UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM

Date: September 11, 2013 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT: 

### Inorganic Sulfites. Hum an Heal th Assessment Scoping Document in Support of Registra tio n Review.

PC C ode: 077601 and 111409 DP Barcode: D411 060

Decision No.: 477567 Registration No.: NA

Petition Nos.: NA Regulatory Action: Registration Review

Risk Assess Type: Scoping Document CaseNo.: NA

TXRNo.: NA CAS No.: 7681-57-4 and 7446-09-5

MRIDNo.: NA



### FROM:

THRU:

TO: Ide li z Negron-Encarnacion

, Ph.D.

, Chemis}?

_ 

# ??<

L- 1 Ronnie Bever

, Ph.D., Toxicologist

## ~~**1** Alexandra LaMay, M.Sci., Bio logi st 

## U

Risk Assessment Branch V

Health Effects Division (7509P)

Michael Metzger, Branch Chief / 

# IJ j})

Risk Assessment Branch V

# ~/1 ?t

# ~ / Jeffrey Dawson

, Chemist

Immediate Office

Hea lth Effects Divis ion (7509P)

Khue Nguyen

, Risk Manager Reviewer

Neil Anderson

, Branch Chief

Risk Management 

### & Implementation Branch VII

Pesticide Re-evaluation Division (7508P)

Page 1 of25EXECUTIVE SUMMARY

E PA's Hea lth E ffects Division (HED) has evaluated the available data and the most recent

human health risk assessments for the inorganic su lfites (i.e. sulfur dioxide and sod ium

metabisulfite (an S0 2 generator)) to determine the scope of work necessary to support the registration rev i ew process. HED has considered the curren t use patterns (OPPIN Database and

curre n t labels) as well as the available toxicity and exposure information for the inorganic

sulfites. The inorganic sulfites are fungicides u s ed to treat botrytis ciner e a, the fungus which

causes bunch rot

, or gray mold on grapes. In addition

, su l fur dioxide may be used for sanitation

of wine corks and barre l s
, and for the control of botrytis cinerea in figs. Other sources of sulfites

include uses in alcohol reg ulat ed by the A l cohol and Tobacco Tax and Trade Bureau, and uses as food add itive s and as compo nent s of pharmaceuticals regulated by the Food and Drug

Administration (FDA).

Toxicity /Hazard

The two chemicals

, sulfur dioxide (inhalation exposure) and sulfites (such as sodi um metabisulfite

, a metabolite resulting in dietary exposure) have distinct toxicities. The Agency toxicological databases for sulfur dioxide and sodium metabisulfite) lack any OPP HED studies.
However, there is a large volume of published data detailing the toxicity of sulfur dioxide

, not only in animals but also in humans, including sensitive su bpopulati ons of humans. HED guideline studies may not be necessary to support registration revi ew

. Rather, for sulfites, the

HED will consider the results of an asse ss m ent of clinical human data currently in progres s at the

Food and Drug Adm ini stration (FDA). Therefore

, at this time the Agency is requesting no new toxicity data. For sulfur dioxide, the HED recommends that registrants submit relevant, published toxicity studies and present a compelling we i ght

- of-evidence ratio na le summarizing

wh y use of the data from these studies will suffice for endpoint selection to determine risks from

exposure to sulfur dioxide gas through inh alation

. Because these publi s hed articles are not currently available t o the Agency, they have not been reviewed by HED yet

, and only a summary of the toxicity is provided below.

Sulfur Dioxide: The primary mechanism of action of s ulfur dioxide i s that of an irritant, the lung s being the mo s t sensitive organ. Lung effects can be observed after acute exposure, and the

time of peak ef f ect is 5-l 

### 0 minutes. The most sensitive end points are increased airway resistance ( s Raw) and decreased forced expiratory volume in 1 second (FEV 1 ). Asthmatics are the

s ensitive group to su lfur dioxide exposure, and exercise (promoting mouth-breathing)

exacerbates thi s effect. Sulfur dioxide is considered not classifiable ( Group 3) as to carcinogenicity by I ARC (1992). No adverse effect was reported at any do s e on the
musculoskeletal, hepatic, renal, or endocrine systems or body weight in humans. Toxicological

studies provide very littl e biological plausibility for reproductive outcomes re l ated to 

## so2

exposure. It is unclear if durations of treatment longer than 5-l 0 minut es will increase th e severity of the symptoms.

Inorganic Sulfites: In general, symp t oms in sulfite-sensitive humans ( atopic population) to oral ingestion of su lfit e s include flushing

, ting lin g
, pruritis

, dysphagia

, che s t pain

, urticaria, angioedema, acute b roncho-constrict ion

, hypotension, anaphylactic shock

, and loss of

consciousness. It has been stated that broncho-constriction is the most commonly reported

Page 2 of25

### Page 3 of 25

adverse reaction to sul f

ites in a sub

- group of asthmatic subjects. D ata indicate that the current regulatory standard of 10 ppm of sulfites in/on grapes and figs is protective, even for the sensitive population.

Residue Chemistry

T olerances are establi shed in the 40 CFR §180. 636 for residues of sulfites in/on grapes and figs

. The tolerance expression needs to be modified according to the Interim Guidance on Tolerance Expressions ( S. Knizner, 27/May/2009 )

. For sulfur dioxide end

- use products, residue d ata depicting the label use pattern may be required. Alternatively, modified use pattern supported by the available residue chemistry data may be proposed. In addition, labels issues may need to be

addressed such as inclusion of a statement restricting u se of both

, sulfur dioxide pads and fumigation with gaseous sulfur dioxide

, in products that are currently silent with this respect

.

Dietary Exposure

Sulfites are the residues of concern for consumption of grapes and figs. Other sources of sulfites

in/ on food are regulated by other agencies. The Food and Drug Administration (FDA) is currently undergoing an effort to prepare a dietary risk assessment considering several sources of exposure to sulfites in food. The EPA will work with the FDA in order to address the dietary exposure of sulfites.

Aggregate Risk Assessment Exposure to sulfites is expected to occur mainly through the oral (dietary) route ; dermal and inhalation exposure will be insignificant . Based on this , the aggregate assessment includ es only the dietary exposure scenario.

Exposure to s ulfur dioxide is primarily through inhalation; significant oral and dermal exposures are not expected. Additionally, the inhalation endpoint for sulfur dioxide is different from that for the ingested sulfite residues

. Based on this

, bystander exposure to sulfur dioxide would not be aggregated with other routes of exposure.

Occupational & Residential Exposure Sulfur dioxide and sodium metabisulfite are not registered for residential uses. However,

b ystander exposure to SO 2 

### may occur as a result of offgassing from sulfur dioxide fumigation inside warehouses and transportation vehicles. Bystander risk will need to be evaluated depending on the information to be provided by registrants with regard to s ulfur dioxide emissions and the label prescribed use conditions. Fumigation use information is also required under Registration Review for assessment of potential buffers for aeration of enclosed spaces.

There is potential for occupational applicator e xposure to sulfur dioxide during fumigation. Data to address potential occupational applicator exposures are required under registration review. An updated occupational handler risk assessment may be required during registration review based

on exposure and/or toxicity data . There is potential for occupational post

- application exposure to sulfur dioxide while handling treated commodities or in facilities after fumigation. Data addressing potential exposures due to off

- gassing from treated facilities/comm odities for workers conducting post

- application activities need to be submitted to the Agency. A new occupational

post

- application assessment may be required under registration review based on exposure and/or toxicity information.

### Page 4 of 25

1.0 I NORGANIC 

### S ULFITES 

### F ORM ULATIONS AND 

### U SE 

### P ATTERNS



### HED used the Biological and Economics Analysis Division (BEAD) Label Data System to identify all agricultural and non

- agricultural uses of sulfur dioxide and sodium metabisulfite

. See

the BEAD Label Data Reports for sulfur dio xide ( 0 2/ 0 5/2013 ) and sodium metabisulfite (10/30/2009) for a complete list. In addition, the BEAD Chemical Profile for Registration Review was used to characterize the use pattern s of sulfur dioxide (04/11/2013, T. Chandgoyal et.al.) and sodium metabisul fite (12/07/2010, M. Ranville et. al.). These products are used as a postharvest treatment for grape s to control gray mold disease which is caused by b otrytis

cinerea

. In addition, sulfur dioxide is used in the wine industry for the sanitation of corks a nd barrels, and an emergency exception is in place for the use of sulfur dioxide to control botrytis

cinerea in figs.

Products containing sulfur dioxide as the active ingredient are formulated as liquid under pressure (99.9

- 100% sulfur dioxide) which tur ns into gas upon release of pressure. Sulfur dioxide is registered for post

- harvest fumigation of grapes h eld in cold storage in enclosed spaces (e.g. trailers, railcars, transportation vehicles and warehouses )

.

So dium metabisulfite products are compos ed of anhydrous solid active ingredient. When anhydrous sodium metabisulfite products absorb moisture from air, they produce sulf ur dioxide

gas. Semi

- sealed pads or bags impregnated with sodium metabisulfite ( concentrations vary from

8.6

- 98.5% a.i.) are placed inside storage and shipment containers of fresh grapes. The pads

release sulfur dioxide up to 1

- 5 ppm within the containers as they absorb moisture (EPA, 2007).

Based on a focus meeting with the registrants ( 04/30/2013) of sulfur dioxide and sodi um metabisulfite end

- use products, the former is used on grapes/figs produced in the USA for domestic consumption while the latter is mainly used for grapes to be imported to the USA for domestic consumption. In addition, the sodium metabisulfite pads may be used for grapes produced in the USA and exported to other countries.

Conclusions: Label statements were specified in the 2007 RED for sulfur dioxide and sodium

metabisulfite end

- use products. It is noted that limits to the sulfur dioxide concentrat ion released to the atmosphere during aera tion were included in these label statements recommended in the RED, see Appendix D. These limits should be included o n the labels of sulfur dioxide end

- use products. An initial fumigation with sulfur dioxide foll owed by the use of pads is recommended on the label of some sodium metabisulfite pads only. The labels of other end use products formulated with sodium metabisulfite and sulfur dioxide are silent. During registration review label revisions may be address ed by inclusion of a statement on the label of these products indicating that the combined use of pads and fumigation with sulfur dioxide is not allowed. In addition, label revisions may be proposed by HED during registration review as part of

harmonizati on efforts within inorganic sulfite end

- use products and revisions to all fumigant

labels.

### Page 5 of 25

2.0 H AZARD 

### I DENTIFICATION 

### /T OXICOLOGY



### The Agency toxicological database for sulfur dioxide and inorganic sulfites lacks any OPP HED

studies . H owever , t here is a la rge volume of published data detailing the toxicity of sulfur dioxide, not only in animals but also in humans, including sensitive sub

- population s of humans. HED guideline studies may not be necessary to support registration review . Rather

, for sulfites, the HED will consider the results of an assessment of clinical human data currently in progress at the Food and Drug Administration (FDA). Therefore, at this time the Agency is not requesting new toxicity data. For sulfur dioxide, the HED recommends tha t registrants submit relevant, published toxicity data and present a compelling weight

- of

- evidence rationale summarizing why use of the data from these studies will suffice for endpoint selection to determine risks from exposure to sulfur dioxide gas throu gh inhalation (see HASPOC memo; 05/21/2013)

. A summary of the toxicity of the literature studies in the OPP HED database is provided below

.

Sulfur dioxide is a gas to which humans may be exposed primarily via the inhalation route

. Sulfite residues can a ccumulate in/ on grapes and figs leading to oral exposure

. As explained below, inhalation and oral exposure result in differing toxic syndromes.

Sulfur dioxide: The primary mechanism of action of sulfur dioxide is that of an irritant. On

contact with moist mucous membranes, sulfur dioxide produces sulfurous acid, which is a direct irritant and inhibits mucociliary transport. The irritant induced stimulation of airway sensory end organs causes vagal stimulation and airway smooth muscle contraction. T he most sensitive organ system to the gas is the lungs; however, eye and dermal irritation may result at higher

concentrations. E ffects in the respiratory system can be observed after acute exposure, and the time of peak effect is 5

- 10 minutes. The most sensitive endpoints are increased airway resistance (sRaw) and decreased forced expiratory volume in 1 second (FEV 1 

### ). An increase of 100% in

sRaw or 15% in FEV 1 

### is considered adverse.

Asthmatics are the sensitive group to sulfur dioxide exposure, and e xercise (promoting mouth

breathing) exacerbates this effect. Exercising asthmatics may be adversely affected at very low

concentrations of sulfur dioxide. These effects on FEV1 and sRaw can be apparent in laboring

asthmatics at concentrations as low as 0. 2 ppm. Exposure of the general population to 20 ppm sulfur dioxide can result in respiratory system irritation, decreased lung function, airway inflammation, enhanced airway hyper

- responsiveness, irritation of skin and eyes, and clastogenic

effects in hum ans.

Sulfur dioxide is considered not classifiable (Group 3) as to carcinogenicity by IARC (1992). No adverse effect was reported at any dose on the musculoskeletal, hepatic, renal, or endocrine systems or body weight in humans. Epidemiologic studies on birth outcomes have observed positive associations between sulfur dioxide ( SO 2 

### ) exposure and low birth weight; however, toxicological studies provide very little biological plausibility for reproductive outcomes related

to SO 2 

### exposure. The inconsisten t results across trimesters of pregnancy and the lack of evidence regarding confounding by co

- pollutants further limit the interpretation of these studies. Currently, the most sensitive endpoint occurs in laboring asthmatics during acute exposure (peak

ef fect at 5

- 10 minutes ); it is unclear if longer durations of treatment will increase the severity of

### Page 6 of 25

the symptoms (i.e. result in a lower point of departure)

. Because sulfur dioxide is a gas and endpoints for inhalation exposure are expected to be protecti ve of dermal effects, dermal risk will not be assessed during registration review.

Sulfite residues: The FDA requires ingredient labels to list sulfite concentrations in excess of 10 ppm (expressed as SO 2 

### ); however, both sulfur dioxide (21CFR 182.3862) a nd sodium metabisulfite (21CFR 182.3766) are listed as Generally Recognized As Safe ( GRAS ) by the FDA, with limitations, as food preservatives. The provocative dose level established by the FDA is 3.7 mg sulfite (or 5 mg sulfite salt), which they do not a nticipate to cause a hazard to health.

At 3.7

- 10 mg sulfite, the FDA does not expect an acute, life

- threatening, anaphylactic

- like

reaction. Sulfite

- sensitive individuals would not experience more than a moderate acute sensitivity reaction. At greater t han 10 mg sulfite, a severe anaphylactic type of reaction may

occur in sulfite

- sensitive individuals. The 3.7 mg sulfite dosage may be achieved by consuming

about 1 pound of grapes with a sulfite tolerance level of 10 ppm. However, this dosage was set

ba sed on liquid bolus or capsular administration with the response measured within 15 minutes. It is unlikely that anyone would consume a pound of grapes within 15 minutes, particularly if adverse symptoms are developing. In general, symptoms in sulfite

- se nsitive humans include flushing, tingling, pruritis, dysphagia, chest pain, urticaria, angioedema, acute broncho

constriction, hypotension, anaphylactic shock, and loss of consciousness. It has been stated that

broncho

- constriction is the most commonly re ported adverse reaction to sul f ites in a sub

- group of asthmatic subjects.

There is a s ubpopulation of humans that demonstrate hypersensitivity to sulfites (atopic population). T he reaction to sulfite residues can be particularly severe in hypersensitive individuals who are also asthmatics, because the reaction can trigger an asthma attack. D ata indicate that the current regulatory standard of 10 ppm (a residue level common to that naturally

occurri ng in many foods) is protective, even for the sensitive p opulation.

3.0 R ESIDUE 

### C HEMISTRY



### The inorganic sulfites scoping document includes the chemicals sulfur dioxide and sodium metabisulfite. The latter liberates sulfur dioxide in humid conditions which is the compound responsible for the pesticidal activity. 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 tr eated with radiolabel sulfur dioxide once per week for 16 weeks (J.R. Tomerlin, D344469, 10/09/2007 and B. Cropp

- Kohlligian, D185546, 09/08/1993). Sulfi te and sulfate were identified as the main residues in/on grapes treated with sulfur dioxide. Sulfate is a

natural constituent in the human body and is necessary for the biosynthesis of sulfur

- containing compounds. The main sources of sulfate are food (due to food additive uses) and drinking water. A study reported residues of sulfate in food and beverag es at levels up to 4.9 mg/g in dried apples and 500 mg/L in coconut milk (IMNA 2004 ). Based on the ubiquitous nature of sulfate,

it s nutrient characteristics, and the low level of sulfate expected in/on grapes

, it is not considered

a residue of concern.

### Page 7 of 25

As stated in the 2007 RED, the Food and Drug Administration (FDA) required ingredient labels to list sulfite concentrations in excess of 10 ppm (expressed as SO 2 

### ) in order to protect su lfite

sensitive individuals. For the registration of the sodium meta bisulfite 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 impo rted 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. Harber, 02/08/1989 and 02/25/1989). In the 2007 RED, the 10

ppm toler ance for residues of sulfur dioxide in/on grapes was supported

.

For sulfur dioxide end use products, current labels allow a high dosage use 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 use at weekly intervals

supports initial application of 0.5% followed by 12 applications of 0.2 5% (M. J. Bradley, D156294, 09/13/1990). 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 commodi ty. However, subsequent applications should be restricted to 0.25% as represented by available residue data since these applications more likely

to a ffect residue levels of grapes reaching the market . Based on information provided by pesticide registrant s 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. A modified use pattern supported by the available residue data may be proposed by the registrant. Alternatively, if the current labeled rate is requested by the registrant, additional residue data supporting the labeled

use must be submitted.

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 su lfur dioxide. The FDA Center for Food Safety and Applied Nutrition evaluated 16 samples of grapes from 1999 to 2009. One sample of grapes imported from Mexico exceeded the tolerance and sulfur dioxide was declared in the product.

Currently, the 40 CF R § 180.444 has permanent tolerance for sulfite residues (determined as sulfur dioxide) in/on grapes at 10 ppm. In addition, a time

- limited tolerance for sulfites in/on figs (10 ppm) is included (P. Savoia, D392201, 09/01/2011). HED established interim g uidance on writing tolerance expressions for enforcement purposes (S. Knizner, 27/May/2009). In order to add clarity to the language used to establish the coverage of the tolerance expression and

measurement of the level of the residue in the Raw Agricult ural Commodity ( RAC ) the text in the 40 CFR § 180. 444 should read: “(a) General. (1) Tolerances are established for residues of

s ulfur dioxide and sodium metabisulfite (sulfur dioxide generator) , including their metabolites and degradates, in or on the co mmodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those sulfite residues convertible to sulfur dioxide, expressed as sulfur dioxide, in or on the commodity.”

### Page 8 of 25

Conclusions : The residue chemistry deficiencies /recommendations below need to be addressed

. For sulfur dioxide end

- use products, residue data depicting the label use pattern may be required. Alternatively, modified use pattern supported by the available residue chemistry data ma y be proposed. Modification of the tolerance expression in the 40 CFR § 180. 444 according to the new HED guidance.

4.0 D IETARY 

### E XPOSURE



### Based on the grape metabolism study, sulfites were identified as the residue of concern. The FDA require s ingredient l abels to list sulfite concentrations in excess of 10 ppm (expressed as

SO 2 

### ) in order to protect sulfite sensitive individuals. A tolerance of 10 ppm for grapes and figs was supported by the 2007 RED. Assuming the provocative dose established by the FDA ( 3.7 mg), r esidues of sulfites at the tolerance level are not expected to be of concern for the US population.

Sulfites also occur naturally in some foods as a result of ferme ntation . In addition, other sources of sulfites include uses in alcohol regula ted by the Alcohol and Tobacco Tax and Trade Bureau, and uses as food additives and as components of pharmaceuticals regulated by the FDA. Uses as

food additives may result in concentrations >100 ppm in dried fruits, juices, molasses, and sauerkraut juice, between 50 and 100 ppm in dried potatoes, grape juice, wine vinegar, gravies, fruit topping, and maraschino cherries, and between 10 ppm and 50 ppm in pectin, fresh shrimp, corn syrup, sauerkraut, pickled foods, corn starch, hominy, frozen potatoes, maple syrup, imported jams and jellies, and fresh mushrooms (Lester 1995 as cited in CIR 2003).

The pesticide uses of the inorganic sulfites may lead to lower sulfites residue levels than those resulting from food additive uses. H owever, the Agency may consi der other sources of sulfites during registration review. The FDA is undergoing an effort to prepare a dietary risk assessment considering several sources of exposure to sulfites in food . In addition, a new point of departure may be selected based on hum an clinical trial data

.

Conclusions: The EPA will work with the FDA to determine residue levels in various foods and appropriate methods for assuring safe levels of dietary consumption of sulfite residues

.

5.0 T OLERANCE 

### A SSESSMENT AND 

### I NTERNATIONAL 

### H AR MONIZATION



### Where possible, EPA encourages the harmonization of the US Tolerances and Maximum Residue Limits (MRLs) in key export markets . A table with the US tolerances, the Canada MRLs, Mexico MRLs and Codex MRLs for sulfur dioxide in registered RACs is provided in Appendix C

- International Residue Limits

. There are currently no established Codex, Canadian

and /or Mexican MRLs for sulfur dioxide in/on grapes ; therefore, harmonization is not germane

to this action

.

### Page 9 of 25

6.0 R ESIDENTIAL 

### E XPOSURE



### There are curr ently no registered residential uses of sodium metabisulfite or sulfur dioxide. There is the potential for bystander exposures which can occur from emissions during treatment

and aeration of commodities and structures. Structures and other treated spaces can leak during

treatment and also will off

- gas during aeration after application which creates a potential for bystander exposure for those nearby such treatments.

In the 2007 RED for inorganic sulfites, a Probabilistic Exposure and Risk Model for Fum igants (PERFUM) analysis was completed and 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. To address this concern, it was stated that a ma ximum release concentration was established at 30 ppm for warehouse treatments and at 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 treat ed air following warehouse fumigation at a greater flow rate and a greater height above ground level, thereby reducing the potential for bystander exposure. Based on the results of the PERFUM model, these release concentration levels are expected to limit bystander exposure potential to sulfur dioxide concentrations at or below 0.25 ppm, which is the ambient air quality standard set by the California Air Resources Board. Refer to Appendix D for recommended label revisions from the 2007 RED. The RED also sh owed the correlation between buffer zone size and release concentration for the sulfur dioxide grape fumigation scenario.

The Agency has specifically focused on assessing acute inhalation exposures resulting from fumigation applications because peak air concentrations typically occur at the beginning of

active aeration. For registration review and as done for other fumigants, these exposures will need to be characterized, including the use of computer modeling analyses ( e.g. , PERFUM) and estimation of p otential buffer zones required assure bystander and worker safety. Fumigation use and emission/aeration information are required to address potential bystander exposure. Residential assessments may be needed during registration review if a significant po tential for

risk concern is identified.

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, su lfur 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) who has worked extensively on sulfur dioxide 1 

### , including setting national

ambie nt air quality standards (NAAQS) for sulfur dioxide. Therefore, ambient air monitoring data are not required by OPP for its use as a fumigant; rather, OPP defers to OAQPS for regulation of ambient air levels.

Conclusions: As done in other fumigant risk assessments, bystander risk to sulfur dioxide emissions from treated commodities and structures may need to be evaluated depending on

1 

### http://www.epa.gov/airquality/sulfurdioxide/

### Page 10 of 25

sulfur dioxide emission information and the label prescribed use conditions. Fumigation use information is also required under Registration Review for assessment of potential buffers for aeration of enclosed spaces. A bystander exposure assessment may be required for Registration

Review.

7.0 A GGREGATE 

### E XPOSURE AND 

### R ISK 

### A SSESSMENT



### In accordance with the FQPA, HED must cons ider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. For sulfites, allergic reactions in sensitive individuals are the reason for required limitations in sulfite ingestion rather than any systemic toxicity. In the absence of significant systemic toxicity, a quantitative dietary (food and drinking water) risk assessment was not performed for the RED

. Since similar effects would not be expected to occur through dermal or inhalatio n exposure, and significant incidental oral exposure is not expected, the aggregate assessment includes only the dietary exposure scenario, for which quantification of risks is not appropriate. For sulfur dioxide, exposure is primarily through inhalation; significant oral and dermal exposures are not expected. Additionally, since the inhalation endpoint for sulfur dioxide is different from that for the ingested sulfite residues, aggregation across routes is not appropriate. Based on this bystander exposur e to sulfur dioxide would not be aggregated with other routes of exposure. HED will reevaluate the need for quantification of aggregate dietary exposures based on the results of the ongoing FDA hazard and risk assessment.

8.0 O CCUPATIONAL 

### E XPOSURE



### 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.

Sulfur dioxide is registered for grape fumigation in trailers, railcars, vehicles and warehouses. Sulfur dioxide is formulated as a liquid under pressure which forms a gas upon release for fumigation. The gas is dispensed from a steel cylinder through a hose into the i nterior of an enclosed, sealed structure. Occupational exposure limits (can be found in Appendix A. After treatment, the structure remains closed for a period of time after which aeration begins. Labels require use of a respirator when sulfur dioxide con centrations exceed 2 parts per million (ppm). The label prohibits people not wearing a NIOSH

- approved self contained breathing apparatus (SCBA) from entering the treated areas until air levels of sulfur dioxide have declined to 2 parts per million (ppm) o r less. The personal protective equipment (PPE) requirements and labeling language ensure that workers are not exposed to sulfur dioxide levels of concern.

Sulfur dioxide may also be used to treat barrels and corks used in wine production and for fumigati on of figs. In both cases, cylinderized SO 2 

### is used.

Handlers

### Page 11 of 25

There is potential for occupational applicator inhalation exposure to sulfur dioxide during fumigation. Applicator exposures are likely to be of short

- and intermediate

- term exposure
duration . No worker exposure data were submitted to the Agency regarding the fumigation of structures, barrels or corks used in wine production and/or food commodities. As such, data regarding potential worker exposure associated with structure and commodity fumi gation will be required. Handlers are required to wear protective clothing, gloves and boots. Respiratory protection is also required when checking connections or making gas applications.

Post

- application Workers There is potential for occupational po st

- application inhalation exposure to sulfur dioxide while handling treated grapes or wine making supplies. These exposures can possibly occur because

SO 2 

### may continue to volatilize from treated commodities or the metabisulfite pads might contain

residual quantities of SO 2 

### . This exposure may be short

- and intermediate

- term in duration for workers. Exposure data for cold

- storage workers and perhaps those further down the distribution chain (e.g., supermarket workers who unpack grape pallets) are required because of these possible exposures. Emission

- rate data for potential exposures due to off

- gassing from treated facilities/commodities for workers conducting post

- application activities need to be submitted to the Agency.

There is potential for occupatio nal post

- application inhalation exposure to sulfur dioxide in/on fumigated commodities contained in warehouses, cold storage rooms, trucks, vans, boxcars, and other vehicles. Air/ worker monitoring data are required under Registration Review. As part of registration review, tasks for workers near fumigation facilities/operations need to be defined to properly assess post

- application activities (i.e. aerators, fork

- lift operators, etc.). Potential exposures due to off

- gassing will be assessed for workers conducting post

- application activities near treatment operations.

Conclusions : A new occupational handler risk reassessment may be required during registration review based on exposure and/or toxicity data . A new occupational post

- application assessment may be required under registration review based on exposure and/or toxicity data.

9.0 P UBLIC 

### H EALTH AND 

### P ESTICIDE 

### E PIDEMIOLOGY 

### D ATA

Adapted from: E. Evans and S. Recore

, D411761, 05/ 15 / 2013



### OPP’s Incident Data System ( IDS ) includes reports of alleged huma n health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental agencies, and individual consumers. IDS reco rds incidents resulting in higher severity outcomes in more detail, in a module called the Main IDS module. Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide. The less severe human incidents (minor, unknown, or no effects outcomes) are reported by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS.

### Page 12 of 25

For the M ain IDS from January 1, 200 8 to F ebruary 19, 2013 there were no incidents reported in the database involving sulfur dioxide or sodium metabisulfite . In the A ggregate IDS , from January 1, 200 8 to February 19, 2013, there were no reported incidents involving sulfur dioxide

or sodium metabi sulfite

.

The SENSOR

- Pesticides database covers 11 states from 1998

- 2009, although reporting varies from state to state. A query of SENSOR

- Pesticides from 1998

- 2009 identifies 30 cases, stemming from 27 events, involving sulfur dioxide. Twenty five case s involved a single active ingredient and 6 cases involved multiple active ingredients. Of the 25 single ai cases, all were

work

- related. One case was high in severity, 10 were moderate in severity and 14 were low in severity. Twenty four of the cases o ccurred in California. Respiratory effects were the most commonly reported symptom. Fourteen of the 25 cases were conducting routine work activity not involved with pesticide application at the time they were exposed; three cases were applying the pestic ide, five cases were mixing or loading the pesticide, and the remaining three were conducting unknown work activities. Limited or missing case detail from the California case reports makes it difficult to further pinpoint a pattern from these incidents. The 2007 RED made sulfur dioxide product label changes and clarified PPE language meant to better protect workers. Because many of the SENSOR

- Pesticides cases from California did not include a case description; a query of sulfur dioxide cases was conducte d in California’s Pesticide Illness Surveillance System (PISP). The PISP query finds that only 3 sulfur dioxide cases have been reported since 2007; which supports the conclusion that sulfur dioxide does not present a risk of

concern at this time.

For sodium metabisulfite (PC code 111409 ) and sodium bisulfite ( PC code 078201; active ingredient previously identified), and a query of SENSOR

- Pesticides 1998

- 2009 identifies a total of 4 cases, stemming from 2 events. There were three fatalities and one lo w severity case reported. This multiple fatality event was considered by EPA in the 2007 Inorganic Sulfites RED and the deaths were determined not to be resultant of a pesticidal use. 2



### Conclusions: No sulfur dioxide cases have been reported into IDS. SE NSOR

- Pesticides, however, continues to see a low frequency of occupational sulfur dioxide cases reported from California related to grape fumigation. EPA will continue to monitor these incidents to see if sulfur dioxide incidents are declining as a result of the mitigation requirements. Based on the low frequency and severity of reported cases there does not appear to be a risk of concern at this time. One event involving sodium bisulfite reported to SENSOR

- Pesticides in 1999 resulted in

three fatalities . EPA was aware of this event at the time of the 2007 RED and determined the fatalities were not related to pesticide use of the chemical. Therefore pesticide incidents are low in frequency and there does not appear to be a concern for sodium bisulfate a t this time.

10.0 E NVIRONMENTAL 

### J USTICE



### Potential areas of environmental justice concerns, to the extent possible, were considered in this 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,"

2 Ibid.

### Page 13 of 25

( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a la rge 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 activit ies in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessmen ts for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized s ubgroups

, 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. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystander s and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

11.0 C UMULATIVE 

### R ISK 

### A SSESSMENT



### Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA ha s not made a common mechanism of toxicity finding as

to sulfur dioxide/sodium metabisulfite and any other substances and sulfur dioxide/sodium

metabisulfite does not appear to produce a toxic metabolite produced by other substances. For the purposes of thi s tolerance action, therefore, EPA has not assumed that sulfur dioxide/sodium

metabisulfite has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

a nd to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechan ism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

12.0 E NDOCRINE 

### D ISRUPTOR 

### S CREENING 

### P ROGRAM



### As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these s tudies 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

ch ronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for sulfur dioxide/sodium metabisulfite, EPA reviewed these data and selected the most sensitive endpo ints for relevant

### Page 14 of 25

risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), sulfur dioxide/sodium metabisulfite 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 ef fects 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

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, 2013 3 

### and includes some pesticides scheduled for Registration Review and chemicals found in water

. For further information on the status of the EDSP, th e policies and procedures, the list s of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 4



### In the interim, EPA is making no human health or environmental safety findings associated with

the EDSP scre ening of sulfur dioxide/sodium metabisulfite . Before completing this Registration Review, the Agency will make an EDSP FFDCA section 408(p) determination.

13.0 H UMAN 

### S TUDIES



### The Agency is aware of studies involving human subjects are available in the scien tific literature.

The 2007 RED referenced regulatory levels established by other agencies which are based on

studies that involved intentional exposure of human subjects. In addition, OPP may be coordinating with other agencies on the human health risk a ssessment for the inorganic sulfites. If after considering any of these studies and/or those submitted by the registrants the EPA

decides to rel y on one or more of them, the Agency will ensure that all regulatory requirements are met, including EPA ethics reviews or Human Studies Review Board reviews of any data from research involving intentional exposure of human subjects.

3 See http://www.regulations.g ov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

4 http://www.epa.gov/endo/

### Page 15 of 25

14.0 D ATA 

### R EQUIREMENTS



### Occupational/Residential Exposure 5



### 875.1400 Inhalation Exposure Study for Applicators . These studies are requ ired to assess exposures for applicators involved in fumigating commodities/materials and/or structural

facilities.

875.1700 Product Use Information . This information is required to assess product use parameters by major use region, frequency, and applic ation equipment.

875.2500 Post

-

Application Inhalation Exposure Study. This study is required to assess post

application exposures for workers near fumigation facilities/operations or who work directly with previously treated commodities/materials.

Speci al Studies

- Monitoring data on fumigated commodities . Special studies are required to evaluate emission rates for sulfur dioxide from treated commodities/materials and the potential for occupational exposure due to those emissions in the channels of trade after fumigation activities are complete.

Residue Chemistry

860.1500 Crop Field Trials. This study is required to support the high dosage use of sulfur dioxide end use products as stated in the label.

15.0 R EFERENCES



### EPA 2002

. 2002 Edition of the Drink ing 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, Chlo ride 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

Drinki ng

- water Quality; http://www.who.int/water_sanitation_health/dwq/chemicals/sulfate.pdf

Sulfur Dioxide and Inorganic Sulfites: Summary of Hazard and Science Policy Counci l (HASPOC) Meeting of May 9, 2013 : Recommendation on Multiple Toxicology Studies; Julie Van Alstine, MPH; 05/21/2013.

5 Ambient air data are typically required for fumigants. However, sulfur dioxide is a criteria pol lutant and EPA has set National Ambient Air Quality Standards (NAAQS) for sulfur dioxide, therefore, additional data are not required for use as a fumigant.

### Page 16 of 25

Inorganic Sulfites (Sulfur Dioxide and Sodium Bisulfite): Review of Human Incidents ; Elizabeth

Evans and Shanna Recore ; D411761 ; 05/ 15 / 2 013

.

Sulfur Dioxide. Section 18 Emergency Exception for the Post

- Harvest Use of Sulfur Dioxide on Fresh Figs to Control Botrytis Cinerea in California; D392201; 09/01/2011.

### Page 17 of 25

Appendix A: Toxicology Database and Data Requirements

A1. Toxicology Data Re quirements

The requirements (40 CFR 158.500) for food use for sulfur dioxide are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical

Require d (CFR) Satisfied a

870.1100 Acute Oral Toxicity

................................ ................................ ................ 870.1200 Acute Dermal Toxicity

................................ ................................ ............ 870.1300 Acute Inhalation Toxicity

................................ ................................ ....... 870.2400 Primary Eye Irritation

................................ ................................ ............. 870.2500 Primary Dermal Irritation

................................ ................................ ........ 870.2600 Dermal Sensitization

................................ ................................ ............... yes

yes

yes

yes

yes

yes no

no

no

no

no

no
870.310 0 Oral Subchronic (rodent)

................................ ................................ ........ 870.3150 Oral Subchronic (nonrodent)

................................ ................................ ... 870.3200 21

- Day Dermal

................................ ................................ ....................... 870.3250 90

- Day Dermal

................................ ................................ ....................... 870.3465 90

- Day Inhalation

................................ ................................ ................... yes

yes

yes

no, cr

yes, cr n o b

no b

no b

- N o a
870.3700a Developmental Toxicity (rodent)

................................ ............................ 870.3 700b Developmental Toxicity (nonrodent)

................................ ...................... 870.3800 Reproduction

................................ ................................ ........................... yes

yes

yes N o a

N o a

N o a
870.4100a Chronic Toxicity (rodent)

................................ ................................ ........ 870.4100b Chronic Toxicity (nonrodent)

................................ ................................ . 870.4200a Oncogenicity (rat)

................................ ................................ ................... 870.4200b Oncogenicity (mouse)

................................ ................................ ............. 870.4300 Chronic/ Oncogenicity

................................ ................................ ............. yes

yes

yes

yes

no N o a

N o a

N o a

no

= 870.5100 Mutagenicity

— Gene Mutation

- bacterial

................................ ............... 870.5300 Mutagenicity

— Gene Mutation

– mammalian

................................ ......... 870.5 375 Mutagenicity

— In vitro Chromosomal Aberrations

................................ . 870.5 385 Mutagenicity

— In vivo Chromosom al Aberration s.... 870.5 395 Mutagenicity

— Erythrocyte Micronucleus Test

................................ ...... yes

yes

yes

yes

yes N o a

N o a

N o a

N o a

N o a
870.6100a Acute Delayed Neurotox. (hen)

................................ ............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ................................ .... 870.6200a Acute N eurotox. Screening Battery

................................ ......................... 870.6200b 90

- D ay Neuro tox. Screening Battery

................................ ...................... 870.6300 Develop. Neuro tox.

................................ ................................ ................. n o , cr

no , cr

yes

yes

no , cr -

- N o a

N o a

- 870.7485 General Metabolism

................................ ................................ ................ 870.7600 Dermal Penetration

................................ ................................ ................. 870.7800 Immunotoxicity

................................ ................................ ....................... yes

no, cr

yes N o a

- N o a

a The requirements for these s tudies may be met by performing the guideline study. Alternatively , t he HASPOC is aware that numerous

literature studies exist for sulfur dioxide , and the HASPOC further believes that many of these literature studies may be sufficient to provide

informati on which could be used in lieu of guideline studies. Also, it is expected that HED will be able to rely on the ongoing FDA review

of human clinical data for hazard characterization of sulfites , and guideline toxicity studies will not be required.

b The requirements for these studies have been waived by HASPOC.



### A2. Toxicology Database

Table A2.1. Sulfur Dioxide Air Concentrations used for Regulatory/Guideline Purposes 1

Exposure Limit Agency/Group Regulatory/Guideline Level (ppm)

1

- hour WHO 0.13

Ca lifornia Air Resources Board 0.25 AIHA (ERPG

- 1) 0.3 State of Washington 0.25

### Page 18 of 25 State of North Dakota 0.27

State of Montana 0.5

3

- hour US EPA 0. 5

State of Florida 0.5

State of Maine 0.4

State of New Mexico 0.5

State of New York 0.25

St ate of Oregon 0.02

1 Adapted from the 2007 RED.

A2.1. Exposure Limits and Health Effects (Adapted from OSHA) 1

Exposure Limit Limit Values HE Codes Health Factors and Target Organs

OSHA Permissible Exposure Limit (PEL)

- General Industry

See 29 CFR 1910.1000 Table Z

- 1 5 ppm (13 mg/m 3 ) TWA HE14 Upper respiratory irritation,

nosebleeds

OSHA PEL

- Cons truction Industry

See 29 CFR 1926.55 Appendix A 5 ppm (13 mg/m 3 ) TWA HE14 Upper respiratory irritation,

nosebleeds

OSHA PEL

- Shipyard Employment

See 29 CFR 1915.1000 Table Z

Shipyards 5 ppm (13 mg/m 3 ) TWA HE14 Upper r espiratory irritation,

nosebleeds

National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limit (REL) 2 ppm (5 mg/m 3 ) TWA

5 ppm (13 mg/m 3 ) STEL HE4 Blindness

HE9 Bronchoconstriction

HE11 Breathing difficulties

HE14 E ye and respiratory irritation,

eye and skin burning

American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) (2009) 0.25 ppm (0.65 mg/m 3 )

STEL

A4 HE9 Bronchoconstriction,

exacerbation of asthma

HE10 Decreased lung function,

chronic respiratory symptoms

HE11 Lower respiratory irritation

and symptoms

HE14 Upper respiratory irritation

CAL/OSHA PELs 2 ppm (5 mg/m 3 ) TWA

5 ppm (10 mg/m 3 ) STEL

1 http://www.osha.gov/dts/chemicalsampling/data/CH_268500.html

### Page 19 of 25

A.2.2. Regulatory Values for Sulfur Dioxide and Inorganic Sulfites a

EPA Sulfite residues on grapes, postharvest; used as fungicide and preservative: 10 ppm

EPA Pesticide worker protection: When concentrations exceed 2.0 ppm in the fumigation area,

NIOSH/MSHA

- approved respirators must be worn

EPA Bystander inhalation: 0.25 ppm

EPA National P rimary Ambient Air Quality Standards (NAAQS). Sulfur oxides: long term

concentration averaging 0.03 ppm over 1 year (annual arithmetic mean) REVOKED ; short term concentration averaging 0.14 ppm over 24 hrs (not to be exceeded more than once a year)

REVOKE D ; 1

- hour exposure limit: 0.075 ppm

California Acceptable ambient air concentration: 0.25 ppm for 1 hr; 0.04 ppm for 24 hr

OSHA PEL Short

- term exposure limit: 5 ppm ; time

- weighted avg: 2 ppm

WHO 10 min exposure limit: 0.2 ppm ; 1

- hr exposure limit: 0.13 ppm ; 24

- hour exposure limit: 0.04

- 0.06

ppm; annual arithmetic mean: 0.015

- 0.023 ppm
FDA Generally recognized as safe ( GRAS ) when used in accordance with good manufacturing or

feeding practice, except that it is not used in meats or in food recognized as source of vitamin B1

CERCLA Extremely hazardous substance; reporting requirements when stored in excess of 500 lbs.

ACGIH 15

- min short term exposure limit (STEL): 0.25 ppm ; A4; Not classifiable as a human carcinogen

NIOSH Recommended Exposure Limit: 10

- hr time

- weighted avg: 2 ppm

NIOSH Recommended Exposure Limit: 15

- min short

- term exposure limit: 5 ppm

NIOSH Immediately dangerous to life or health: 100 ppm

IARC Carcinogen classification Group 3 ( not classifiable as to its carcinogenicity in humans)

American

Industrial Hygiene

Association ERPG

- 1, the maximum airborne concentration below which it is believed that nearly all persons

could be exposed for up to 1 hour without experiencing other than mild transient adverse health effects or perceiving a cl early defined, objectionable odor: 0.3 ppm

a From the National Library of Medicine’s Hazardous Substance Data Bank, last revised on April 30, 2010, ATSDR (December 1998), Reregistration Eligibility Decision

– Inorganic Sulfites (May 2007), www.OSHA.gov , and www.arb.ca.gov/research/aaqs/aaqs2.pdf

.

### Page 20 of 25

Appendix B: Chemistry

1.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

1.1 Identification of Active Ingredi ent

Table 1 .1 Test Compound Nomenclature

Chemical Structure

Empirical Formu la SO 2 Na 2 S 2 O 5 Common Name /

IUPAC name Sulfur Dioxide Sodium Metabisulfite

CAS Registry Number 7446

- 09

- 05 7681

- 57

- 4



### 1.2 Physical and Chemical Properties

Table 1.2 Physico

- Chemical Properties

Property S ulfur Dioxide References Sodium Metabisulfite References
Molecular Weight 64.06

ATSDR,

1998a

NIOSH,

1994 190.19

HSDB,

2005 Color/Form Colorless gas White crystals or powder

Odor Strong suffocating

odor Slight odor of sulfur

dioxide Melting point

- 72.7 °C 150 °C
Boiling point

- 10 ° C Decomposes OECD,

2001 Density 2.927 g/L 1.4 g/cm 3 HSDB,

2005 Solubility in Water 22.8 g/100mL (0 °C) 54 g/L (20 °C)

1 Adapted from the RED (May 2007) for the Inorganic Sulfites.

### Page 21 of 25

Appendix C: International Residue Limits



### Sulfur Dioxide (PC Code 077601 )

Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180. 444 : A toleranc e is established as follows for sulfite residues of the fungicide sulfur dioxide (determined as (SO2)) None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex Grape, postharvest 10

Completed: M. Negussie; 03/13/2013

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.



### (b) Section 18 emergency exemptions. Time

- limited tolerances specified in the following table are established for residues of sulfur dioxide, including its metabolites and degradates in or on the specified agricultural commodities, resulting fr om use of the pesticide pursuant to FFIFRA section 18 emergency exemptions. Compliance with the tolerance levels specified below is to be determined by measuring only sulfur dioxide (SO 2 

### ). The tolerances expire on the date specified

in the table.

Commodit y Parts per

million Expiration/revocation date

Fig 10 12/31/14

### Page 22 of 25

Appendix D: Label Revisions Recommended in the 2007 RED

Table 1 .: Label Statements for Sulfur Dioxide End

- Use Products “When treating grapes for Botrytis cinerea (bunch rot/gray mold) or black widow spider in a warehouse fumigation chamber, do not release treated air into the atmosphere containing concentrations of sulfur dioxide in excess of 30 ppm (as determined by a Sensidyne or Kitagawa syringe sampler, or a Draeger handpump).”

“Wh en treating grapes in a truck, trailer or other transport vehicle, do not release treated air into the atmosphere containing concentrations of sulfur dioxide in excess of 2 ppm (as determined by a Sensidyne or Kitagawa syringe sampler, or a Draeger handpum p).” “Sulfur dioxide concentration in transport vehicles must be below 2 ppm before moving over public roads or highways.” “Before moving or using this product, handlers must be trained how to appropriately use respirators which conform to OSHA requiremen ts (described in 29 CFR Part 1910.124) and how to appropriately handle and use sulfur dioxide.” “When making gas applications or checking connections wear a NIOSH/MSHA approved full face respirator with an organic

- vapor removing cartridge, in addition to sulfur dioxide impervious gloves, boots and coveralls over long

- sleeved shirt and long pants.” “If a sulfur dioxide concentration of 2 ppm is exceeded at any time, all persons working in the fumigation area must wear a NIOSH/MSHA approved full face respir ator with an organic

- vapor removing cartridge. If sulfur dioxide concentrations of 10 ppm are exceeded, or when concentrations are unknown, an approved self

- contained breathing mask (SCBA) or combination air supplied SCBA respirator must be used by all per sons working in the fumigation area.” “Do not perform sulfur dioxide aerations concurrently from multiple chambers.”

Table 2

. Label Statements for Sodium Metabisulfite End

- Use Products (pad labeling) “This pad contains sodium metabisulfite which may t rigger an asthmatic response in sulfite

sensitive individuals.” “This pad must be removed and disposed of prior to displaying grapes for sale. Do not allow consumers access to pads.” “If pad is torn: Carefully dispose of pad, pad contents, and grapes whi ch have contacted pad contents.” “For Disposal: Place pad in a plastic bag, seal bag and place in an outdoor trash receptacle (dumpster).”

### Page 23 of 25

Appendix F: Data Call

- In

Guideline Number: 875.1400 Study Title: Inhalation Exposure Study for Applicators (f or sulfur dioxide fumigation in enclosed spaces). Rationale for Requiring the Data The inhalation exposure route is very important for exposure scenarios such as fumigation activities where gases will be generated. However, very limited worker exposure monitoring data are available for

workers involved in the fumigation of commodities, other materials, and/or structural facilities . These data do not address the breadth of possible activities associated with sulfur dioxide uses that are of potential risk concern. Traditional sources of worker exposure information (e.g., Pesticide Handlers Exposure Database or PHED) have not been used to supplement the existing data and do not apply because of the highly volatile nature of sulfur dioxide

. To protect worker s from inhalation exposure to pesticides, the Agency requires inhalation exposure monitoring data. These data will ensure that the Agency has the most accurate information possible to assess exposures for those involved in the fumigation process. In additi on, these data will be used during registration review to evaluate the potential for sulfur dioxide occupational exposure to fumigators who treat structural facilities, commodities, and other materials, and will inform the Agency as to how to manage any ri sks which may be identified based on these data which will reflect the current use practices

for sulfur dioxide

. Practical Utility of the Data

How will the data be used? The inhalation exposure data will be used to assess occupational risks for worker s involved in fumigation activities during treatment of commodities, materials and/or structural facilities. How could the data impact the Agency’s future decision

- making? The inhalation exposure data will be used to determine the accuracy of the inhalat ion risks to occupational applicators during fumigation activities based on modern fumigation practices. If future risk assessments are performed without these data, the Agency will have to factor a significant degree of uncertainty into its regulatory dec ision

- making process and that the current mitigation measures (i.e., personal protective equipment) may not provide adequate protection for workers applying sulfur dioxide in structural facilities and/or during the treatment of commodities and other materi als. The lack of these data will limit the flexibility of the Agency and registrants with respect to the ability to evaluate risks associated with the modern use practices associated with sulfur dioxide . It will also allow the Agency to refine its previou s risk assessment and could be used to defend challenges to the sulfur

dioxide decision and to consider additional sources of exposure to those involved in the fumigation

process.

Guideline Number: 875.1700 Study Title: Product Usage Information

Rat ionale for Requiring the Data The Agency’s understanding of sulfur dioxide products and usage is limited to the directions found on pesticide labels and estimates of the amounts used to treat certain commodities or structures. The Agency,

believes that t he current understanding of the sulfur dioxide usage pattern is not sufficient to assess the full range of potential exposure associated with its use because how it is applied, how much is applied, and associated fumigation practices (e.g., aeration method s) can impact exposures and these data are not available in a systematic manner. Additional data are necessary to understand sulfur dioxide usage in terms of both commodity and facility

### Page 24 of 25

fumigations and the potential exposures as a result of these uses. Th ese data will ensure that the Agency has the most accurate information possible to assess product usage parameters by major use region, frequency, season, maximum and typical rates, and application equipment/procedures. In addition, these

data will be used during registration review to evaluate the potential exposure for workers and the general public.

Practical Utility of the Data

How will the data be used?

This information will be used to confirm the end

- use products, use patterns, usage assumptions and parameters to determine exposures to sulfur dioxide for humans or provide the basis for possible refinements to the process based on a more thorough understanding of modern fumigation practices. How could the data change the Agency’s decision?

Additi onal precautions and/or restrictions may be necessary to protect workers and the general public from exposures to sulfur dioxide as a consequence of commodity/material fumigations and/or fumigation of structural facilities. These data will allow the Agency to refine its previous risk assessment and could be used to defend challenges to the sulfur dioxide decision.

Guideline Number: 875.2500 Study Title: Post

- Application Inhalation Exposure Study (for sulfur dioxide fumigation in enclosed spaces).

Rati onale for Requiring the Data Postapplication inhalation exposure to sulfur dioxide is predicted to occur as a result of the registered uses

of sulfur dioxide , including commodity/material fumigation and/or structural fumigations. The existing

data for ex posure to sulfur dioxide are limited in terms of the variety of post

- application activities and the potential exposures due to off

- gassing from treated structural facilities and commodities. The original data requirements were not broad enough to assess r isks to occupational workers near fumigated facilities treated with sulfur dioxide or who have to work directly with sulfur dioxide treated commodities/materials that could result in post

- application exposures which may be a concern. These data

will ensure that the Agency has the most accurate information possible to assess post

- application exposures for workers near fumigation structural facilities/operations or who work with treated commodities/materials. In addition, these data will be used in registrati on review to determine if the potential for postapplication occupational exposure for workers near fumigation facilities/operations is below the Agency’s level of concern or establish further risk management needs that would apply to the

use of sulfur diox ide

. Practical Utility of the Data

How will the data be used? These data will be used to determine inhalation exposure to sulfur dioxide for workers conducting a variety of post

- application activities near fumigated facilities/commodities or who work directly with

treated commodities/materials. How could the data impact the Agency’s future decision

- making? The post

- application inhalation exposure study will provide data to support and fully characterize and quantify the exposure and risks of workers exposed to this pesticide. Due to the lack of data, the Agency has used assumptions in developing the risk assessment. These data will allow the Agency to refine its previous risk assessment and could be used to defend challenges to the sulfur dioxide deci sion.

### Page 25 of 25

Special Study: Monitoring data on fumigated commodities with Sulfur dioxide (from sodium metabisulfite pads)

. Rationale for Requiring the Data The potential postapplication exposures associated with commodity fumigation were not quantitati vely assessed when these uses were established. The Agency did not have monitoring data to directly measure

emissions of sulfur dioxide from fumigated commodities/materials. These data will ensure that the Agency has the most accurate information possible on exposure to evaluate emission rates from treated commodities. Postapplication risks estimates will be calculated for workers exposed to sulfur dioxide and will be used to determine if the potential for occupational exposure due to those emissions (i.e. , for postapplication workers who must handle or receive treated commodities) is below the Agency’s level of concern. Practical Utility of the Data

How will the data be used? These data will be used to determine if the exposure to sulfur dioxide from handling treated commodities/materials is below the Agency’s level of concern. In addition, these data will be used to inform emissions factors and buffer zone estimates during the treatment and aeration phases of the fumigations for sulfur dioxide commodi ty uses. How could the data impact the Agency’s future decision

- making? These monitoring data are needed to fully characterize emissions from fumigated commodities. These data will allow the Agency to refine its previous risk assessment in terms of model parameterization (i.e., buffer zones, emissions and other factors). In addition, more precise information appropriate for parameterization of the exposure models could be used to refine the previous risk assessment and to defend challenges to the sulfur d ioxide decision.