Document ID: EPA-HQ-OPP-2006-0335-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-23T04:00Z

Reregistration Eligibility Decision

Inorganic Sulfites

Special Review and Reregistration Division 

Office of Pesticide Programs

U.S. Environmental Protection Agency

1801 South Bell Street

Arlington, VA 22202



Introduction

The Environmental Protection Agency (EPA) has completed its
Reregistration Eligibility Decision (RED) for the inorganic sulfites
case, which includes the chemicals sulfur dioxide and sodium
metabisulfite.  This assessment provides information to support the
issuance of a Reregistration Eligibility Decision for inorganic
sulfites.  EPA’s pesticide reregistration process provides for the
review of older pesticides (those initially registered prior to November
1984) under the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) to ensure that they meet current scientific and regulatory
standards. 

In this document, EPA presents the results of its review of the
potential human health effects of dietary, drinking water and
occupational/bystander exposure to inorganic sulfites, as well as its
ecological risk findings.  Evaluations performed by the World Health
Organization (WHO), the International Agency for Research on Cancer
(IARC), and the Agency for Toxic Substances and Disease Registry (ATSDR)
were relied upon for this assessment, in addition to peer-reviewed
evaluations performed by the Cosmetic Ingredient Review (CIR), the
Organization for Economic Cooperation and Development-Screening
Information Data Set (OECD-SIDS) and from other open literature sources.
 Based on this assessment, the Agency has determined that products
containing sulfur dioxide or sodium metabisulfite are eligible for
reregistration provided the necessary label changes are made.  As a
result of this assessment, one tolerance has been reassessed.

I.  Use Information

The inorganic sulfites reregistration case includes the chemicals sulfur
dioxide (CAS No. 7446-09-5) and sodium metabisulfite (CAS No.
7681-57-4).  As active ingredients, these chemicals are fungicides
typically used to treat for Botrytis cinerea, the fungus which causes
bunch rot, or gray mold disease on grapes.  The sulfur dioxide products
are formulated as a compressed liquid that converts to a gas upon
release.  These products are used in cold-storage warehouses, trucks,
vans and train cars for post-harvest grape fumigation.  In addition to
the fungicidal use against Botrytis cinerea, sulfur dioxide is also used
in combination with carbon dioxide to treat for black widow spider on
grapes in warehouse settings.  The black widow spider treatment is not
included on any sulfur dioxide product labels, as this use is permitted
solely under a FIFRA 24(c) carbon dioxide registration (CA920007).  The
sodium metabisulfite products are composed of the anhydrous, solid
active ingredient contained in semi-sealed pads which are added to
containers holding grapes prior to shipping.  The pads absorb moisture
generated by grapes, and release low levels of sulfur dioxide in the
range of 1-5 ppm.  

End-use inorganic sulfite products contain sulfur dioxide at 99.9 to
100%, and sodium metabisulfite at 37.5 to 98.5%.  The Agency currently
has six of the ten sodium metabisulfite products designated as
containing sodium bisulfite (078201) as the active ingredient.  As of
the publication of this RED, the Agency will transfer these
registrations to the sodium metabisulfite designation (111409).  The
tolerance being reassessed in this document, with the
respectivecitation in the Code of Federal Regulations (CFR), and the
use pattern as an active ingredient is listed in Table 1. 

Table 1. Tolerance Being Reassessed for Inorganic Sulfites

Tolerance Expression	

CAS No.	

40 CFR	

PC Code 	

Limit	

Use Pattern

Active Ingredient

Sulfur dioxide (as sulfite residues)	

7446-09-5	

§180.444	

77601	

10 ppm	

grape, postharvest/used as fungicide and preservative

Sodium metabisulfite (as sulfite residues)	

7681-57-4	

 §180.444 	

111409	

10 ppm	

grape, postharvest/used as fungicide and preservative

Both sulfur dioxide (21CFR §182.3862) and sodium metabisulfite (21CFR
§182.3766) are listed as GRAS (Generally Recognized as Safe) by the FDA
(Food and Drug Administration) as preservatives in certain foods. 
Sodium metabisulfite is also used up to a concentration of 1% as an
antioxidant in hair care products and as a reducing agent in cosmetic
formulations (CIR 2003). Sources of sulfur dioxide include the
combustion of fossil fuels, smelting of sulfide ores, volcanic
emissions, and other natural sources.  Sulfur dioxide is also used to
manufacture hydro- sulfites, to bleach wood pulp and paper, to process,
disinfect, and bleach food, for waste and water treatment, in metal and
ore refining, and in oil refining (ATSDR-MMG 2004).

II.  Physical/Chemical Properties

The physical and chemical properties of the inorganic sulfites are
provided in Table 2. 

Table 2.  Physical/Chemical Properties of Inorganic Sulfites

	

Sulfur Dioxide	

References	

Sodium Metabisulfite	

References

Molecular weight	

64.06	

ATSDR, 1998a

(*NIOSH, 1994)	

190.109	

HSDB, 2005

Color/Form	

colorless

white crystals or powder

	

Odor	

strong odor; suffocating

slight odor of sulfur dioxide

	

Melting point	

-72.7oC

150o C

	

Boiling point	

-10o C

Decomposes	

OECD, 2001

Density 	

2.927 g/L (gas)

1.434 g/L (liquid)

1.4	

HSDB, 2005

Solubilities	

22.8 g/100 mL (water at 0o C)

8.5 mL/100 mL (water at 25o C)*

11.3 g/100 mL (water at 20o C)

0.58 g/100 mL (water at 90o C)

54,000 mg/L water @ 20o C

81.7 g/100 mL water @ 100o C

	

Vapor Pressure	

3000 mm Hg at 20o C

Not available

Relative vapor density	

2.25 (air = 1)	

NIOSH, 1994

	

Relative density	

1.4 at -10o C (water = 1)

Specific gravity	

2.26	

MSDS, 1996

	

III.  Hazard Assessment

A. Acute Toxicity

Sufficient toxicity information is available for both sulfur dioxide and
sodium metabisulfite from publicly available sources.  

Sodium Metabisulfite

Table 3.  Acute Toxicity Data for Sodium Metabisulfite

Study Type	

Species	

Lethal Dose (LD50) or Lethal Concentration (LC50) 	

Toxicity Category1	

Reference

Acute Oral 	

rat	

LD50 = 1540 mg/kg, death observed (1250 mg/kg

LD50 = 1131 mg/kg	

III 	  TOXNET, 2005

OECD, 2001

Acute Dermal 	rat	LD50  >  2000 mg/kg	III	TOXNET, 2005

Acute Inhalation	

Not Available

 Dermal Sensitization	

guinea pig	

Non-sensitizer 	

----	

OECD, 2001

Skin and Eye Irritation

	rabbit	

Not irritating to the skin; Irritating to the eyes	

Not provided	OECD, 2001

1 The toxicity category ratings were not provided by OECD. 

At high oral doses (> 1% or 10,000 ppm in the diet), effects seen in
rats were local irritation, including inflammatory changes and
hyperplasia in the stomach (WHO, 1999).  Although dermal toxicity
studies performed with sodium metabisulfite in laboratory animals have
not been submitted to the Agency, a report by the Cosmetic Ingredient
Review Committee (CIR, 2003) indicates that dermal penetration is
unlikely due to the highly charged nature of sulfites.  Cosmetic
products containing sodium metabisulfite range from shampoos and hair
coloring products, to eye and skin lotions, and makeup foundations. 
Sodium metabisulfite was not sensitizing in the standard skin
sensitization test in the guinea pig.  

Sulfur Dioxide:

Table 4.  Acute Toxicity Data for Sulfur Dioxide

Study Type	

Species	

 Lethal Dose (LD50) or Lethal Concentration (LC50) Results	

Toxicity Category1	

Reference

Acute Oral 	

Not Available

Acute Dermal	

Not Available

Acute Inhalation	

guinea pig	

Lowest published LC: 1039 ppm/24 hr (2.7 mg/L/24 hr)	

IV	NIOSH, 2004

	guinea pig	

LC50 = 1000 ppm/20 hr; 130 ppm/154 hr

=2620 mg/m3/20hr or 2.6 mg/L	

IV	

HSDB, 2005

	mouse	LC50: 3000ppm/30 min (7.9 mg/L/30min)	

IV	

NIOSH, 2004

	mouse	

LC50 = 150 ppm/847 hr; 

1000 ppm/4 hr (2.6 mg/L)	

IV	

HSDB, 2005

	

rat	

Lethal concentration (LC50): 2520 ppm/1 hr or 1.65 mg/L; 2168 mg/m3; 20
mg/m3/5 hr; 30 mg/m3	III	

NIOSH, 2004

         Dermal                sensitization	                           
                                Not Available

1 The toxicity category ratings were not provided by NIOSH. 

B.  Reproduction/Developmental Toxicity/Endocrine Disruption:

No evidence of reproductive toxicity was observed in rats exposed orally
to 942 mg/kg bw/day of sodium metabisulfite (2% in the diet) in a diet
supplemented with thiamine (OECD 2001).  Developmental studies reported
by the CIR 2003 indicate sodium metabisulfite produced no adverse
findings, either maternal or fetal, in mice up to 160 mg/kg in a water
solution, in rats up to 110 mg/kg in the diet, in hamsters up to 120
mg/kg in the diet, or in rabbits up to 123 mg/kg in the diet.  These
results are supported by developmental information reported by WHO
(1999) in which no effects were observed on implantation, or on maternal
or fetal survival in sodium metabisulfite doses of up to 150, 110 and
120 mg/kg bw in mice, rats, and hamsters, respectively (WHO Series 18). 
Reproductive effects were not observed in rats exposed to 5-30 ppm
sulfur dioxide for a period from 9 days prior to mating until 12-14 days
of pregnancy; or in mice exposed to 25 ppm sulfur dioxide 7 hours/day on
gestation days 6-15; or in rabbits exposed to 70 ppm sulfur dioxide 7
hours/day on gestation days 6-18 (ATSDR, 1998a).

C.  Carcinogenicity:

Sulfur dioxide and sodium metabisulfite are currently not classifiable
(Group 3) as to their carcinogenicity to humans (IARC 1992).  As for
laboratory animals, there was limited evidence for the carcinogenicity
to sulfur dioxide, based on inhalation studies reviewed by the IARC,
which indicated an increased incidence of lung tumors in female mice
after exposure to sulfur dioxide.  However, the concentrations of sulfur
dioxide evaluated in these inhalation studies were not reported. 
Conclusions of the OECD SIDS report indicated 2% sodium metabisulfite
via feed (20,000 ppm or 1,000 mg/kg/day) for 104 weeks was not
carcinogenic in Wistar rats.  

D.  Genotoxicity/Mutagenicity:

Sodium metabisulfite was negative in an Ames/microsome assay (SRI
International 1978b as cited by CIR 2003).  Negative results were also
reported for a host-mediated assay using mice to test mutagenicity
against bacteria and yeast, in a cytogenetic assay using rats (Litton
Bionetics 1972 as cited in CIR 2003), and a cytogenetic assay using
sulfite oxidase-deficient hamsters and mice (Renner and Wever 1983 as
cited in CIR 2003).  Sodium metabisulfite was negative in one dominant
lethal assay using rats while another study indicated further testing
was needed (CIR 2003).  However, genetic toxicity studies summarized by
the OECD 2001 indicate sodium metabisulfite is equivocal in in vitro
testing, but is not genotoxic in the in vivo testing.

E.  Special Considerations for Infants and Children

There is sufficient toxicological information for sulfur dioxide and
sodium metabisulfite to address FQPA considerations.  The available
information indicates that there is no evidence of increased
quantitative or qualitative susceptibility of the offspring after in
utero or post-natal exposure.  Based on this information, there is no
concern, at this time, for increased sensitivity to infants and children
to sulfur dioxide and sodium metabisulfite when used on postharvest
grapes. 

	F.  Incident Data

In evaluating incidents to humans from sulfur dioxide and sodium
metabisulfite exposure, the Agency evaluated data from the National
Pesticide Information Center, the National Institute of Occupational
Safety and Health (NIOSH), National Poison Control Centers, the
California Department of Pesticide Regulation (CDPR), and the Agency’s
Incident Data System.  The CDPR sulfur dioxide search identified 87
incident reviews from 1982 through 2003, many of which resulted from
non-pesticidal uses.  The NIOSH system search indicated that 19
incidents were reported involving sulfur dioxide from 1998 through 2003.
 Most of these cases involved effects such as chest pains, dizziness,
numb hands, teary eyes, blurred vision, itching, and rashes. A 1991
report from the CDPR system also identified a case involving a delivery
worker developing an asthmatic response following exposure to sulfur
dioxide drift from a nearby fumigation facility.  No incidents were
reported for sodium metabisulfite; however, sodium bisulfite was
implicated in the deaths of three workers using sodium bisulfite with a
non-pesticidal use pattern.

IV. Occupational Risk Assessment

Regulatory exposure levels for inhalation exposure to sulfur dioxide
include the OSHA PEL, NIOSH IDLH, and AIHA ERPG-1.  The OSHA PEL
(permissible exposure limit) is set at 5 ppm and is based on a time
weighted average over an 8 hour workshift.  The NIOSH IDLH (immediately
dangerous to life or health) is 100 ppm and the AIHA ERPG-1 is 0.3 ppm. 
The AIHA (American Industrial Hygiene Association) ERPG-1 is the maximum
airborne concentrations 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 clearly
defined, objectionable odor.

Sodium Metabisulfite

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.  In each crate the sodium metabisulfite pads are 
separated from the 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 to a level of 1-5 ppm
within the crate.  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.  Grapes are usually kept in these containers for 4-6 weeks
before arrival at retail establishments.  Once the grapes arrive for
retail sale, the pads are removed from the crates and discarded.  The
low level of sulfur dioxide present in the crates or released to the
surrounding environment is not expected to result in an occupational
inhalation exposure of concern, as any exposure is expected to be of
short duration and at or below the 8 hour OSHA PEL.  Furthermore, 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.

Pad disposal directions vary among the product labels; therefore, the
Agency has determined that standardization of the labeling on the pad
itself, is necessary.  This labeling will include revised handling and
disposal statements, in addition to a statement for asthmatics and
sulfite sensitive individuals which identifies the presence of sulfites
in these products.  These label statements are detailed in Section XIII
of this document.  Based on the product use patterns, the low levels of
sulfur dioxide released and the additional label requirements included
in this document, the Agency expects occupational exposures to sodium
metabisulfite to be below levels of concern.

Sulfur Dioxide

Products which contain sulfur dioxide as the active ingredient are
formulated as a liquid under pressure which forms a gas upon release for
grape fumigation.  These products are stored in steel cylinders and
applied to the treatment area via a hose system with a detector tube at
a maximum rate of 1% concentration (based on measured volume of the
fumigation chamber) for the initial fumigation, and up to 0.5% gas
concentration for maintenance fumigations.  Grapes are fumigated on a
7-10 day interval, and may be treated up to 20 times.  Fumigation may
occur in various types of cold-storage warehouses, or in truck trailers,
vans and railcars.  

Current sulfur dioxide end-use product labels require various levels of
personal protective equipment (PPE) during application and while
checking hose connections.  Workers must use sulfur dioxide detection
devices (Draeger handpumps, Sensidyne or Kitagawa syringe samplers) to
monitor the concentration in the fumigation area.  If concentrations
exceed 2.0 ppm in the fumigation area, the use of a NIOSH/MSHA approved
respirator is required for “short exposures of limited duration.” 
Labels also require a self-contained breathing apparatus (SCBA) or
combination air-supplied respirator/SCBA for exposures to unknown
concentrations, re-entry into a treated area with concentrations in
excess of 2.0 ppm, and for emergencies.  Other PPE requirements on
current labels include protective clothing, gloves and boots impervious
to sulfur dioxide, in addition to eye protection.  These PPE
requirements, as well as the respirator requirements, however, are
inconsistent among product labels.  Respirator requirements are also not
clear regarding when a standard respirator (with an
organic-vapor-removing cartridge) is acceptable or when a SCBA
respirator is required.  In order to clarify when SCBA respiratory
protection is necessary and to address other PPE inconsistencies, the
Agency has developed standard personal protective equipment (PPE) label
requirements as stated in Section XIII of this document.

The Agency believes that the current PPE requirements with the
additional labeling language required in this reregistration decision
are adequate to ensure that workers are not exposed to sulfur dioxide
levels of concern.  

V. Bystander Inhalation Risk Assessment

Several regulatory endpoints and standards for ambient air
concentrations of sulfur dioxide have been established at the state,
Federal and international levels (see Table 5).  The endpoint selected
by the Agency for the bystander inhalation risk assessment is 0.25 ppm
sulfur dioxide, with a 1-hour exposure duration.  The 0.25 ppm
concentration is based on an ambient air quality standard set by the
California Air Resources Board.  This endpoint is deemed most applicable
to this exposure scenario, as it is based on effects of concern for
bystanders (such as broncho-constriction, shortness of breath, wheezing,
and chest tightness during physical activity in persons with asthma),
and is recognized by the State in which nearly all grape treatments
occur.  Further, considering the 15-30 minute aeration period used with
the grape treatment, an endpoint based on an exposure duration of 1-hour
is considered appropriate.  The following table lists additional
regulatory and guideline concentrations for sulfur dioxide in ambient
air.   

Table 5. Sulfur Dioxide Air Concentrations used for Regulatory/Guideline
Purposes

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

1-hour	WHO	0.13

	California Air Resources Board	0.25

	AIHA (ERPG-1)	0.3

	State of Washington	0.25

	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

	State of Oregon	0.02

Based on the Probabilistic Exposure and Risk Model for Fumigants,
version 2.1.1 (PERFUM2) and available incident data, the Agency has
concerns for bystander exposure during grape fumigations which involve
the release of high levels of sulfur dioxide during aeration.  For
Botrytis cinerea treatments, a practice known as “total utilization”
is almost exclusively employed.  Total utilization involves circulating
the sulfur dioxide gas (typically 1000 to 2500 ppm) within the
fumigation chamber until it is almost completely absorbed into the
grapes, packaging material and any ambient moisture.  As a result, only
very low concentrations (i.e., less than 30 ppm) of sulfur dioxide are
typically released from the ventilation stack during the aeration phase.
 However, current product labels do not limit sulfur dioxide release
concentrations for this treatment; therefore if total utilization is not
employed and much higher levels of sulfur dioxide are vented to the
atmosphere, bystander exposure is a concern.  To address this concern,
the Agency is establishing a maximum release concentration for Botrytis
cinerea warehouse treatments of 30 ppm, and truck/trailer treatments of
2 ppm.  The disparity between these two release concentrations is based
on the fact that the release of treated air following warehouse
fumigation is performed at a flow rate of 2700 to 8100 ft3/min and at a
typical height of 15 feet above ground level, thereby further reducing
the potential for bystander exposure.  Based on the results of the
PERFUM2 model, this 30 ppm release concentration level is expected to
limit bystander exposure potential with this use to sulfur dioxide
concentrations at or below 0.25 ppm.  This bystander exposure scenario
is considered “worst-case,” in that it assumes the ventilation stack
is at the edge of the treatment warehouse, and the warehouse is in close
proximity to the fumigation facility property line.

Treatment for black widow spider, however, is performed at a much higher
concentration of sulfur dioxide (up to 10,000 ppm) than is used for
Botrytis cinerea treatments.  Further, due to the potential for damaging
the fruit, these high concentrations may not be held in contact with the
grapes for more than approximately 30 minutes; thus total utilization is
not feasible.  As a result, much higher sulfur dioxide concentrations
are released during aeration for treatment of black widow spider;
therefore, the Agency has bystander exposure concerns for this use.  To
address bystander concerns during black widow spider treatment, the
Agency is also placing a limit of 30 ppm on the sulfur dioxide release
concentration during the aeration phase of black widow spider treatment.
 As stated above, based on the results of the PERFUM2 model, this
release restriction is expected to limit bystander exposure potential
with this use to sulfur dioxide concentrations at or below 0.25 ppm. 
The Agency has been working with the California Table Grape Commission
(CTGC) and the California Grape and Tree Fruit League (CGTFL) to
determine the feasibility of using air scrubbers during black widow
spider treatments to reduce the release concentrations.  However, the
use of scrubbers requires additional time, which results in the treated
grapes being exposed to high concentrations of sulfur dioxide for longer
than 30 minutes, risking damage to the fruit.  Hence, CTGL and CGTFL
have indicated a need to perform a comprehensive fumigation study in
order to determine the lowest sulfur dioxide release concentration which
can be achieved using scrubbers or other such equipment, without
damaging the fruit.  If such a fumigation study is performed, the Agency
may reconsider the 30 ppm release limit for black widow spider treatment
if the study findings indicate that 30 ppm cannot be achieved without
damaging the treated fruit.  However, any reconsideration of the release
limit would be in conjunction with the use of higher ventilation stacks,
a buffer zone to protect bystanders, or other measures to ensure that
bystanders are not exposed to sulfur dioxide levels above 0.25 ppm as a
result of this use.  As reference, the following table details the
correlation between buffer zone size and release concentration for the
sulfur dioxide grape fumigation scenario.

Table 6.  PERFUM2 Sulfur Dioxide Grape Fumigation Parameters

 for 0.25 ppm Endpoint

Buffer Size (meters)	Release concentration (ppm)

15	55

30	90

65	150

The details of the PERFUM2 assessments supporting the 30 ppm release
rate, as well as the findings in Table 6 are attached as Appendix III. 
Required label language resulting from the release limits implemented in
this section are detailed in Section XIII of this document.

VI.  Dietary Exposure Assessment

Both sulfur dioxide (21CFR 182.3862) and sodium metabisulfite (21CFR
182.3766) are listed as GRAS by the FDA, with limitations, as food
preservatives.  Sulfites are found in many foods, primarily as a result
of the GRAS preservative use.  It is estimated that sulfite
concentrations of >100 ppm may be found in dried fruits (excluding dark
raisins and prunes), lemon and lime juices, wine, molasses, and
sauerkraut juice.  Dried potatoes, grape juice, wine vinegar, gravies,
fruit topping, and maraschino cherries may contain between 50 and 100
ppm sulfur dioxide.  Foods containing between 10 ppm and 50 ppm include
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 World Health Organization has emphasized the use of appropriate
labeling for alerting individuals who cannot tolerate sulfites.  After
receiving and reviewing reports of adverse reactions in certain
individuals following ingestion of sulfiting agents used as
preservatives in food products, beverages, and fresh fruits and
vegetables, the FDA required ingredient labels to list sulfite
concentrations in excess of 10 ppm.

The uses of products containing inorganic sulfites are limited to use as
indoor fumigants and as fungicidal control agents on grapes.  A
tolerance limit of 10 ppm (expressed as sulfite) for sulfur dioxide is
established in 40 CFR 180.444, and sufficient data are available to
support the reassessment of this tolerance.  This 10 ppm tolerance is
relatively low compared to concentrations of sulfites in many common
foods and viewed as “GRAS” by FDA.  Further this level is below the
level for which FDA requires labeling to alert sulfite-sensitive
individuals.   Therefore, residues resulting from the postharvest use of
sulfur dioxide and sodium metabisulfite on grapes are not expected to be
at a level of concern for the general population or any population
subgroups.

VII. Drinking Water

Based on the use pattern and fate characteristics of these chemicals,
the Agency does not have any drinking water concerns for sulfur dioxide
and sodium metabisulfite.

VIII.  Aggregate Assessment

The aggregate risk assessment integrates the assessments conducted for
dietary, drinking water, and residential exposure if applicable. 
Currently there are no residential uses for either sulfur dioxide or
sodium metabisulfite, as the use of inorganic sulfites is limited to
fumigation of postharvest grapes, and bystander inhalation exposure
concerns are being addressed in this decision document.  Further, no
common effects were seen in inhalation and oral toxicity studies. Based
on environmental fate information for both chemicals, concentrations of
concern are not expected in drinking water.  Therefore, based on the
uses of sulfur dioxide and sodium metabisulfite, no anticipated presence
in drinking water, expected low residues on grapes, and consideration of
the presence of sulfites in other common foods as a result of an FDA
GRAS determination, the Agency has determined that aggregate exposure to
sulfites does not pose a risk concern.

IX.  Cumulative Exposure

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.”  EPA does not have, at this time,
available data to determine whether inorganic sulfites have a common
mechanism of toxicity with other substances.  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 inorganic sulfites and any other substances, and inorganic
sulfites do not appear to produce a toxic metabolite produced by other
substances.   

For the purposes of this tolerance action, therefore, EPA has assumed
that inorganic sulfites do not have a common mechanism of toxicity with
other substances.  For information regarding the Agency’s efforts to
determine which chemicals have a common mechanism of toxicity and 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 mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

X.  Human Health Risk Characterization

Taking into consideration all available information on sulfur dioxide
and sodium metabisulfite, including the specific use pattern and limited
exposure potential, FDA’s classification of generally recognized as
safe (GRAS), as well the historical presence of sodium metabisulfite in
cosmetics and hair care products, the use of sulfur dioxide and sodium
metabisulfite on postharvest grapes is unlikely to pose a significant
risk to the general population or any population subgroup.  Potential
bystander exposure concerns have been addressed, and anticipated
occupational exposures are not expected to pose a risk of concern to
workers.  

XI.  Ecological Risk Assessment

Sulfur dioxide (SO2) is a nonflammable, colorless gas.  It is very
soluble in water, with its solubility varying from 5.88 % at 104 °F to
22.9% at 32 °F.  In moist air or fogs, it combines with water to form
sulfurous acid (H2SO3), but it is only very slowly oxidized to sulfuric
acid.  Sulfur dioxide has a high vapor pressure (3,000 mm Hg at 20°C)
and, thus is typically present in a gaseous phase.  It can be absorbed
in soil, with uptake being dependent on the pH and moisture content of
the soil (ATSDR, 1998a).  The Environmental Fate and Effects Division
(EFED) has reported that the only environmental fate data potentially
needed for sulfur dioxide would be a hydrolysis study; however, the
Agency has determined that the chemistry of sulfur dioxide is so well
documented in the open literature that an additional study is not
necessary (EPA, 1993b).  Sodium metabisulfite dissolves in water and
forms sodium cations, disulfite anions and sulfur dioxide (OECD, 2001).

Concentration of sulfur dioxide as low as 1-2 ppm have been reported to
cause severe stress to green plants, and dissolved sulfur dioxide could
be toxic to aquatic life.  A few acute toxicity tests for sodium
metabisulfite have been reported.  The 96-hour LC50 was 100 mg/L for
fish and the 72-hr EC50 for algae was 48.1 mg/L.  An acute 48-hr EC50
for daphnids has been reported to be 88.76 mg/L and a chronic NOEC of
>10 mg/L was reported.  In addition, a memo from the Ecological Effects
Branch of EFED (EPA 1992), stated that all ecotoxicological studies for
the indoor food uses of sodium bisulfite were waived, as it was
determined that there would be little likelihood of a hazard to
non-target organisms.  Therefore, based on the high vapor pressure, the
current use pattern (indoor food-use) and limits established for sulfur
dioxide release in this decision document, the Agency has no ecological
risk concerns resulting from the pesticidal use of sulfur dioxide and
sodium metabisulfite.

XII. Tolerance Reassessment

The Agency is proposing no changes in the level or definition of the
existing tolerance.  Therefore, the current tolerance established at
40CFR 180.444 for sulfur dioxide residues (expressed as sulfite) in
grapes is now considered reassessed under section 408(q) of the FFDCA.

XIII. Labeling for End-Use Products

The following tables have been developed by the Agency, and indicate the
required label statements for sulfur dioxide and sodium metabisulfite
end-use products: 

Table 7.  Label Revisions

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).”

“When 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 handpump).”

“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 requirements
(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 respirator 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
persons working in the fumigation area.”

“Do not perform sulfur dioxide aerations concurrently from multiple
chambers.”



Table 8.  Label Revisions

Label Statements for Sodium Metabisulfite End-Use Products (pad
labeling)

“This pad contains sodium metabisulfite which may trigger 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
which have contacted pad contents.”

“For Disposal: Place pad in a plastic bag, seal bag and place in an
outdoor trash receptacle (dumpster).”

XIV.  References

Agency for Toxic Substances and Disease Registry.  1998a.  Toxicological
Profile for Sulfur Dioxide.
http://www.atsdr.cdc.gov/toxprofiles/tp116.html 

Agency for Toxic Substances and Disease Registry.  2004.  Medical
Management Guidelines (MMGs) for Sulfur Dioxide (SO2). 
http://www.atsdr.cdc.gov/MHMI/mmg116.html 

Cosmetic Ingredient Review (CIR) 2003.  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 (Suppl
2): 63-88.

Hazardous Substances Data Bank (HSDB). 2005. Sulfur Dioxide.
http://toxnet.nlm.nih.gov.

Hazardous Substances Data Bank (HSDB). 2005. Sodium Metabisulfite.
http://toxnet.nlm.nih.gov.

International Agency for Research on Cancer (IARC). 1992, IARC
Monographs; Vol 54.

Material Safety Data Sheet for Sulfur Dioxide.  Printed 2005; Last
updated 1996. BOC Gases.

http://phyvirtual.nju.edu.cn/material/MSDS/G79.pdf

NIOSH (National Institute for Occupational Safety and Health.  2004. 
The Registry of Toxic Effects of Chemical Substances: Sulfur Dioxide. 
http://www.cdc.gov/niosh/rtecs/ws456d70.html

OECD (Organization for Economic Co-operation and Development) SIDS
(Screening Information Data Set).  2001.  Disodium disulphite (CAS No.
7681-57-4).  Http://www.inichem.org/documents/sids/sids/disodium.pdf

U.S. EPA. 1992.  Memo to Bruce Sidwell, PM 53; Accelerated
Reregistration Branch, Special Review and Reregistration Division from
Douglas Urban, Acting Branch Chief; Ecological Effects Branch,
Environmental Fate and Effects Division.  Re: Phase 4 Review of
Reregistration Case #4056 for Sodium Bisulfite (DP Barcode D182472)

U.S. EPA. 1993b.  Memo to Fred Betz, Acting Chief; Accelerated
Reregistration Branch, Special Review and Reregistration Division and
Bruce Sidwell, PM 53; Accelerated Reregistration Branch, Special Review
and Reregistration Division from Silvia Termes, Chemist; Environmental
Fate and Ground Water Branch, Environmental Fate and Effects Division. 
Re: Sulfur Dioxide (“The Fruit Doctor”), Reregistration Case #4086.

World Health Organization (WHO) 1999. Safety Evaluation of Certain Food
Additives.  WHO Food Additives Series 42.  International Programme on
Chemical Safety.  Sulfur Dioxide and Sulfites (addendum).

World Health Organization (WHO). Sulfur Dioxide and Sulfite.  WHO Food
Additives Series 18.  International Programme on Chemical Safety. 

Sodium metabisulfite and sulfur dioxide are GRAS when used in accordance
with good manufacturing practice, except that it is not used in meats;
in food recognized as a source of vitamin B1; on fruits or vegetables
intended to be served raw to consumers or sold raw to consumers; or to
be presented to consumers as fresh.

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