air and Maintenance Fumigation with Total utilization – This scenario involved initial fumigation with forced air (used when insect control is not needed) and maintenance fumigation with total utilization @ 2,500 ppm at 32oF for 12 weeks.
During the course of the fumigation simulations, SO2 concentrations were measured.
13 Memo, D411060, I. Negrón-Encarnación, 09/11/2013. Inorganic Sulfites. Human Health Assessment Scoping Document in Support of Registration Review. 14 Walse, S. 2018. Sulfur Dioxide Off-gassing Following Fumigation of California Table Grapes. MRID 50654701. 15 Walse, S. 2018. Measurement of Sulfur Dioxide Emissions as Related to Worker Exposures Resulting from Table Grape Packages Containing Sulfur Dioxide-Generating Paper Pads, Plastic Sheets, or Plastic Liners that are used to Preserve Table Grapes. MRID 50971301. 16 D448667, Lowe, K. 03/19/2020. Sulfur Dioxide: Review of “Sulfur Dioxide Off-gassing Following Fumigation of California Table Grapes” D448360, Lowe, K. 03/19/2020 Sulfur Dioxide: Review of “Measurement of Sulfur Dioxide Emissions as Related to Worker Exposures Resulting from Table Grape Packages Containing Sulfur Dioxide-Generating Paper Pads, Plastic Sheets, or Plastic Liners that are used to Preserve Table Grapes”. 17 Total utilization is a process which uses precise quantities of fumigant, and typically substantially less than for traditional fumigation, in order to ensure an efficacious dose of sulfur dioxide is applied, but residual concentrations of sulfur dioxide at the end of the fumigation period are 2 ppm or less.
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For the commercial-scale study (which involved four 88 box pallets of table grapes), the study authors reported that for scenario #1, where the grapes were treated with 10,000 ppm SO2 for 30 minutes followed by aeration for 30 to 120 min and then transferred to cold storage at 32oF, the duration of the aeration time was found to inversely relate to the SO2 off-gassing levels. With a 120-min aeration time, SO2 off-gassing levels from packaged table grape pallets once in cold storage averaged 6 ppm initially and decreased rapidly to comply with the California OSHA permissible exposure limit (PEL) of 2 ppm SO2, an 8-hour time-weighted average concentration. In addition, as noted above in Section 2, after fumigation and aeration, registered labels require that treated areas must be undisturbed until the level of sulfur dioxide is at or below 2.0 ppm as determined by use of a direct detection device. Entry by any person into the treated area is restricted before this time unless provided with a respiratory protection device (SCBA or combination air supplied/SCBA respirator).
In the submitted study, for both scenario #2 [where grapes were treated with 400 ppm SO2 at 32oF three times a week for 12 consecutive weeks (i.e., high frequency, low dose maintenance fumigation with total utilization)] and scenario #3 [where grapes were treated with either 10,000, o 5,000 or 2,500 ppm SO2 at 32 F weekly for 12 consecutive weeks (i.e., initial fumigation-forced air and maintenance fumigation with total utilization)], levels of SO2 off-gassing were below the limit of detection (LOD) of 200 ppb for all replicate trials.
These study results indicate that, after fumigation and aeration, sulfur dioxide concentrations quickly fall below most regulatory standards for SO2, including the OSHA PEL (5 ppm for an 8- hour TWA) and the NIOSH REL (2 ppm for a 10-hr TWA). The measured air concentrations for scenarios #2 and #3 were also below the American Industrial Hygiene Association Emergency Response Planning Guideline Level (ERPG-1) of 300 ppb, which is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour without experiencing more than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor, and the ACGIH TLV STEL of 250 ppb, which is the maximum allowable average airborne concentration over any 15-minute period.
Current registered labels require aeration after fumigation until levels of SO2 are below 2.0 ppm. In addition, labels state that entry into treated areas is not allowed unless respiratory protection is worn. Based on the results of the submitted study and considering the current label requirements for aeration to reduce SO2 concentrations to below 2.0 ppm, HED does not believe there is a concern for occupational post-application workers following SO2 gas fumigation.
Sodium Metabisulfite As with the gas fumigation study, the study with sodium metabisulfite pads was conducted in three parts: laboratory scale, pilot-scale, and commercial-scale experiments. The studies were conducted to represent different scenarios (import versus export) and packaging types. For the commercial scale study, pallets containing 88 boxes of grapes with a single product and packaging type were transferred to a 1000 ft3 controlled-atmosphere room where an airstream metered to a flow of 3L/min was directed through the room and exhaust was monitored for SO2 concentrations. For this study, the calculated LOD for SO2 was 100 ppb. Results from the study indicated that SO2 concentrations were below the method LOD following the use of SO2-
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generating products to treat pallets of table grapes in both the import and export scenarios throughout the 30-day experiment.
The results from this study indicate that concentrations of SO2 after treatment with sodium metabisulfite-containing pads are below most regulatory standards including the OSHA PEL (5 ppm for an 8-hour TWA), the NIOSH REL (2 ppm for a 10-hr TWA), the American Industrial Hygiene Association ERPG-1 of 300 ppb, and the ACGIH TLV STEL of 250 ppb.
Based on the results of the submitted study, HED does not believe there is a concern for occupational post-application workers following the use of sodium metabisulfite pads, including those in cold-storage facilities and those further down the distribution chain.
15.0 Public Health and Pesticide Epidemiology Data
HED has prepared an updated incident and epidemiology report for inorganic sulfites in support of Registration Review.18 Inorganic sulfites incidents were previously reviewed in 2013. 19 At that time, based on the low frequency and severity of inorganic sulfites incident cases reported to Incident Data System (IDS) and NIOSH Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides further investigation was not warranted.
In the current IDS analysis from January 1, 2014 to November 4, 2019, no incidents involving inorganic sulfites were reported to either Main or Aggregate IDS.
A query of SENSOR-Pesticides from 2010-2015 identified 10 cases were identified involving sulfur dioxide (PC Code 077601). No cases involving sodium disulfite (PC Code 111409) were identified. All cases were coded as work related. Four cases were classified as moderate severity and six cases were classified as low severity. Most individuals experienced respiratory effects followed by nervous system effects.
The Agricultural Health Study (AHS) is a federally-funded study that evaluates associations between pesticide exposures and cancer and other health outcomes and represents a collaborative effort between the US National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), CDC’s National Institute of Occupational Safety and Health (NIOSH), and the US EPA. Inorganic sulfites are not included in the AHS, and therefore this study does not provide information for this report.
Based on the continued low frequency and severity of inorganic sulfites incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time.
16.0 Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, were considered in this
18 D455761, S. Recore, 01/13/2020, Inorganic Sulfites: Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment. 19 D411761, E. Evans and S. Recore, 05/15/2013, Inorganic Sulfites (Sulfur Dioxide and Sodium Bisulfite): Review of Human Incidents.
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human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (https://www.archives.gov/files/federal-register/executive-orders/pdf/12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated. Spray drift can also potentially result in post-application exposure and it was considered in this analysis. Further considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to other types of possible bystander exposures and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
17.0 Cumulative Risk Assessment
Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to the inorganic sulfites and any other substances and the inorganic sulfites do not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not assumed that the inorganic sulfites have a common mechanism of toxicity with other substances. In 2016, EPA’s Office of Pesticide Programs released a guidance document entitled, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis [https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide-cumulative-risk- assessment-framework]. This document provides guidance on how to screen groups of pesticides for cumulative evaluation using a two-step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk-based screening approach. This framework supplements the existing guidance documents for establishing common mechanism groups (CMGs)20 and conducting cumulative risk assessments (CRA)21. During Registration Review, the agency will utilize this framework to determine if the available toxicological data for the inorganic sulfites suggests a candidate CMG may be established with other pesticides. If a CMG is established, a screening-level toxicology and exposure analysis may be conducted to provide an initial screen for multiple pesticide exposure.
20 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) 21 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USEPA, 2002)
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18.0 Human Studies
HED has not independently reviewed the basis for the OAR standard of 75 ppb for SO2 air concentration levels. Nor has HED independently reviewed the basis for the FDA standard of 10 ppm in foods. Rather, HED has relied on the subject matter expertise of these two organizations who have extensive experience with their respective chemicals, and adopted these standards for the human health risk assessment based on that expertise. HED did not independently review or consider any human studies in completing this assessment.
19.0 References
EPA 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. EPA 822/R/02/038. Washington, DC: Office of Water, EPA.
National Academy of Sciences, Institute of Medicine, Food and Nutrition Board, 2004, Chapter 7: Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate. http://www.nal.usda.gov/fnic/DRI/DRI Water/water full report.pdf
Sulfate in Drinking-water; Background document for development of WHO Guidelines for Drinking-water Quality; http://www.who.int/water_sanitation_health/dwq/chemicals/sulfate.pdf
Sulfur Dioxide and Inorganic Sulfites: Summary of Hazard and Science Policy Council (HASPOC) Meeting of May 9, 2013: Recommendation on Multiple Toxicology Studies; Julie Van Alstine, MPH; TXR 0056660, 05/21/2013.
CIR 2003. Cosmetic Ingredient Expert Review Panel; Final Report on the Safety Assessment of Sodium Sulfite, Potassium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite and Potassium Metabisulfite. International Journal of Toxicology 22 (S2): 63-88 (2003).
USEPA 2017. National Center for Environmental Assessment – RTP Office of Research and Development: Integrated Science Assessment for Sulfur Oxides – Health Criteria (December 2017). EPA/600-R-17/451
IARC 1992. International Agency for Research on Cancer. Sulphur dioxide and some sulfites, bisulfites and metabisulfites. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 54:131-188.
OECD 2001. Organization for Economic Cooperation and Development; Screening Information Data Set for Sodium Metabisulfite, (7681-57-4) (November 2001).
NIOSH 2018. National Institute for Occupational Safety and Health. The Registry of Toxic Effects of Chemical substances: Sulfur Dioxide. https://www.cdc.gov/niosh- rtecs/WS456D70.html
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HSDB 2018. Hazardous Substances Data Bank. https://pubchem.ncbi.nlm.nih.gov/compound/1119#section=Toxicity
76FR 56644. Sulfur Dioxide: Pesticide Tolerances for Emergency Exemptions. Federal Register. Vol 76, No. 178. September 14, 2011.
ATSDR 1998. Toxicological Profile for Sulfur Dioxide. Agency for Toxic Substance Disease Registry.
WHO 1999. World Health Organization. Safety Evaluation of Certain Food Additivies. WHO Food Additives Series 42. International Programme on Chemical Safety. Sulfur Dioxide and Sulfites (addendum).
Gunnison and Palmes (1976). A Model for the Metabolism of sulfite in Mammals. Toxicology and Applied Pharmacology 38: 111-126.
Gunnison A et. al. (1977). Comparative Sulfite Metabolism in the Rat, Rabbit, and Rhesus Monkey. Toxicology and Applied Pharmacology 42: 99-109.
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