Document ID: EPA-HQ-OPP-2006-0328-0017
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-09-22T04:00Z

Chlorine Dioxide

Final Risk Assessment

Case 4023

Antimicrobials Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

200 Pennsylvania Avenue, NW

Washington, DC 20460

August 2, 2006

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc126479281"  	EXECUTIVE
SUMMARY	  PAGEREF _Toc126479281 \h  3  

  HYPERLINK \l "_Toc126479282"  1.0	PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc126479282 \h  12  

  HYPERLINK \l "_Toc126479283"  1.1  	Chemical Identification	  PAGEREF
_Toc126479283 \h  12  

  HYPERLINK \l "_Toc126479284"  1.2	Physical/Chemical Properties	 
PAGEREF _Toc126479284 \h  12  

  HYPERLINK \l "_Toc126479285"  2.0	ENVIRONMENTAL FATE ASSESSMENT	 
PAGEREF _Toc126479285 \h  13  

  HYPERLINK \l "_Toc126479286"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc126479286 \h  13  

  HYPERLINK \l "_Toc126479287"  3.1	Hazard Profile	  PAGEREF
_Toc126479287 \h  13  

  HYPERLINK \l "_Toc126479288"  3.2	FQPA Considerations	 17

  HYPERLINK \l "_Toc126479289"  3.3	Dose-Response Assessment	  PAGEREF
_Toc126479289 \h  18  

    3.4      Endocrine
Disruption……………………………………………………
………………………...19

  HYPERLINK \l "_Toc126479290"  4.0	EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc126479290 \h  20  

  HYPERLINK \l "_Toc126479291"  4.1	Summary of Registered Uses	  PAGEREF
_Toc126479291 \h  20  

  HYPERLINK \l "_Toc126479292"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc126479292 \h  20  

  HYPERLINK \l "_Toc126479293"  4.3	Drinking Water Exposures and Risks	 
PAGEREF _Toc126479293 \h  24  

  HYPERLINK \l "_Toc126479294"  4.4	Residential Exposure/Risk Pathway	 
PAGEREF _Toc126479294 \h  25  

  HYPERLINK \l "_Toc126479295"  4.4.1	Residential Handler Scenarios	 
PAGEREF _Toc126479295 \h  25  

  HYPERLINK \l "_Toc126479296"  4.4.2	Residential Post Application
Exposure	  PAGEREF _Toc126479296 \h  27  

  HYPERLINK \l "_Toc126479297"  5.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATIONS	  PAGEREF _Toc126479297 \h  29  

  HYPERLINK \l "_Toc126479298"  5.1	Acute and Chronic Aggregate Risks	 
PAGEREF _Toc126479298 \h  30  

  HYPERLINK \l "_Toc126479299"  5.2	Short- and Intermediate-Term
Aggregate Exposures and Risks	  PAGEREF _Toc126479299 \h  31  

  HYPERLINK \l "_Toc126479300"  6.0	CUMULATIVE RISK	  PAGEREF
_Toc126479300 \h  33  

  HYPERLINK \l "_Toc126479301"  7.0	OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc126479301 \h  33  

  HYPERLINK \l "_Toc126479302"  7.1	Occupational Handler	  PAGEREF
_Toc126479302 \h  34  

  HYPERLINK \l "_Toc126479303"  7.2	Occupational Post Application
Exposure	  PAGEREF _Toc126479303 \h  36  

  HYPERLINK \l "_Toc126479304"  8.0	INCIDENT REPORT ASSESSMENT	  PAGEREF
_Toc126479304 \h  39  

  HYPERLINK \l "_Toc126479305"  9.0	ECOTOXICOLOGY ASSESSMENT	 38

   HYPERLINK \l "_Toc126479307"  10.0
REFERENCES……………………………………………………
……………………………….44 EXECUTIVE SUMMARY tc "

 TOC \f 

TABLE OF CONTENTS

1.0	EXECUTIVE SUMMARY	1

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	9

2.1  	Chemical Identification	9

2.2	Physical/Chemical Properties		9

3.0	ENVIRONMENTAL FATE ASSESSMENT	10

4.0	HAZARD CHARACTERIZATION	11

4.1	Hazard Profile	11

4.2	FQPA Considerations	15

4.3	Dose-Response Assessment	16

4.4 	Endocrine Disruption	18

5.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION	19

5.1	Summary of Registered Uses	19

5.2	Dietary Exposure/Risk for Active Ingredient Uses	19

		5.2.1 Residue Profile	20

		5.2.2 Acute Dietary	20

		5.2.3 Chronic Dietary	20

		5.2.4 Cancer, Dietary	21

	5.3	Dietary Exposure/Risk for Inert Ingredient Uses	21

5.4	Drinking Water Exposures and Risks	24

5.5	Residential Exposure/Risks for Active Ingredient Uses	25

5.5.1	Residential Handler Scenarios	25

			5.5.1.1	 Paint Exposures and Risks	25

	5.5.1.2	 Cleaning Product Exposures and Risks	26

	5.5.2	Residential Post-application Exposure	27

	5.6 	Residential Exposure and Risks From Inert Ingredient Uses	32

6.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS	38

6.1	Acute and Chronic Risk	38

6.2	Short- and Intermediate-Term Aggregate Exposures and Risks	39

7.0 	CUMULATIVE RISK	44

8.0	OCCUPATIONAL EXPOSURE	45

8.1	Occupational Handler	45

8.2	Occupational Post-application Exposure	48

9.0	ECOTOXICOLOGY ASSESSMENT	49

10.0    DATA NEEDS	52

11.0   INCIDENT REPORT ASSESSMENT	52

REFERENCES	53

 

1.0	EXECUTIVE SUMMARY" 

	Chlorine dioxide and sodium chlorite are active ingredients in numerous
products used in the control of bacteria, fungi, and algal slimes.  In
addition, chlorine dioxide and sodium chlorite are used as material
preservatives and as disinfectants.  At this time, products containing
chlorine dioxide and sodium chlorite are intended for agricultural,
commercial, industrial, medical and residential use.  The agricultural
premises and equipment uses include the disinfection of hard surfaces
and equipment (such as hatching facilities and mushroom houses) and
water systems (such as chiller water and humidification water in poultry
houses).  Commercial, industrial, and medical uses include disinfection
of ventilation systems, hard surfaces (e.g., floors, walls, and
laboratory equipment), water systems, pulp/paper mills, and food rinses.
 Residential uses include disinfection of hard surfaces (e.g., floors,
bathrooms), heating ventilating and air-conditioning (HVAC) systems, and
pool & spa water circulation system treatments.  In addition, there is a
continuous release gas product (sachet) for the home to control odors. 

Environmental Fate:  Chlorine dioxide and sodium chlorite are assessed
together because chlorine dioxide is produced by a reaction of sodium
chlorite (and sometimes sodium chlorate) with hypochlorite /acid.  In
addition, chlorite is a breakdown product of chlorine dioxide.  A major
route of exposure is through drinking water.

Chlorine dioxide has a short half life and in the presence of sunlight
and will break down into chloride and chlorate ions, and ultimately,
oxygen is formed.  Sodium chlorite dissolves in water, breaking down
into chloride and chlorate ions under similar conditions as chlorine
dioxide. Chlorate and chlorite ions tend to only undergo biodegradation
under anaerobic conditions degrading to chloride and oxygen. 
Biodegradation of chlorate and chlorite have been observed in anoxic
groundwater, sediments and some soils.  No adsorption/desorption
constants (Kds) have been measured or reported in published literature
for either chlorite or chlorate. These ions are likely to be mobile and
may travel from surface to groundwater easily.  The estimated log Kow of
chlorine dioxide is -3.22 and for sodium chlorite is -7.17.  It is not
expected that either would bioaccumulate in aquatic organisms.  

	Hazard: The acute toxicity of chlorine dioxide (79% a.i.) is moderate
by the oral route (LD50 = 292 mg/kg [males]; 340 mg/kg [females];
Toxicity Category II).  The acute toxicity of chlorine dioxide using
sodium chlorite as the test material (80% a.i.) is considered minimal by
the dermal route (LD50 > 2000 mg/kg; Toxicity Category III).  By the
inhalation route, using sodium chlorite as the test material (80.6%),
chlorine dioxide was moderately toxic (LC50 = 0.29 mg/L, Toxicity
Category II). For primary eye irritation, chlorine dioxide (2% a.i.) was
a mild irritant (Toxicity Category III), but the technical test material
was not used.  For primary dermal irritation, sodium chlorite (80% a.i.)
was a primary irritant (Toxicity Category II).  For dermal
sensitization, there are no acceptable animal studies for chlorine
dioxide or sodium chlorite.

The subchronic toxicity database is considered adequate for
characterizing the subchronic oral and inhalation toxicity of chlorine
dioxide/chlorite.  Daniel et al. (1990) exposed groups of 10 male and 10
female Sprague-Dawley rats to chlorine dioxide in drinking water for 90
days at concentrations of 0, 25, 50, 100, or 200 mg/L (0, 2, 4, 6, or 12
mg/kg-day chlorine dioxide for males and 0, 2, 5, 8, or 15 mg/kg-day
chlorine dioxide for females).  The LOAEL for this study is 25 mg/L (2
mg/kg-day) based on a significant increase in incidence of nasal
lesions.  In a study by Harrington et al. (1995), rats (15/sex/group)
were administered doses of 0, 10, 25, or 80 mg/kg-day sodium chlorite
(equivalent to 0, 7.4, 19, or 60 mg chlorite/kg-day, respectively) via
gavage for 13 weeks.  The NOAEL for this study is 7.4 mg/kg-day, and the
LOAEL is 19 mg/kg-day, based on stomach lesions and increases in spleen
and adrenal weights.  Dalhamn (1957) and Paulet and Desbrousses (1970,
1972, and 1974) are co-critical inhalation toxicity studies included in
the subchronic toxicity database for chlorine dioxide/chlorite.   A
NOAEL of 0.1 ppm (~ 0.28 mg/m3) was selected from Dalhamn (1957) and a
LOAEL of 1.0 ppm (~2.8 mg/m3) was selected from Paulet and Desbrousses
(1970, 1972, and 1974), based on respiratory distress and decreased body
weights observed in exposed animals.

In a developmental toxicity study (Orme et al., 1985), a NOAEL of 20
mg/L (3 mg/kg/day) was established based on neurodevelopmental effects
in the offspring of rats exposed to chlorine dioxide in drinking water. 
A developmental toxicity study (MRID 41715701) conducted in rabbits
using sodium chlorite (purity 80.58%) showed a dose-related increase in
incidence of does with reduced fecal output during the dosing period,
days 7 to 19, which was considered consistent with decreased food
consumption; the NOAEL for developmental and maternal toxicity was 200
ppm (12-14 mg/kg/day).  A two-generational reproductive toxicity study
(CMA, 1996, MRID 4535890) was conducted with sufficient numbers of
animals of both sexes and examined numerous endpoints.  The NOAEL for
this study is 35 ppm (2.9 mg/kg-day chlorite) and the LOAEL is 70 ppm
(5.7 mg/kg-day chlorite) based on lowered auditory startle amplitude and
altered liver weights in two generations. 

One chronic toxicity study (Haag, 1949) is included in the toxicity
database for chlorine dioxide.  The study was determined to be of
limited use in the assessment of chronic toxicity because an
insufficient number of animals were tested per group and pathology was
conducted on only a small number of animals.  In addition, the study did
not provide adequate evaluations of more sensitive parameters, which
would have been more useful in the overall assessment of chronic
toxicity.

Chlorine dioxide has not been formally assessed for carcinogenic   SEQ
CHAPTER \h \r 1 potential.  The available dermal carcinogenicity studies
do not definitively characterize the carcinogenicity of chlorine
dioxide, and additional studies may be required. One subchronic study
(Daniel et al., 1990) examined the effects of administration of chlorine
dioxide to groups of male and female Sprague-Dawley rats (10/sex/dose)
at dose levels of 0, 25, 50, 100, or 200 mg/L for 90 days in drinking
water.  A significant increase in the incidence of nasal lesions (goblet
cell hyperplasia and inflammation of nasal turbinates) was found at all
dose levels tested.  The significance of these findings is uncertain as
they have not been observed in other long-term studies of chlorine
dioxide. 

Data on the mutagenicity of chlorine dioxide exist in the open
scientific literature as well as within the Agency’s database of
submitted studies.  In Miller et al. (1986) negative effects were
reported in Salmonella strains TA98 and TA100 from a 400-fold drinking
water concentrate of chlorine dioxide, whereas a 4000-fold concentrate
was mutagenic to strain TA98 only in the absence of metabolic
activation.  In Accession No. 265867, chlorine dioxide was positive for
forward mutations under non-activated conditions (dose-related from
3.2-24.3 µg/ml) and activated conditions (48.3µg/mL) in L5178Y/TK
cells, positive for structural chromosome aberrations under
non-activated and activated conditions (10, 15, and 50 µg/ml), and
negative for increased transformed foci up to cytotoxic levels.  In vivo
micronucleus and bone marrow chromosomal aberration assays in Swiss CD-1
mice administered 0.1–0.4 mg chlorine dioxide via gavage for 5
consecutive days were negative, as was a sperm-head abnormality assay in
B6C3F1 mice administered 0.1–0.4 mg via gavage for 5 consecutive days
(0, 3.2, 8, and 16 mg/kg-day) (Meier et al., 1985).

Neurotoxicity of chlorine dioxide has been observed.  In the
two-generation reproduction toxicity study (CMA, 1996), significant
changes were observed in maximum response in startle amplitude and
absolute brain weight in F1 rat pups at a dose of 3 mg/kg/day.  In the
Orme et al. (1985) developmental toxicity study, neurobehavioral
deficits consisting of decreased exploratory and locomotor activities
were observed in offspring at a maternal dose of 14 mg/kg/day.

	Toxicity Endpoints: The toxicity endpoints used in this document to
assess potential risks include acute and chronic dietary reference
doses, and short-, intermediate- and/or long-term incidental oral,
dermal, and inhalation doses.  

	Dietary/Oral Endpoints: The chronic NOAEL is 3 mg/kg/day.  This
endpoint is based on a two-generation reproduction toxicity study (CMA,
1996) and a developmental toxicity study in rats (Orme et al., 1985). 
An uncertainty factor of 100 (10x for interspecies extrapolation and 10x
for intraspecies variability) was applied.  An acute dietary endpoint
was not identified in the data base for chlorine dioxide.

	

	Dermal Absorption:  There is one published report on the kinetics of
chlorine dioxide following dermal administration (Scatina et al., Fund.
Appl. Toxicol. 4: 479-484).  This study measured kinetics of elimination
and was not specifically designed to measure the extent of absorption. 
Based on the results of this study, it is apparent that absorption of
chlorine dioxide is fairly rapid, even after repeated dermal
administration.  However a dermal absorption study, with chlorine
dioxide conducted in accordance with the OPPTS 870.7600 guideline, would
provide definitive data on the percent dermal absorption of chlorine
dioxide.  Until more definitive data are available, a default value of
100% will be employed for chlorine dioxide. 

	Dermal Endpoints: The short-, intermediate-, and chronic-term dermal
endpoint is 3 mg/kg/day and is based on a two-generation reproduction
toxicity study and a developmental toxicity study in rats (CMA, 1996;
Orme et al.,1985).   The target MOE is 100 for residential and
occupational exposure.

Inhalation Endpoints: The inhalation route of exposure to chlorine
dioxide is assessed for three distinct subpopulations:  (1) occupational
exposures (8 hours/day, 5 days/week), (2) one-time exposures for
residential uses (e.g., HVAC systems, mopping floors, etc), and (3)
long-term exposure for continuous release products in the home (24
hours/day, 7 days/week).  Several animal studies were used to develop
reference concentrations (RfCs).  The effects seen at various
concentrations include rhinorrhea, altered respiration, respiratory
infection, bronchial inflammation, alveolar congestion and hemorrhage,
vascular congestion, and peribronchiolar edema.  Readers are referred to
USEPA (2000a) for a detailed review of the effects seen at specific
concentrations and exposure durations along with the derivation of the
RfC.  In summary, the occupational RfC is determined to be 0.003 ppm and
represents an 8-hour time weighted average (TWA).  The one-time
residential exposure scenario is represented by the RfC of 0.05 ppm and
the RfC for long-term, continuous exposure is 0.00007 ppm.  The RfC
methodology incorporates the uncertainty factors into the concentration.
 For inhalation, the RfC is compared directly to the air concentration
of interest.  Inhalation risks are of concern if the air concentrations
people are exposed to exceed the RfC.

	 FQPA Safety Factor:  When the original toxicity endpoint assessment
was conducted, the Hazard Identification Assessment Review Committee
(HIARC) concluded that an extra 10x uncertainty factor under the Food
Quality Protection Act should be considered in risk assessments
conducted for chlorine dioxide.  This recommendation was based upon
evidence of susceptibility in a two-generation reproduction toxicity
study in rats and evidence of susceptibility from scientific literature
reports. 

Since that time, the Health Effects Division of the Office of Pesticide
Programs issued policy guidance September of 2001 regarding the
determination of the appropriate FQPA safety factor in tolerance
assessment.  This guidance states that whereas in the past “...OPP has
routinely applied an additional FQPA safety factor where data on a
pesticide shows increased susceptibility or sensitivity (either
qualitative or quantitative) in the developing organism,”  It is the
intent that “...OPP will now put greater emphasis on analyzing the
degree of concern and, rather than apply an additional safety factor
based solely on the identification of heightened sensitivity or
susceptibility, will conduct a case-by-case weight of evidence approach
that qualitatively examines the level of concern for sensitivity /
susceptibility and assess whether traditional uncertainty factors
already incorporated into the risk assessment are adequate to protect
the safety of infants and children.  Using this approach, in many cases
the concerns regarding pre- and postnatal toxicity can be addressed when
a Reference Dose (RfD) or Margin of Exposure (MOE) is based on the pre-
or postnatal endpoints in the offspring.”

The endpoint selected for both dietary and non-dietary exposures to
chlorine dioxide was based upon adverse effects observed in offspring
from developmental and reproductive toxicity data.  Consistent with the
approach used by the EPA’s Office of Water for use of chlorine dioxide
as a drinking water disinfectant and the updated guidance on selection
of a safety factor under FQPA, the endpoint selected for assessment of
risk from dietary and non-dietary exposure to chlorine dioxide was felt
to be protective of potentially susceptible populations including
children, based upon the selection of an endpoint and effects observed
in offspring and the use of an NOAEL value based on those effects. 
Therefore, it was concluded that an additional safety factor under FQPA
was not necessary.

	Dietary Exposure:  The Agency has conducted a dietary exposure and risk
assessment for use of chlorine dioxide in products used in the control
of bacteria, fungi, and algal slimes; as well as its use as a material
preservative and disinfectant all of which may end in indirect food
contact scenarios.  For chronic dietary exposure, the risk from indirect
food contact is highest for children (61% of the chronic PAD).   For an
adult, the chronic dietary exposure is 16% of the chronic PAD.

	For direct food contact, AD conducted a chronic risk assessment for the
fruit and vegetable washes which were applied post-harvest.  The chronic
risks appear to be below the levels of concern (7.5% of cPAD for adults
and 42% of the cPAD for children between the ages of 1 and 2 years of
age).

	Total dietary risks (from direct and indirect food contact) are
slightly above the Agency’s level of concern for children (103% of the
cPAD).  However, the chronic risks appear to be below the level of
concern for adults (23% of the cPAD).

	Water Exposure and Risk:  	Chlorine dioxide and sodium chlorite are
used as disinfectants in many water treatment plants.  Office of water
conducted an eighteen month monitoring study for the determination of
maximum contaminant levels (MCL) and maximum contaminant level goals
(MCLG) of chlorite in the drinking water that reached consumers.  AD
used the results from this study and determined for all infants less
than one year of age, the cPAD (145%) exceeds the level of concern.

	Residential Exposure and Risk:  Residential uses of chlorine dioxide
and/or sodium chlorite products that are applied by homeowners include
the control of mold and mildew.  For the exposure assessment, household
cleaning products were grouped together to be represented by a higher
application rate from a sodium chlorite product.  The post application
scenario is based on a product that applies chlorine dioxide to floors
that have the potential for children playing.  Three scenarios (mopping,
spraying, and placing tablets into pools/spas) were examined for
residential uses in the risk assessment.  The scenarios were evaluated
based on the Residential Exposure Assessment Standard Operating
Procedures (SOPs), product label maximum application rates, related use
information, Agency standard assumptions, Pesticide Handlers Exposure
Database (PHED) unit exposure data, and Chemical Manufacturing
Association (CMA) unit exposure data.  The calculated dermal MOE is less
than the target MOE of 100 for only the application of tablets to pool
water circulation systems.  The dermal MOE for applications to pool
water systems is 46. This risk can be mitigated with the use of gloves
(MOE= 500).

		Residential post application exposures result when bystanders (adults
and children) come in contact with chlorine dioxide in areas where
pesticide-treated end-use products have recently been applied (e.g.,
treated hard surfaces/floors), or when children incidentally ingest the
pesticide residues through mouthing the treated end products/treated
articles (i.e., hand-to-mouth or object-to-mouth contact).    SEQ
CHAPTER \h \r 1 For the purposes of this screening-level assessment,
four post application scenarios have been considered: (1) exposure to
residue from hard floors that have been cleaned/mopped with a generic
cleaner containing chlorine dioxide, (2) exposure to chlorine dioxide
used by commercial applicators to clean residential HVAC systems, (3)
exposure to a continuous release (gas) deodorizer, and (4) pool & spa
treatments.

	  SEQ CHAPTER \h \r 1 The child short- and intermediate-term dermal MOE
for contact following hard surface disinfection is above the target MOE
of 100 for residential and daycare settings (MOE = 280).   SEQ CHAPTER
\h \r 1    SEQ CHAPTER \h \r 1 The short- and intermediate-term
incidental oral MOE following hard surface disinfection are above the
target MOE of 100 for residential and daycare settings (MOE = 2,300),
and thus are not of concern.  

	Inhalation exposures due to post application activities could occur for
children and adults after the treatment of floors; adults and children
after the treatment of HVAC systems; and adults and children during the
use of continuous release (gas) deodorizers. Chlorine dioxide and/or
sodium chlorite can be applied as an aqueous solution to hard surfaces
such as floors and as a dust to carpets.  For the floor treatments, a
theoretical approach to estimating chlorine dioxide air concentrations
indicates an 8-hour time weighted average (TWA )air concentration of
0.02 ppm after a 1-hour restricted entry interval (REI).  If one could
assume that residents would stay out of the house for the first hour,
the 8-hour TWA is 0.02 ppm which is below the RfC of 0.05 ppm.  

For HVAC treatments, monitoring data are available.  The air
concentrations monitored indicated the highest peak concentration of
0.02 ppm and the average of the peak concentrations was below the
detection limit of 0.01 ppm.  The short-term inhalation RfC for chlorine
dioxide is 0.05 ppm.  Therefore, inhalation exposures from HVAC
treatments are not expected to be a concern.  

	For the continuous release deodorizers, a bounding estimate of air
concentration is presented based on the application rate and the
label-referenced longevity of the pouches/sachets.  The theoretical
constant air concentration would be 0.52 ppm assuming no air exchange
and no build up of chlorine dioxide over time because of the short half
life.  The RfC for long-term continuous exposure is 0.00007 ppm. 
Therefore, the theoretical concentration from the product’s release is
of concern.  

	Aggregate Exposure and Risk:  In order for a pesticide registration to
continue, it must be shown that the use does not result in
“unreasonable adverse effects on the environment”. Aggregate
exposure is the total exposure to a single chemical (or its residues)
that may occur from dietary (i.e., food and drinking water),
residential, and other non-occupational sources, and from all known or
plausible exposure routes (oral, dermal, and inhalation).  Aggregate
risk assessment were conducted for acute (1 day), short-term (1-30
days), intermediate-term (1-6 months) and chronic (several months to
lifetime) exposures.

	The acute and chronic aggregate risk assessments are based on dietary
and drinking water exposures.  For chlorine dioxide acute dietary risks
were not assessed based on the lack of acute endpoints. Dietary
exposures from indirect food uses (e.g., use in food-contact packaging)
and from direct food uses were aggregated together along with the
drinking water exposures for a total dietary exposure.  The chronic
aggregate risk estimates associated with chlorine dioxide from dietary
uses are below the Agency’s level of concern for adults at 67% of the
cPAD.  However the dietary risks are above the level of concern for
children (165% of the cPAD).

 	The short- and intermediate-term aggregate assessments were conducted
for adults and children.  The following representative scenarios were
included in the aggregate assessments:

Short-term, Adults:

dietary, chronic direct and indirect

handling cleaning products via spray (dermal only)

handling cleaning products via mopping (dermal only)

drinking water, chronic

Short-and intermediate term, Children:

dietary, chronic direct and indirect

post application exposure to cleaning product residues (dermal and oral)

drinking water, chronic

	Since the toxicity endpoints for the oral and dermal routes of exposure
are based on the same study and same toxic effect, these two routes are
aggregated together.  The inhalation route is based on a different
effect and therefore that route is not included in the aggregate.  For
the aggregate of the inhalation route, only the continuous release
product may co-occur with the other uses and the inhalation risk for the
continuous release is of concern by itself.  The aggregate risks (oral +
dermal) are not of concern for adults, as the total aggregate MOE is
130, which is above the target of 100.  For children, the aggregate risk
estimates are again below the target MOE of 100 (MOE=44) and thus are of
concern.  It should be noted that several conservative assumptions were
used in this assessment.  

	Occupational Exposure and Risk: Potential occupational handler exposure
from the use of chlorine dioxide products can occur in various use
sites, including agricultural premises, food handling, commercial and
institutional premises, medical premises, human drinking water systems,
industrial processes and water systems, application to material
preservatives, and swimming pools and other aquatic areas.    

For the occupational handler dermal risk assessment, the short- and
intermediate-term risks calculated at baseline exposure (no gloves and
no respirators) were above target MOEs for all scenarios (i.e., dermal
MOEs were >100), except for the following: 

Agricultural premises and equipment:

application to hard surfaces: low pressure handwand (MOE=31), 

application to hard surfaces: mopping (MOE=70), and

application to hard surfaces: foam applicator equipment (MOE=52). 

Food Handling, Commercial/Institutional, and Medical Premises and
Equipment:

application to hard surfaces: mopping (MOE=66 for commercial and 3 for
medical facilities).

	

	There is the potential for the off gassing of chlorine dioxide during
some applications that are not totally enclosed (e.g., spray aqueous
solution, mopping, pouring, etc).  Although no occupational air
monitoring data have been submitted to assess the inhalation route, EPA
has obtained air concentration measurements from OSHA.  OSHA maintains a
data base known as the Integrated Management Information System (IMIS). 
The IMIS entries for chlorine dioxide are available for 7 industry
Standard Industrial Classification (SIC) codes.  The summary results of
the 33 observations taken from 8-hour TWA personal air samplers for
chlorine dioxide indicate that 21 of those measurements were below the
LOD of 0.004 ppm.  In addition, of the 33 TWA measurements, only 3 were
at or above 0.1 ppm.  It is also important to note that the OSHA PEL for
chlorine dioxide is 0.1 ppm.  Facilities using chlorine dioxide are not
required to mitigate inhalation exposures until the air concentration
reaches 0.1 ppm.  Based on the occupational inhalation toxicological
endpoint selected for chlorine dioxide (i.e., RfC of 0.003 ppm), levels
at or near the PEL are of concern.  In fact, the capability (i.e., LOD)
of the OSHA sampling method is insufficient for the occupational RfC
presented in this document.  Reconciliation of the EPA risk-based RfC
and the current OSHA standards will be made during the regulatory
decision phase of the Reregistration Eligibility Decision (RED) for
chlorine dioxide. 

Incident Reports:  There are some reported incidents associated with
exposure to end-use products containing chlorine dioxide.  Inhalation is
the primary route of exposure.  Most of the incidents are related to
irritation reaction.    

	Ecological Hazard and Risk:  For terrestrial animals, the results of
studies to examine the toxicity of chlorine dioxide/sodium chlorite to
birds indicate these chemicals range from slightly to highly toxic to
birds on an acute oral basis and from slightly toxic to practically
non-toxic on a subacute dietary basis.  For freshwater aquatic animals,
the results of studies examining the toxicity of chlorine dioxide/sodium
chlorite to freshwater fish indicate these chemicals range from slightly
toxic to practically non-toxic on an acute basis.  For aquatic
invertebrates, the studies indicate that chlorine dioxide and sodium
chlorite range from very highly toxic for technical grade sodium
chlorite a.i. to practically non-toxic for the formulated product on an
acute basis.  Results of toxicity studies indicate that chlorine
dioxide/sodium chlorite are slightly toxic to estuarine/marine fish on
an acute basis and range from highly toxic to slightly toxic to
estuarine/marine invertebrates on an acute basis.  

For terrestrial plants, results of toxicity studies indicate that
chlorine dioxide/sodium chlorite are moderately toxic to terrestrial
plants.  However, since the maximum label rate for many of the chlorine
dioxide/sodium chlorite once-through cooling labels was not used in
these tests, it is necessary to conduct Tier II testing with rice.  For
aquatic plants, toxicity study results indicate chlorine dioxide/sodium
chlorite are moderately toxic to aquatic plants.  The once-through
cooling tower use of chlorine dioxide/sodium chlorite requires that 5
aquatic plant tests be conducted due to the algaecidal nature of the
chemical and the likelihood of exposure to aquatic plants in surface
waters receiving industrial facility outfall from the cooling system;
however, only one study (1 species) under this topic has been submitted
and 5 are required.  The following aquatic plant studies are still
required: blue-green cyanobacteria (Anabaena flos-aquae), freshwater
diatom (Navicula pelliculosa), marine diatom (Skeletonema costatum) and
floating macrophyte (Lemna gibba).   

Acute risk to aquatic organisms may occur from the use of chlorine
dioxide/sodium chlorite in once-through cooling towers based on the
screening level assessment conducted.  At the highest doses, the model
shows risk to freshwater and marine/estuarine fish and invertebrates and
aquatic plants, and at the lowest doses the model shows risk only to
freshwater invertebrates.  Chronic risk to aquatic organisms cannot be
assessed at this time due to the lack of chronic toxicity endpoints for
fish and aquatic invertebrates.  When the required aquatic chronic
toxicity testing described above is submitted, chronic risk to these
organisms will be assessed.

Listed Species: Acute risks to listed birds and mammals are not
anticipated from the use of chlorine dioxide and sodium chlorite
products due to low exposure and low toxicity.  The screening level
model used in this assessment indicates that there may be acute risks to
listed aquatic organisms from the once through cooling tower use of
chlorine dioxide/sodium chlorite.  Further, potential indirect effects
on any species dependent upon a species that experiences effects from
use of chlorine dioxide/sodium chlorite cannot be precluded based on the
screening level ecological risk assessment.  These findings are based
solely on EPA’s screening level assessment and do not constitute
“may effect” findings under the Endangered Species Act.

Chronic risks to listed aquatic organisms cannot be assessed at this
time; this risk will be assessed when required chronic toxicity data are
submitted to and evaluated by the Agency.  

1.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION tc "2.0
PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION" 

											

	1.1  	Chemical Identification  tc "2.1  	Chemical Identification " \l 2

	Chemical identification parameters, including CAS Number and molecular
formula are provided in Table 1.

Table 1.  Chemical Identification Information for 

Chlorine Dioxide and Sodium Chlorite

Property	Chlorine Dioxide	Sodium Chlorite

OPP Chemical Code	020503	020502

CAS Number	10049-04-4	7758-19-2

Molecular Formula	ClO2	NaClO2

	1.2	Physical/Chemical Properties  tc "2.2	Physical/Chemical Properties
" \l 2 

	The physical and chemical properties of chlorine dioxide and sodium
chlorite are shown in Table 2.

Table 2.  Physical/Chemical Properties of Chlorine Dioxide and Sodium
Chlorite

Property	Chlorine Dioxide	Sodium Chlorite

Molecular Weight	67.45 g/mol	90.45 g/mol

Color	Yellow to Reddish Yellow	White

Melting Point	-59oC	180-200oC (decomposes)

Boiling Point	11oC	n/a

Odor	Strongly pungent, chlorine-like	n/a

Physical State	Gas at room temperature	Solid

Density	1.64 g/ml at 0oC (liquid)

1.614 g/ml at 10o C (liquid)	2.468 g/ml (as a solid)

Vapor Pressure	490 mm Hg (0oC)

>760 mm Hg (25oC)	n/a

Stability	Dilute solutions are stable if kept cool and in the dark.

 Unstable when exposed to sunlight	n/a

Solubility (water)	3.01 g/L at 25oC and 34.5 mmHg	390 g/L at 30oC

2.0	ENVIRONMENTAL FATE ASSESSMENT	

A detailed environmental fate assessment for chlorine dioxide and sodium
chlorite is presented in the attached appendix.  

Chlorine dioxide and sodium chlorite are assessed together because
chlorine dioxide is produced by a reaction of sodium chlorite (and
sometime sodium chlorate) and hypochlorite/acid.  In addition, chlorite
is a breakdown product of chlorine dioxide.  Major antimicrobial uses of
chlorine dioxide and/or sodium chlorite are as water disinfectants and
pulp/paper industry disinfectants. The major route of exposure,
therefore, is through drinking water.

Chlorine dioxide has a short half life and in the presence of sunlight
and will break down into chloride and chlorate ions (between pH 4 and
7).  At pH lower than 4, its breakdown products are chlorite and
chlorate. Chlorite is the dominant breakdown product.  Ultimately,
oxygen is formed.  Sodium chlorite dissolves in water, breaking down
into chloride and chlorate ions under similar conditions as chlorine
dioxide. Chemical degradation of sodium chlorite commonly occurs in
water as well as in the presence of suspended soil particles containing
ions, like Fe(II), Mn(II),  I-, and S-2, through redox reactions. The
final breakdown products are chloride and oxygen.  These same end
products are obtained when sodium chlorite is heated.

Chlorate and chlorite ions tend to only undergo biodegradation only
under anaerobic conditions.  Biodegradation of chlorate and chlorite
have been observed in anoxic groundwater, sediments and some soils. The
end products are the same as stated above: chloride and oxygen.  No
adsorption/desorption constants (Kds) have been measured or reported in
published literature for either chlorite or chlorate. These ions are
likely to be mobile and may travel from surface to groundwater easily. 
The estimated log Kow of chlorine dioxide is -3.22 and for sodium
chlorite is -7.17.  It is not expected that either would bioaccumulate
in aquatic organisms.  

3.0	HAZARD CHARACTERIZATION tc "

3.0	ENVIRONMENTAL FATE ASSESSMENT

	The environmental fate assessment for 1,2-benzisothiazolin-3-one was
based on limited information; data were only available for hydrolysis,
aerobic soil metabolism, and adsorption/desorption.  These data indicate
that 1,2-benzisothiazolin-3-one is hydrolytically stable (half-life > 30
days), but breaks down fairly quickly in aerobic soils (half-life < 24
hours in sandy loam soil).  1,2-benzisothiazolin-3-one shows moderate to
strong binding to soils, with adsorption Kd values estimated to be
between 1.24 to 9.56.  If used outdoors, 1,2-benzisothiazolin-3-one may
possibly move with soil during rainfall events and potentially reach
surface waters.  However, it breaks down aerobically on the surface
soils.  Since it has a moderate binding potential to soils, it is not
likely to migrate into the ground and there is low potential for ground
water contamination.  Furthermore, with a Kow value of 20 at 25 o C,
1,2-benzisothiazolin-3-one is unlikely to bioaccumulate in aquatic
organisms.

4.0	HAZARD CHARACTERIZATION" 

	3.1	Hazard Profile  tc "4.1	Hazard Profile " \l 2 

	A detailed hazard assessment for chlorine dioxide is presented in the
attached appendix.  

	Acute Toxicity.  The acute toxicity of chlorine dioxide (79% a.i.) is
considered moderate by the oral route (Toxicity Category II) and minimal
by the dermal route using sodium chlorite as the test material (80%
a.i.) (Toxicity Category III).  By the inhalation route, chlorine
dioxide was moderately toxic (Toxicity Category II) using sodium
chlorite as the test material (80.6%). For primary eye irritation,
chlorine dioxide (2% a.i.) was a mild irritant (Toxicity Category III),
but the technical test material was not used.  For primary dermal
irritation, sodium chlorite (80% a.i.) was a primary irritant (Toxicity
Category II).  There are no acceptable animal studies for chlorine
dioxide or sodium chlorite for dermal sensitization.  Table 3 presents
the acute toxicity data for chlorine dioxide/sodium chlorite and Table 4
highlights the key toxicological studies for chlorine dioxide.

	Subchronic Toxicity.  

	Chlorine dioxide:  A subchronic oral toxicity study (Daniel et al.,
1990) conducted in the rat showed systemic effects after repeated oral
administration of chlorine dioxide in the drinking water at doses of 0,
25, 50, 100 or 200mg/L.  A significant decrease in body weights and body
weight gain was evident (26-29% lower than controls) in males at the 200
mg/L treatment level.  Significant reductions were also observed in
water (in the ≥50 mg/L treatment for males and ≥25 mg/L treatment
for females) and food consumption (in the 200 mg/L treatment for males).
 Both absolute liver (for males; ≥50 mg/L) and spleen weights (for
females; ≥25 mg/L) decreased.  In males exposed to 100 or 200 mg/L,
serum lactate dehydrogenase and aspartate aminotransferase levels
decreased and serum creatinine levels increased.  A significant increase
in incidence of nasal lesions (goblet cell hyperplasia and inflammation
of nasal turbinates) was found in males (( 25 mg/L) and females (( 100
mg/L).

	Subchronic inhalation toxicity studies (Dalhamn, 1957; Paulet and
Desbrousses, 1970, 1972, and 1974) conducted in the rat have resulted in
pulmonary edema and nasal bleeding (at levels of 260 ppm during a single
2-hour exposure) as well as respiratory distress and bronchopneumonia
(in rats exposed to 3-minute exposure of decreasing concentrations of
chlorine dioxide from 3,400 ppm to 800 ppm once a week for 3 consecutive
weeks).  At levels of 10 ppm (4 hours/day for 9 days in a 13-day
period), rats exhibited rhinorrhea, altered respiration, and respiratory
infection. 

	Sodium chlorite:  A subchronic oral toxicity study (Harrington et al.,
1995) conducted in the rat showed systemic effects after repeated oral
(gavage) administration of sodium chlorite at doses of  0, 10, 25 or 80
mg/L (corresponding to 0, 7.4, 19 or 60 mg/kg/day).  Four animals died
in the 60 mg/kg/day treatment level and both males and females exhibited
salivation, significantly decreased erythrocyte counts, and decreased
total serum protein levels. In the 60 mg/kg/day treatment level, males
exhibited significantly decreased hematocrit and hemoglobin levels and
increased methemoglobin and neutrophil levels, while females exhibited
significantly decreased methemoglobin levels. In the 60 mg/kg/day
treatment level, the following observations were also noted:
morphological changes in erythrocytes in some animals of both sexes,
significant increases in relative adrenal and spleen weights in the
males, increases in absolute and relative spleen and adrenal weight in
females, and increases in relative liver and kidney weights in the
females. The 60 mg/kg/day treatment level also exhibited histopathologic
alterations such as squamous epithelial hyperplasia, hyperkeratosis,
ulceration, chronic inflammation, and edema in the stomachs of seven
males and eight females.  In the 19 mg/kg/day treatment level,
alterations such as occasional salivation in two males, hematologic
alterations in males (increased methemoglobin levels and neutrophil
count, decreased lymphocyte count), increases in absolute and relative
spleen and adrenal weights in females, and histologic alterations in the
stomach of two males, similar to those seen in the high-dose group, were
reported.  

	Developmental Toxicity.  

	Chlorine dioxide:  A developmental toxicity study (Orme et al., 1985)
was conducted in rats with chlorine dioxide administered in the drinking
water at doses of 0, 1, 20 or 100 mg/L.  A depression of serum thyroxin
(T4) and an increase of serum triiodothyronine (T3) were observed in
pups at weaning at the 100 mg/L (14 mg/kg/day) dose level, as well as a
decrease in neurobehavioral exploratory and locomotor activities.  These
effects, however, were not observed in pups at the 20 mg/L dose level (3
mg/kg).  Pups administered chlorine dioxide by gavage at 14 mg/kg/day on
post-natal days 5-20 showed a larger depression of serum T4 levels and
greater delays in development of exploratory and locomotor behavior
activity.  

	

	Sodium chlorite: A developmental toxicity study (MRID 41715701) was
conducted in rabbits using sodium chlorite (purity 80.58%) administered
in the drinking water at doses of 0, 200, 600 or 1200 ppm).  Mean intake
of the test compound via the drinking water was suppressed in a
dose-related fashion at the highest levels, especially over the first
few days of dosing. The sole treatment-related clinical effect was a
dose-related increase in incidence of does with reduced fecal output
during the dosing period, days 7 to 19, which was considered consistent
with decreased food consumption. Among gross findings in scheduled
sacrifices were:  pitted kidneys in two mid-dose and one high-dose
animal; alopecia in two low-dose, three mid-dose, and two high-dose
does; and thoracic fluid in one low-dose animal.  

	Reproductive Toxicity.  A two-generation reproduction study (CMA, 1996)
was conducted in which sodium chlorite was administered to rats (F0
generation) in their drinking water at concentrations of 0, 35, 70 or
300 ppm. The F1 generation was given the same treatment as their
parents.  Because of a reduced number of litters in the 70 ppm F1-F2a
generation, the F1 animals were re-mated to produce a F2b generation. 
All generations, primarily in the 70 and 300 ppm treatment groups,
exhibited decreases in water and food consumption, and body weight gain.
 In the 300 ppm treatment group, there were significant reductions in
absolute and relative liver weight in the F0 females and F1 males and
females, reduced pup survival, reduced body weight at birth and
throughout lactation in F1 and F2 rats, lower thymus and spleen weight
in both generations, lowered incidence of pups exhibiting normal
righting reflex and with eyes open on postnatal day 15, alteration in
clinical condition in F2 animals chosen for neurotoxicity, decrease in
absolute brain weight for F1 males and F2 females, delay in sexual
development in males (preputial separation) and females (vaginal
opening) in F1 and F2 rats, and lower red blood cell parameters in F1
rats.  Reduced absolute and relative liver weights were also observed in
the 70 ppm treatment groups for F0 females and F1 males.    

Chronic Toxicity.  A chronic toxicity study (Haag, 1949) was conducted
with a group of rats exposed to 0, 1, 2, 4, 8, 100, or 1,000 mg/L
chlorite in the drinking water (0, 0.09, 0.18, 0.35, 0.7, 9.3, or 81
mg/kg-day) for 2 years.  Animals exposed to chlorite concentrations of
100 or 1,000 mg/L exhibited treatment-related renal pathology.  These
effects were also observed in a group of animals administered sodium
chloride at a concentration equimolar to 1,000 mg sodium chlorite/L. 
The study was limited because an insufficient number of animals were
tested per group, pathology was conducted on a small number of animals,
and it did not provide adequate evaluations of more sensitive
parameters, which would have been more useful in the overall assessment
of chronic toxicity.

Carcinogenicity.  Robinson et al. (1986) assessed the potential for
chlorine dioxide to induce proliferative epidermal hyperplasia in
dorsally shaved female SENCAR mice exposed to 0, 1, 10, 100, 300, or
1,000 ppm liquid chlorine dioxide.   The data from this study are
considered inadequate for characterizing the carcinogenicity of chlorine
dioxide/chlorite.  A dermal carcinogenicity study (Kurokawa et al.,
1984) evaluated the ability of chlorite to act as a complete carcinogen.
  In this study, groups of 20 female SENCAR mice were exposed twice
weekly for 51 weeks to 20 mg/mL sodium chlorite in acetone. The study
was also considered inadequate because the exposure was for less than a
lifetime, a high incidence of Sendai virus was found in the rats, and
mortality was high in the mouse control group because of excessive
fighting.

	Mutagenicity.  Several studies exist on the mutagenicity of chlorine
dioxide both in the open literature and in the Agency’s database of
submitted studies.  In one study (Miller et al., 1986), negative effects
in Salmonella strains TA98 and TA100 from a 400-fold drinking water
concentrate of chlorine dioxide and positive effects in a 4000-fold
concentrate to strain TA98 only in the absence of metabolic activation
were reported.  Another study indicated chlorine dioxide was positive
for forward mutations under non-activated and activation conditions in
L5178Y/TK cells (Accession no. 265867).  Chlorine dioxide was positive
for structural chromosome aberrations under non-activated and activated
conditions (Accession no. 265867) and was negative for increased
transformed foci up to cytotoxic levels (Accession no. 265867).  In vivo
micronucleus and bone marrow chromosomal aberration assays in Swiss CD-1
mice administered 0.1–0.4 mg chlorine dioxide via gavage for 5
consecutive days were negative, as was a sperm-head abnormality assay in
B6C3F1 mice administered 0.1–0.4 mg via gavage for 5 consecutive days
(0, 3.2, 8, and 16 mg/kg-day) (Meier et al., 1985).

	Metabolism.  Oral studies have provided information regarding the
pharmacokinetics of both chlorine dioxide and chlorite.  Chlorine
dioxide rapidly dissociates, predominantly into chlorite (which itself
is highly reactive) and chloride ion (Cl-), ultimately the major
metabolite of both chlorine dioxide and chlorite in biological systems
(Abdel-Rahman et al., 1984). Urine is the primary route of elimination,
predominantly in the form of chloride ion (Abdel-Rahman et al., 1984).
Chlorite (ClO2-) does not persist in the atmosphere either in ionic form
or as chlorite salt.  The rapid appearance of 36Cl in plasma following
oral administration of chlorine dioxide (36ClO2) or chlorite (36ClO2-)
has been shown in laboratory animals (Abdel-Rahman et al., 1984).  In
rats, absorbed 36Cl (from 36ClO2 or 36ClO2 sources) is slowly cleared
from the blood and is widely distributed throughout the body
(Abdel-Rahman et al., 1984). 

	Neurotoxicity.  In a two-generation reproduction toxicity study (CMA,
1996) conducted with sodium chlorite (81.4% purity) administered in the
drinking water, significant changes were observed in maximum response in
startle amplitude and absolute brain weight in F1 rat pups at a dose of
3 mg/kg/day.  In another developmental toxicity study (Orme et al.,
1985), neurobehavioral deficits in offspring were observed at a maternal
dose of 14 mg/kg/day.

Table 3.  Acute Toxicity Profile for Chlorine Dioxide/Sodium chlorite

Guideline Number	Study Typea / Test substance (% a.i.)	MRID Number/
Citation	Results	Toxicity Category

870.1100	Acute oral

(79% chlorine dioxide)	43558601	LD50 = 292 mg/kg (males)

LD50 = 340 mg/kg (females)	II

870.1200	Acute dermal

(80% sodium chlorite)	40168704	LD50 > 2000 mg/kg	III

870.1300	Acute inhalation

(80.6% sodium chlorite)	42484101	LC50 = 0.29 mg/L	II

870.2400	Primary eye irritation

(2% chlorine dioxide)	43441903	Mild irritant	III

870.2500	Primary dermal irritation

(80% sodium chlorite)	40168704	Primary irritant	II

870.2600	Dermal sensitization	No acceptable sensitization study
available.

a The available acute studies are all graded as acceptable.  An
acceptable dermal sensitization study is not available in the database. 
 

	3.2	FQPA Considerations  tc "4.2	FQPA Considerations " \l 2 

	Under the Food Quality Protection Act (FQPA), P.L. 104-170, which was
promulgated in 1996 as an amendment to the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug and
Cosmetic Act (FFDCA), the Agency was directed to "ensure that there is a
reasonable certainty that no harm will result to infants and children"
from aggregate exposure to a pesticide chemical residue.  The law
further states that in the case of threshold effects, for purposes of
providing this reasonable certainty of no harm, "an additional tenfold
margin of safety for the pesticide chemical residue and other sources of
exposure shall be applied for infants and children to take into account
potential pre- and post-natal toxicity and completeness of the data with
respect to exposure and toxicity to infants and children. 
Notwithstanding such requirement for an additional margin of safety, the
Administrator may use a different margin of safety for the pesticide
residue only if, on the basis of reliable data, such margin will be safe
for infants and children."

	When the original toxicity endpoint assessment was conducted, the
Hazard Identification Assessment Review Committee (HIARC) concluded that
an extra 10x uncertainty factor under the Food Quality Protection Act
should be considered in risk assessments conducted for chlorine dioxide.
 This recommendation was based upon evidence of susceptibility in a
two-generation reproduction toxicity study in rats and evidence of
susceptibility from scientific literature reports. 

Since that time, the Health Effects Division of the Office of Pesticide
Programs issued policy guidance September of 2001 regarding the
determination of the appropriate FQPA safety factor in tolerance
assessment.  This guidance states that whereas in the past “...OPP has
routinely applied an additional FQPA safety factor where data on a
pesticide shows increased susceptibility or sensitivity (either
qualitative or quantitative) in the developing organism,”  It is the
intent that “...OPP will now put greater emphasis on analyzing the
degree of concern and, rather than apply an additional safety factor
based solely on the identification of heightened sensitivity or
susceptibility, will conduct a case-by-case weight of evidence approach
that qualitatively examines the level of concern for sensitivity /
susceptibility and assess whether traditional uncertainty factors
already incorporated into the risk assessment are adequate to protect
the safety of infants and children.  Using this approach, in many cases
the concerns regarding pre- and postnatal toxicity can be addressed when
a Reference Dose (RfD) or Margin of Exposure (MOE) is based on the pre-
or postnatal endpoints in the offspring.”

The endpoint selected for both dietary and non-dietary exposures to
chlorine dioxide was based upon adverse effects observed in offspring
from developmental and reproductive toxicity data.  Consistent with the
approach used by the EPA’s Office of Water for use of chlorine dioxide
as a drinking water disinfectant and the updated guidance on selection
of a safety factor under FQPA, the endpoint selected for assessment of
risk from dietary and non-dietary exposure to chlorine dioxide was felt
to be protective of potentially susceptible populations including
children, based upon the selection of an endpoint and effects observed
in offspring and the use of an NOAEL value based on those effects. 
Therefore, it was concluded that an additional safety factor under FQPA
was not necessary.

3.3	Dose-Response Assessment  tc "4.3	Dose-Response Assessment " \l 2 

	The doses and toxicological endpoints selected by ADTC for various
exposure scenarios are summarized in Table 4 below.

Table 4. Summary of Toxicological Doses and Endpoint Selection for
Chlorine dioxide/ Sodium chlorite

Exposure Scenario	Dose Used in Risk Assessment (mg/kg/day)	UF/MOE for
Risk Assessment	Study and Toxicological Effects

Acute Dietary	An acute dietary endpoint was not identified in the data
base for chlorine dioxide.  This risk assessment is not required.

Chronic Dietary	NOAEL = 3 mg/kg/day	UF = 100 (10x inter-species
extrapolation, 10x intra-species variation)

Chronic PAD = 0.03 mg/kg/day	Two-generation reproduction toxicity study
(CMA, 1996) - decreases in absolute brain and liver weight, and lowered
auditory startle amplitude at LOAEL of 6 mg/kg/day

Developmental Toxicity - Rat (Orme et al., 1985)- neurobehavioral and
exploratory deficits in rat pups at LOAEL of 14 mg/kg/day

Incidental Oral

(short and intermediate term)	NOAEL = 3 mg/kg/day	MOE  = 100	See summary
for chronic dietary assessment

Short-Term

Dermala

(1-30 days)	NOAEL = 3 mg/kg/day	MOE = 100	See summary for  chronic
dietary assessment

Intermediate-Term Dermala

(30-days-6 months)	NOAEL = 3 mg/kg/day	MOE = 100	See summary for chronic
dietary assessment

Long-Term Dermala

( > 6 months)	NOAEL = 3 mg/kg/day	MOE = 100	See summary for chronic
dietary assessment

Inhalation

(occupational and homeowner short-term)	Homeowner short-term: 

LOAEL = 28 mg/m3 (10 ppm)b

Occupational exposure: 

LOAEL  = 2.8 mg/m3 (1.0 ppm)b

NOAEL = 0.28 mg/m3 (0.1 ppm)b.	Homeowner short-term ‘RfC’ = 0.14
mg/m3 (0.05 ppm)b

Occupational ‘RfC’ = 0.009 mg/m3 (0.003 ppm)b	Inhalation toxicity
studies- Rat

Dalhamn, 1957; Paulet and Debrousses, 1970, 1972.

Inhalation (homeowner long-term)	Agency RfC methodology used to derive
an RfC value of 2 x 10-4 mg/m3 (USEPA, 2000a)	(Paulet and Desbrousses,
1970, 1972) selected as co-critical studies (USEPA, 2000a)

a Based on the use of an oral endpoint for dermal risk assessments and
the lack of a dermal absorption study, a dermal absorption value of 100%
as a default will be used.

b Unit conversion:  1 ppm ClO2 x 67.46/24.45 = 2.8 mg/m3

	

 	3.4    Endocrine Disruption

	The Food Quality Protection Act (FQPA,1996) requires that EPA develop a
screening program to determine whether certain substances (including all
pesticides and inerts) “may have an effect in humans that is similar
to an effect produced by a naturally occurring estrogen, or such other
endocrine effect….”  Following the recommendations of its Endocrine
Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA
determined that there was a scientific basis for including, as part of
the program, the androgen and thyroid hormone systems, in addition to
the estrogen hormone system.  EPA also adopted EDSTAC’s
recommendations that the Program include evaluations of potential
effects in wildlife.  For pesticide chemicals, EPA will use FIFRA and,
to the extent that effects in wildlife may help determine whether a
substance may have an effect in humans, FFDCA authority to require
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).

	When the appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, chlorine
dioxide may be subjected to additional screening and/or testing to
better characterize effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION tc "5.0	EXPOSURE ASSESSMENT
AND CHARACTERIZATION" 

	4.1	Summary of Registered Uses  tc "5.1	Summary of Registered Uses " \l
2 

	Chlorine dioxide and sodium chlorite are active ingredients in numerous
products used in the control of bacteria, fungi, and algal slimes. 
Chlorine dioxide and sodium chlorite are also used as material
preservatives and as disinfectants.  At this time, products containing
chlorine dioxide and sodium chlorite are intended for agricultural
premises, commercial, industrial, medical and residential use.  The
agricultural uses include the disinfection of hard surfaces and
equipment (such as hatching facilities and mushroom houses) and water
systems (such as chiller water and humidification water in poultry
houses).  Commercial, industrial, and medical uses include disinfection
of ventilation systems, hard surfaces (e.g., floors, walls, and
laboratory equipment), water systems, pulp/paper mills, and food rinses.
 Residential uses include disinfection of hard surfaces (e.g., floors,
bathrooms), HVAC systems, and pool & spa water circulation system
treatments.  

	4.2	Dietary Exposure and Risk  tc "4.2 	Dietary Exposure and Risk " \l
2   tc "5.2	Dietary Exposure for Active Ingredient Uses " \l 2 

	A detailed dietary exposure risk assessment for chlorine dioxide is
provided in the Chlorine Dioxide Dietary Risk Assessment, February 24,
2006.  The summary of the exposures and risks are presented below.

	The Agency has carried out the dietary exposure and risk assessment for
use of chlorine dioxide in products used in the control of bacteria,
fungi, and algal slimes, as well as its use as a materials preservative
and disinfectant, all of which may result in indirect food contact
exposures.  No residue chemistry data were submitted by the registrants,
nor were any asked for by the Agency.  To estimate chlorine dioxide
residues on food due to migration of this chemical from sanitizing
and/or disinfecting hard non-porous surfaces which can come into contact
with food, the Agency has used FDA (US Food and Drug Administration)
methodology as well as a methodology established for use in the
Agency’s Reregistration Eligibility Decision (RED) documents. 
Potential use sites include: (1) mushroom houses, (2) poultry
hatcheries, (3) food handling establishments, (4) post-harvest potato
treatments, (5) poultry house disinfection, poultry chiller
water/carcass spray or dip, (6) food processing plants (meat and fish),
(7) dairies, breweries, and bottling plants, and (8) pulp/paper, polymer
slurries, paper adhesive, and paper coating.  

	 

	In the absence of residue data for residues of chlorine dioxide on
treated food contact surfaces, the Agency estimated residue levels that
may occur in food from the application rates on food contact surfaces. 
To estimate the Estimated Daily Intake (EDI), the Agency has used an FDA
model.  The maximum application rate for chlorine dioxide from the
various labeled products is used along with the assumptions that   SEQ
CHAPTER \h \r 1 food can contact 2000 cm2 of treated surfaces and an
assumption that 10% of the pesticide migrates to food.

	

	The dietary risks for adult and children are shown in Table 6.  As
there is no acute dietary endpoint for chlorine dioxide, only chronic
dietary risk is presented.  For adults, the dietary risk is 23% of the
PAD.  For children, the dietary exposure is 103% of the PAD, above the
Agency’s level of concern (100%).

	Label changes similar to the following might help reduce the exposure
concerns for fruit and vegetable washes:  “Water containing up to 3
ppm residual chlorine dioxide may be used for washing fruits and
vegetables that are not raw agricultural commodities in accordance with
21 CFR 173.300.  Treatment of fruits and vegetables with chlorine
dioxide must be followed by blanching, cooking or canning.” 

	

	If the suggested label changes as stipulated above are made, it is
likely the levels of concern (% cPAD) for all populations, including one
to two year old children, would be drastically reduced.

Table 6.  Summary of Dietary Exposure and Risk for Chlorine Dioxide

Use Site	Food Type	Population Subgroup	EDI (mg/person/day)	Chronic
Dietary

Dietary Exposurea (mg/kg/day)	% cPAD b

Indirect Food Use

Food handling establishments/ kitchens	NA	Adult	2.00 x 10-1	9.5E-07
0.00316

Child

8.8E-06	0.0293

Dairies, Breweries, Bottling Plants, Food Contact Surfaces/Food
Processing Plants for Meats and Fishd	Beverages, alcoholic, beer	Adult
1.2 x 10-3	1.70E-05	0.56

	Beverages, non-alcoholic	Adult	1.6 x 10-3	2.40E-05	0.08

Child

1.00E-04	0.33

	Egg Products, Mayonnaise	Adult	1.4 x 10-4	2.00E-06	0.0086

Child

9.33E-06	0.031

	Milk	Adult	1.9 x 10-2	2.70E-04	0.66

Child

1.30E-03	4.2

Pulp/Paper, Polymer Slurries, Paper Adhesive, Paper Coating	NA	Adult	1.1
x 10-1	9.8E-05	0.326 

Child

2.3E-04	0.766

Total Indirect Food-Contact Exposure	Adult	3.3 x 10-1	4.12E-04	1.64

	Child

1-2 years	2.7 x 10-1	1.65E-03	5.35

	Infant

<1

	<5.35 f

Direct Food Use

Post Harvest Application 	Fruit and Vegetable Wash	Adult	 	2.24E-03c,
e	7.5

Child	 	1.27E-02 c, e	42.3

Total Direct Food-Contact Exposure	Adult	 	2.24E-03	7.5

	Child

1-2 years 	 	1.27E-02	42.3g

	Infant

<1

3.49E-03	11.6 f

Inorganic Chlorate Use

Highest Exposure from 

Agricultural Use	Child 

1 – 2 years

	 	8.38E-03c	28

	Infant 

<1 year

4.511E-03	15 f

Total Dietary Exposure

Total Direct and Indirect Food-Contact Exposure	Adult	 	2.65E-03	9.1

	Child 

1-2 years	 	2.27E-02	75.7

	Infant

<1 year

	<31.95 f

a-- For adults, acute and chronic exposure analysis is based on a body
weight of 70 kg.  For adult females, the body weight is 60 kg.  For
children, exposure is based on a body weight of 15 kg.  

b--%PAD = dietary exposure (mg/kg/day) * 100 / cPAD, where cPAD for
adults and children = 0.03 mg/kg/day;   

c--children 1-2 years of age, adults 20-49 years of age

d--food processing plants for meats/fish have exposures which are
similar to other food contact surfaces, exposure numbers not included
for this scenario.

e-- includes all fruits and vegetables and apple and orange juices;
assumes 100% of fruit is washed with chlorine dioxide.

f--Infants (<1 year) are included in this table for comparison purposes
and were not added to the total dietary exposure as it was not the most
highly exposed subpopulation.

g--Assuming 50% of fruits/vegetables are treated, the dietary risk for
children (1 – 6) would represent 21% of the cPAD.

 

In the poultry hatcheries, eggs are produced for the production of
chicks and not for human consumption.  Although it is likely some
sanitizer/disinfectant chemicals may penetrate the egg shells and
bioaccummulate in the developing chicks, at this time the Agency
believes that the amount of the chemical transferred to the developing
chicks is not likely to adversely affect the development of chicks and
will have an even smaller transfer into humans. The Agency has no
dietary risk concerns at this time for this use.

Similarly, the Agency has no concerns at this time for use of chlorine
dioxide and sodium chlorite for stored potato treatment and subsequent
interstate commerce of this commodity.  EPA’s Antimicrobials Division
had asked the States of Idaho and Washington to collect analytical data
on the residues on chlorine dioxide treated post-harvest potatoes
(USEPA, 1998).  Two breakdown products of chlorine dioxide were
measured, chlorite and chlorate.  Chlorite was found to be non-detect in
the samples and only small quantities of chlorate (0.97 to 1.1 µg/g)
were found in only three samples.  The Agency did not see any concerns
for the presence of chlorate at the levels reported in the samples. 

For poultry house disinfection and poultry chiller water/carcass spray
or dip, the application and method of application is exactly the same as
was submitted to FDA for their risk assessment. FDA assessed the risks
involved for this use (FDA Memo: FAP: 4A4433, 1994). FDA extensively
reviewed the efficacy and analytical chemistry data on the residues of
chlorate/chlorite or possibly chlorine dioxide for the scenarios listed.
Residues of chlorite and chlorates were measured on poultry carcasses
after pre-chiller and chiller water treatments. After the pre-chiller,
neither chlorite nor chlorate was detected between 0.009 ppm to 0.011
ppm levels of detection.  In the chiller water treatment, chlorite
detection was at 0.54 ppm at time zero, 0.09 ppm at 10 minutes and at
0.021 ppm after one hour.  The level of detection (LOD) was set at 0.016
ppm. Chlorite was non-detect after 2 hours. Chlorate was non-detect even
at time zero.  It is likely that the residual chlorate/chlorite
associated with the poultry may be going through oxidative processes to
form chlorinated organics. FDA asked the industry to conduct studies on
the formation of chlorinated organics, and no evidence was found for the
formation of chlorinated organics. However, some PCBs were detected at
the background levels. Open literature studies support the results that
with acidified sodium chlorate treatment of poultry no chlorinated
organics are formed.  FDA accepted the studies and concurred with the
results. At this time, the Agency does not have any concerns with the
use of acidified sodium chlorite solution on carcasses.

For food processing plants (meat and fish), the application rates are
similar to those used for food handling establishments, and therefore,
the exposure would also be similar.  At this time, the Agency does not
have any dietary concerns for this application.

	The Agency, at this time, has not established any tolerances or
exemptions from the requirement of tolerance for chlorine dioxide as a
sanitizer in mushroom facilities.  Chlorine dioxide is applied to
equipment at rates that vary between 100 -200 ppm; however transfer of
residue levels on mushrooms is not indicated.  The Agency is not
requiring any tolerances any tolerances of chlorine dioxide on mushroom
uses.  The Agency has not conducted any dietary risk assessment for
mushroom use, as no dietary risks are indicated.

FDA assumptions were used to calculate the dietary exposure from
sanitizing food-contact surfaces; processing equipments; and utensils in
dairies, breweries, canning operations, and meat and vegetable
processing plants.  Based on these assumptions and data on alcoholic
beverages/beer, non-alcoholic beverages, egg products, and salad
dressing/mayonnaise, the highest %cPAD calculated is 4.2% for
children’s consumption of milk.

According to the Agency’s memo of may 9, 2006, the Agency has accepted
the label change from the label for  SLIME-TROL RX33 (USEPA reg #
74655-2) which allowed  for the deletion of the label statement which
referred to the use of the product in pulp and paper as a slimicide. 
Based on this information, the Agency has decided to exclude the dietary
assessment which covers uses of chlorine dioxide and sodium chlorite as
a polymer slurry as filler paper, as a paper adhesive preservative and
as a paper coating preservative.

For direct food uses, AD conducted a chronic risk assessment for the
fruit and vegetable washes (post-harvest) and the chronic risk from
these uses appear to be below the Agency’s level of concern.

 

Table 7. Exposure by Population Group

Population Subgroup	Total exposure

(mg/kg body wt./day)	  % cPAD

U.S. Population	0.003292	      11

Infants <1 year	0.003493	      12

Children 1-6 years	0.009933	      33

Children 7-12 years	0.004208	      14

Females 13-50	0.002689	       9

	4.3	Drinking Water Exposures and Risks  tc "5.4	Drinking Water
Exposures and Risks " \l 2 

	In a memo from Pat Fair of the EPA’s Office of Water, exposure to
chlorine dioxide from drinking water was characterized.  Chlorine
dioxide is used as a disinfectant in water treatment plants in the USA.
Chlorite ions (ClO2) are present in drinking water as a result of
reactions involving chlorine dioxide.  Because of the health concerns
resulting from the presence of the chlorite ions and their subsequent
conversion to chlorate ions, the Agency wanted to make sure that the
level of chlorite ions did not exceed certain specified limits.  The EPA
instituted a system for monitoring the occurrence of chlorite in
drinking water and collected data from July 1997 to December 1998.

DEEM-FCID™, Version 2.0 software (EPA, 2000) was used to determine the
exposure values (Memo from David Hrdy, HED, to Jennifer Slotnick, AD). 
Table 8 presents the exposures and corresponding risks.  The 90th
percentile exposure values will be used in the aggregate risk
assessments, with children represented by the 1-6 year old age category.
 The only subpopulation that the Agency has concerns for is infants
(less than one year old) when exposed to chlorine dioxide treated water.
 All other subpopulations and the general population have risks below
the Agency’s level of concern.

	In addition to the information above, the Agency has reviewed an
additional study on the determination of chlorite in baby formula
prepared from water containing residual chlorite (report by T.V. Tran,
report # TR05-01).  The Agency agrees that there is evidence that the
components of the baby formula react with chlorite in the drinking
water; however, the Agency has no quantitative tool to assess the extent
of reduction in exposure to chlorite if specific chemicals are present
in the baby formula.  Due to these uncertainties, the Agency believes
that for all infants (< 1 year old) as well as non-nursing infants (<1
year old), the % cPAD may likely be less than 100.

Table 8. Chlorite Exposure by Population Group

Population subgroup	Maximum Concentration	90th Percentile Concentration
Median Concentration

	Total exposure

(mg/kg/day)	% cPAD	Total exposure

(mg/kg/day)	% cPAD	Total exposure (mg/kg/day)	% cPAD

U.S. Population	0.014754	49	0.013279	  44	0.008220	27

Infants < 1 year	0.048372	161	0.043535	145	0.026950	90

Children 1-6 years	0.020613	69	0.018552	  62	0.011485	38

Children 7 -12 years	0.013402	45	0.012062	  40	0.007467	25

Females 13-50	0.014274	48	0.012846	  43	0.007952	27

4.4	Residential Exposure/Risk Pathway  tc "5.5	Residential Exposures and
Risks for Active Ingredient Uses " \l 2 

	A detailed human exposure risk assessment for chlorine dioxide is
provided in the attached Appendix.  The summary of the exposures and
risks to the residential population are presented below.

		4.4.1	Residential Handler Scenarios  tc "5.5.1	Residential Handler
Scenarios " \l 3 

	Exposure Scenarios

	Chlorine dioxide and sodium chlorite are active ingredients in numerous
products used in the control of bacteria, fungi, and algal slimes.  In
addition, chlorine dioxide and sodium chlorite are used as material
preservatives and as disinfectants.  Residential uses of chlorine
dioxide and/or sodium chlorite products that are applied by homeowners
include the control of mold and mildew (i.e., EPA Reg. No. 21164-3). 
For the exposure assessment, household cleaning products were grouped
together to be represented by a higher application rate from a sodium
chlorite product (i.e., EPA Reg. No. 21164-3).  The post application
scenario is based on a product that applies chlorine dioxide to floors
that have the potential for children playing.  Three scenarios, mopping,
spraying, and placing tablets in pools/spas, were examined to represent
the residential uses in the risk assessment.

	Exposure Data and Assumptions

There are no chemical-specific exposure data to assess applications to
hard surfaces with a mop or trigger-pump sprayer or to pools/spas. 
However, surrogate data are available.  Dermal exposures were assessed
using the proprietary Chemical Manufacturers Association (CMA) data
(MRID 42587501) for mopping as well as placing tablets in pools/spas and
the Pesticide Handler Exposure Database (PHED, 1998) for spraying.  The
CMA data for mopping are based on individuals mopping floors and
receiving exposure via contact with the mop or with the bucket.  Dermal
exposures were assessed for trigger pump spray application methods using
PHED Version 1.1 values found in the Residential Exposure SOPs (USEPA,
2000b).  The surrogate exposure data in PHED are based on test subjects
applying an insecticide from an aerosol can to baseboards in kitchens. 
The dermal exposures from these techniques have been normalized by the
amount of active ingredient handled and reported as unit exposures (UE)
expressed as mg/lb ai handled.    

	In addition, product label maximum application rates, related use
information, and Agency standard values were used to assess residential
handler exposures.  For example, it was assumed that one gallon of
diluted solution is used for mopping floors, while 0.5 liters (0.13
gallons) are used in the trigger pump spray scenario. The residential
handler scenarios are assumed to be of short-term duration (1-30
consecutive days).  

Risk Characterization

	A summary of the dermal residential handler exposures and risks are
presented in Table 9.  Although the dermal endpoint represents short-,
intermediate-, and long-term durations, the exposure duration of most
homeowner applications of cleaning products is believed to be best
represented by the short-term duration.  The toxicological endpoint is
based on an oral study and no dermal absorption value is available. 
Therefore 100% dermal absorption was assumed.  The calculated dermal
MOEs are above the target MOE of 100 for both of the cleaning scenarios.
 The dermal MOE for applications to hard surfaces via trigger-pump
sprayer is 3,200 and the dermal MOE for application of liquid
formulations via mopping is 1,300.  However, the dermal MOE for the
placement of tablets into pools is 46, and therefore, of concern. This
risk can be mitigated with the use of gloves (MOE=500).

Table 9.  Estimates of Short-term Dermal Exposures and Risks to
Residential Handlers of Chlorine Dioxide

Product	Exposure Scenario	Potential Dermal Dosea

(mg/kg/day)	Dermal MOEb

(Target MOE = 100)

Cleaning	Mopping - 

hard surfaces	0.095	1300

	Trigger-pump sprayer - hard surfaces	0.038	3200

Swimming Pools	Solid Place (tablets)	0.065 (no gloves)

0.006 (gloves)	46 (no gloves)

500 (gloves)

a 	Potential Dermal Dose (mg/kg/day) = Application Rate (lb ai/gallon) *
gallons used *  Dermal Unit Exposure (mg/lb ai) )/ Body Weight (60 kg),
where dermal absorption is 100 percent.

b	Dermal MOE= Dermal NOAEL (3 mg/kg/day)/Absorbed Dermal Dose
(mg/kg/day). 

	The potential inhalation of chlorine dioxide may occur from off gassing
during application of the aqueous solution.  Chlorine dioxide has the
potential to generate a gas during the residential uses of mopping and
spraying.  However, it is unlikely that levels of concern for chlorine
dioxide would be generated outdoors while treating swimming pools & spas
with tablets placed into water. 

	EFAST (Exposure and Fate Assessment Screening Tool) was used to model
the air concentration from general purpose cleaners (  HYPERLINK
"http://www.epa.gov/opptintr/exposure/" 
http://www.epa.gov/opptintr/exposure/ ).  The peak instantaneous air
concentration is 0.265 mg/m3 (0.09 ppm) and the average daily TWA
(time-weighted average) air concentration is determined to be 0.00794
mg/m3 (0.003 ppm).  The residential short-term inhalation endpoint (RfC)
is 0.05 ppm.  Based on the average daily air concentration (representing
both application and post application), the handler inhalation exposures
of chlorine dioxide are not of concern (i.e., the average air
concentration estimated by EFAST of 0.003 ppm is below the RfC of 0.05
ppm).  

	4.4.2	Residential Post Application Exposure  tc "5.5.2	Residential
Post-application Exposure " \l 2 

		Residential post application exposures result when bystanders (adults
and children) come in contact with chlorine dioxide in areas where
pesticide-treated end-use products have recently been applied (e.g.,
treated hard surfaces/floors), or when children incidentally ingest the
pesticide residues through mouthing the treated end products/treated
articles (i.e., hand-to-mouth or object-to-mouth contact).   Because of
the high vapor pressure of chlorine dioxide, inhalation exposure to
chlorine dioxide off gassing is also a potential route of exposure.

	  SEQ CHAPTER \h \r 1 For the purposes of this screening-level
assessment, four scenarios have been considered.  These include: (1)
exposure to residue from hard floors that have been cleaned/mopped with
a generic cleaner containing chlorine dioxide, (2) exposure to chlorine
dioxide used to clean residential HVAC systems, (3) exposure to a
continuous release (gas) deodorizer, and (4) swimming.

Exposure Data and Assumptions

	Typically, most products used in a residential setting result in
exposures occurring over short-term time duration (1 – 30 days).  If
the products are used on a routine basis (i.e., once a week) and the
active ingredient has a long indoor half-life, exposures may occur over
an intermediate-term time duration (30 days – 6 months).  At this
time, AD does not have residue dissipation data or reliable use pattern
data, including the frequency and duration of use of antimicrobial
products in the residential setting.  Even though AD does not believe
that the use patterns of many residential products result in
intermediate-term exposure, they are assessed to provide an upper bound
estimate of exposure.  AD does believe, however, that intermediate-term
exposure to children may occur in day care centers where disinfecting
products are used more frequently.

	A number of conservative assumptions were used in assessing post
application risks including maximum application rates from the label. 
In addition,   SEQ CHAPTER \h \r 1 quantities handled/treated were
estimated based on information from various sources, including the Draft
Standard Operating Procedures (SOPs) for Residential Exposure
Assessments (USEPA 2000b).  In certain cases, no standard values were
available for some scenarios.  Assumptions for these scenarios were
based on AD estimates and could be further refined from input from
affected sectors.  

Risk Characterization

	A summary of the residential dermal and oral post application exposures
and risks are presented in Table 10.    SEQ CHAPTER \h \r 1 The child
short- and intermediate-term dermal MOE for contact following hard
surface disinfection is above the target MOE of 100 for residential and
daycare settings (MOE = 280).    SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 The short- and intermediate-term incidental oral MOE following hard
surface disinfection is above the target MOE of 100 for residential and
daycare settings (MOE = 2,300), and thus is not of concern.    SEQ
CHAPTER \h \r 1  

	Inhalation exposures due to post application activities could occur for
children after the treatment of floors; adults and children after the
treatment of HVAC systems; and adults and children after the use of
continuous release (gas) deodorizers.  Chlorine dioxide and/or sodium
chlorite can be applied as an aqueous solution to hard surfaces such as
floors (as well as dust applications to carpets).  Based on the use
label, which contains the highest rate of application of chlorine
dioxide to disinfect a room, and using several assumptions, the maximum
air concentration of chlorine dioxide can be estimated.  Two methods
were used to assess the inhalation risks to residents.   First, there
are air concentration measurements available after the application of
chlorine dioxide as a dust treatment on carpets (Speronello 2005). 
Although there are limitations to this study (e.g., not conducted under
Good Laboratory Practices (GLPs), minimal information is available in
the study report), it is the only data source available at this time. 
Secondly, a theoretical approach to estimating chlorine dioxide air
concentration is also presented based on dilution and ventilation along
with the half-life of chlorine dioxide.  Based on these estimates, an
8-hour TWA air concentration starting immediately after application has
been determined to be 0.08 ppm which is above the short-term RfC of 0.05
ppm.  To mitigate this risk concern, a second 8-hour TWA air
concentration was calculated assuming a 1-hour restricted entry interval
(REI).  If one could assume that residents would stay out of the house
for the first hour, the 8-hour TWA is 0.02 ppm which is below the RfC of
0.05 ppm.  To accurately determine the initial concentration of chlorine
dioxide in the air after mopping, air monitoring data would be needed.

For HVAC systems, BCI (2002) monitored a chlorine dioxide treatment of a
HVAC system in a residence.  The air concentrations monitored indicated
a maximum value of 0.02 ppm and the average value was below the
detection limit of 0.01 ppm.  The short-term inhalation RfC for chlorine
dioxide is 0.05 ppm.  According to the label, the frequency of HVAC
system treatments is to “treat as required.”  The frequency of
residential (and/or commercial/intuitional) HVAC treatments is expected
to be minimal (most likely less than once per year).  In addition, the
half-life of chlorine dioxide is rapid.  Therefore, inhalation exposure
is expected to be limited to short-term durations and inhalation risks
are not expected to be a concern.  

	For the continuous release deodorizers, a bounding estimate of air
concentration is presented based on the application rate and the
label-referenced longevity of the pouches/sachets.  The theoretical
constant air concentration would be 0.52 ppm assuming no air exchange
and no build up of chlorine dioxide over time because of the short
half-life.  The RfC for long-term continuous exposure is 0.00007 ppm. 
Therefore, the theoretical concentration from the product’s release is
of concern.  This bounding estimate can be refined by determining
residential (and commercial/institutional) ventilation rates,
identifying sensitive analytical detection methods and collecting
monitoring data, and determining the number of hours an individual is
exposed in treatment areas.  However, before any refinements to these
air concentration estimates are attempted, it should be determined if
the product’s efficacy can be maintained at the RfC of ~0.00007 ppm.  

Table 10.  Summary of Short- and Intermediate-Term

Residential Postapplication Exposures and Risks

Scenario	Dose a

(mg/kg/day)	MOEb

(Target MOE>100 dermal and oral)

Dermal Exposure

Hard surface Disinfection	Residential Setting and

Daycare center	0.017	280

Incidental Oral Exposure

Hard surface Disinfection	Residential Setting and

Daycare center	0.0013	2,300

a	Dose calculations for each scenario above are outlined in the attached
Occupational/Residential Assessment.

b	MOE= NOAEL (mg/kg/day) / Dose (mg/kg/day). Oral and dermal NOAEL is 3
mg/kg/day.

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS tc "	6.0
AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS" 

	In order for a pesticide registration to continue, it must be shown
that the use does not result in “unreasonable adverse effects on the
environment”. Section 2 (bb) of FIFRA defines this term to include
“a human dietary risk from residues that result from a use of a
pesticide in or on any food inconsistent with standard under section
408...” of FFDCA.  Consequently, even though no pesticide tolerances
have been established for chlorine dioxide, the standards of FQPA must
still be met, including “that there is reasonable certainty that no
harm will result from aggregate exposure to pesticide chemical residue,
including all anticipated dietary exposures and other exposures for
which there are reliable information.”   Aggregate exposure is the
total exposure to a single chemical (or its residues) that may occur
from dietary (i.e., food and drinking water), residential, and other
non-occupational sources, and from all known or plausible exposure
routes (oral, dermal, and inhalation).  Aggregate risk assessment were
conducted for acute (1 day), short-term (1-30 days), intermediate-term
(1-6 months) and chronic (several months to lifetime) exposures.

	In performing aggregate exposure and risk assessments, the Office of
Pesticide Programs has published guidance outlining the necessary steps
to perform such assessments (General Principles for Performing Aggregate
Exposure and Risk Assessments, November 28, 2001; available at
http://www.epa.gov/pesticides/trac/science/aggregate.pdf).  Steps for
deciding whether to perform aggregate exposure and risk assessments are
listed, which include: identification of toxicological endpoints for
each exposure route and duration; identification of potential exposures
for each pathway (food, water, and/or residential);  reconciliation of
durations and pathways of exposure with durations and pathways of health
effects; determination of which possible residential exposure scenarios
are likely to occur together within a given time frame; determination of
magnitude and duration of exposure for all exposure combinations;
determination of the appropriate technique (deterministic or
probabilistic) for exposure assessment; and determination of the
appropriate risk metric to estimate aggregate risk.

	5.1	Acute and Chronic Aggregate Risks  tc "6.1	Acute and Chronic
Aggregate Risks " \l 2 

	The acute and chronic aggregate risk assessments include only dietary
and drinking water exposures.  An acute risk assessment was not
conducted for chlorine dioxide because there were no acute dietary
endpoints of concern. Drinking water exposure estimates are presented in
Section 4.3.  Acute and chronic dietary risk estimates from direct and
indirect food uses are presented in Table 6 of Section 4.2.  Table 11
presents a summary of these exposures, including the aggregate dietary
exposure (all direct and indirect food contact exposures) as well as a
total dietary aggregate exposure value (drinking water plus
direct/indirect dietary exposures).  

Table 11.  Chlorine Dioxide Chronic Aggregate Exposures and Risks

Exposure Routes	Chronic Dietary Exposures (mg/kg/day)

	Dietary (indirect + direct food contact+ chlorate) Exposuresa	Drinking
water exposures 	Aggregate Dietary Exposuresb	Aggregate Dietary Risks
(%cPAD)

Adults

Oral Ingestion	2.65E-03	1.33E-02	1.6E-02	53.3%

Children (age 1 – 6)

Oral Ingestion	2.27E-02	1.86E-02	4.13e-02	133%

a Dietary (indirect + direct food contact) exposures = sum of dietary
exposures presented in Table 6.

b Aggregate Dietary Exposures = sum of both dietary (direct and indirect
food contact) exposures and drinking water exposures.  

 	5.2	Short- and Intermediate-Term Aggregate Exposures and Risks  tc
"6.2	Short- and Intermediate-Term Aggregate Exposures and Risks " \l 2 

	Short- and intermediate-term aggregate exposures and risks were
assessed for adults and children that could be exposed to chlorine
dioxide residues from the use of products in non-occupational
environments.  The following list summarizes all of the potential
sources of chlorine dioxide exposures for adults and children.

Adult chlorine dioxide exposure sources:

handling of cleaning products containing chlorine dioxide as an active
ingredient during wiping activities;

handling of cleaning products containing chlorine dioxide as an active
ingredient during mopping activities;

eating food having chlorine dioxide residues from use of product on
fruits and vegetables; 

eating food having chlorine dioxide residues from indirect food contact;
and

drinking water containing chlorine dioxide.

	

Child chlorine dioxide exposure sources:

post-application exposures to cleaning product residues containing
chlorine dioxide as an active used on hard surfaces (i.e., floors);

eating food having chlorine dioxide residues from use of product on
fruits and vegetables; 

eating food having chlorine dioxide residues from indirect food contact;
and

drinking water containing chlorine dioxide.

	The use patterns of the products and probability of co-occurrence must
be considered when selecting scenarios for incorporation in the
aggregate assessment.  Table 12 summarizes the scenarios included in the
short- and intermediate-term aggregate assessments.

Table 12. Exposure Scenarios Included in the Aggregate Assessments

	Short-term Aggregate	Intermediate-Term Aggregate

Adults	chronic dietary (direct and indirect)

handling cleaning products – spray (dermal only)

handling cleaning products – mopping (dermal only)

chronic drinking water	N/A

Children	chronic dietary – (direct and indirect)

post-app to cleaning product (dermal and oral)

chronic drinking water	chronic dietary – (direct and indirect)

post application to cleaning product (dermal and oral)

chronic drinking water

The chronic dietary exposures were used in both the short- and
intermediate-term aggregate assessment because chronic dietary exposures
occur nearly every day (as opposed to acute dietary exposures occurring
on a one-time basis).  Therefore, short- or intermediate-term
non-dietary exposures have a much higher probability to co-occur with
the chronic dietary intake rather than the acute dietary intake.  	

Cleaning activities in a residential setting occur on a short-term
basis.  However, the chlorine dioxide-containing cleaning products are
also labeled for use in institutional settings such as day-care
facilities where cleaning activities can occur on an intermediate-term
basis.  Therefore, children could have exposure to cleaning product
residues on a more continuous basis in a day care facility, thus, these
post application scenarios were included in the intermediate-term
aggregate assessment.	

	Since the toxicity endpoints for the oral and dermal routes of exposure
are based on the same study and same toxic effect, these two routes are
aggregated together.  Aggregate risks were calculated using the total
MOE approach outlined in OPP guidance for aggregate risk assessment
(August 1, 1999, Updated “Interim Guidance for Incorporating Drinking
Water Exposure into Aggregate Risk Assessments”).  Table 13 presents a
summary of both dietary and dermal exposures.  Table 14 presents a
summary of the short- and intermediate-term aggregate risk MOEs.  The
aggregate risks are not of concern for adults, as the total aggregate
MOE is 130, which is above the target of 100.  For children, the
aggregate risk estimates are below the target MOE of 100 (MOE=44) and
thus are of concern.    It should be noted that several conservative
assumptions were used in this assessment.  

Table 13. Doses for Short- and Intermediate-term Aggregate Assessment

Exposure Routes	Aggregate Dietary Exposures (mg/kg/day)	Dermal Exposures
(mg/kg/day)

Hard Surface Cleaning

Applicator	Post-Application

Mop	Spray

	Adults

Oral Ingestion	2.0E-02	NA	NA	NA

Dermal	NA	0.0024	0.00095	NA

Children

Oral Ingestion	5.0E-02	NA	NA	0.0013

Dermal	NA	NA	NA	0.017

Table 14. Short- and Intermediate-term Aggregate Risks (MOEs)

Exposure Routes	Aggregate Dietary Risks	Dermal Risks (MOE)	Aggregate
Risks

(MOE)

Hard Surface Cleaning

	Applicator	Post-Application

	Mop	Spray

Adults

Oral Ingestion MOEs	150	NA	NA	NA	150

Dermal MOEs	NA	1300	3200	NA	900

Total MOE	150	1300	3200	NA	130

Children (age 1 – 6)

Oral Ingestion MOEs	60	NA	NA	2300	58

Dermal MOEs	NA	NA	NA	180	180

Total MOE	60	NA	NA	160	44

Infants < 1

Oral Ingestion	55	NA	NA	2300	55

Dermal MOEs	NA	NA	NA	180	180

Total MOE	55	NA	NA	160	41

MOE = NOAEL/dose

Aggregate MOE = 1/((1/MOEdietary) + (1/MOEdrinking water) +
(1/MOEdermal)

All NOAELs = 3 mg/kg/day

Target MOE oral = 100

Target MOE dermal = 100

	

6.0     CUMULATIVE RISK	

	Section 408 of the FFDCA stipulates that when determining the safety of
a pesticide chemical, EPA shall base its assessment of the risk posed by
the chemical on, among other things, available information concerning
the cumulative effects to human health that may result from dietary,
residential, or other non-occupational exposure to other substances that
have a common mechanism of toxicity.  The reason for consideration of
other substances is due to the possibility that low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect as would a
higher level of exposure to any of the other substances individually.  A
person exposed to a pesticide at a level that is considered safe may in
fact experience harm if that person is also exposed to other substances
that cause a common toxic effect by a mechanism common with that of the
subject pesticide, even if the individual exposure levels to the other
substances are also considered safe. 

	EPA has not assumed that chlorine dioxide 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
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/.

7.0	OCCUPATIONAL EXPOSURE	

	A detailed human exposure risk assessment for chlorine dioxide is
provided in the attached Appendix.  The summary of the exposures and
risks to occupational workers are presented below.

	7.1	Occupational Handler  tc "	8.1	Occupational Handler " \l 2 

	Potential occupational handler exposure from the use of chlorine
dioxide products can occur in various use sites, including agricultural
premises, food handling, commercial and institutional premises, medical
premises, human drinking water systems, industrial processes and water
systems, application to material preservatives, and swimming pools and
other aquatic areas.    The occupational exposure scenarios and
estimated risks are presented in Table 15.  Exposure estimates for the
fruits and vegetable wash and the machinists exposed to treated metal
working fluids (MWF) are presented separately.

	To assess the handler risks, AD used surrogate unit exposure data from
both the proprietary Chemical Manufacturers Association (CMA)
antimicrobial exposure study and the Pesticide Handlers Exposure
Database (PHED).  Inhalation handler exposures were combined with post
application exposures to represent a “full-day” or 8-hour time
weighted average (TWA) to be comparable to the inhalation RfC. 
Inhalation exposure to the release of chlorine dioxide gas during the
mixing/loading/application of products producing chlorine dioxide may
occur.  Because the inhalation toxicological endpoint is based on an
8-hour TWA, the assessment of handler inhalation exposures is assessed
as a combination of activities throughout a work day.  The assessment of
inhalation exposure is presented in the post application/bystander
section

						

	For the occupational handler dermal risk assessment, the short- and
intermediate- term risks calculated at baseline exposure (no gloves and
no respirators) were above target MOEs for all scenarios (i.e., dermal
MOEs were >100), except for the following: 

Agricultural premises and equipment:

application to hard surfaces: low pressure handwand (MOE=31), 

application to hard surfaces: mopping (MOE=70), and

application to hard surfaces: foam applicator equipment (MOE=52). 

Food Handling, Commercial/Institutional, and Medical Premises and
Equipment:

application to hard surfaces: mopping (MOE=66 commercial; 3 medical).

To calculate the dermal exposure for a worker treating fruits and
vegetables, the Consumer Exposure Pathway of the Exposure and Fate
Assessment Tool (CEM/E-FAST) was used.  CEM calculates conservative
estimates of inhalation and dermal exposures to consumer products.  The
estimated dermal MOE for the fruit and vegetable wash is 2,300, and
therefore, not of concern. 

	Finally, there is the potential for exposure to machinists contacting
chlorine dioxide when used as a material preservative in metal working
fluid (MWF).  There is a potential for dermal and inhalation exposure
when a worker handles treated metalworking fluids.  Because of the high
vapor pressure of chlorine dioxide, the inhalation route of exposure is
not assessed in the typical manner (i.e., using the OSHA PEL for oil
mist x percent concentration in solution).  See below for the discussion
of the inhalation route of exposure for occupational workers.  	The
dermal route of exposure to machinists occurs after the chemical has
been incorporated into the metalworking fluid and a machinist is
using/handling this treated end-product.  Short-, intermediate-, and
long-term exposure estimates were derived using the 2-hand immersion
model from ChemSTEER.  The results indicate that the short-,
intermediate-, and long-term dermal MOE is 14,000, and therefore, not of
concern.

Table 15.  Short-, Intermediate-Term Risks for Occupational Handlers

Exposure Scenario	Method of Application	Application Rate  (lb ai/
gallon)	Quantity Handled/

Treated per day (gallons)	MOEc

Baseline Dermala

(Target MOE>100)	PPE Gloves Dermalb

(Target MOE>100)

Agricultural Premises and Equipment

Application to hard surfaces	Low pressure handwand	0.015	2	31	No data

	Liquid Pour

0.188	1,300	6,300

	Trigger-pump sprayer

0.26	240	570

	Mopping	0.018	2	70	No data

	Foam applicator equipment	0.06	4	20	52

Food Handling, Commercial/Institutional, and Medical Premises and
Equipment

Application to hard surfaces	Mopping	0.019	2	66	No data

	Trigger-pump sprayer	0.08	0.26	46	110

Human Drinking Water Systems

Water and Storage systems	Metering pump	0.007	34,000	No data	120

Material Preservatives

MWF	Liquid pour	0.0001	300	No data	33,000

Industrial Processes and Water Systems

Paper and pulp white water systems	Metering pump	0.0344 lb ai/ton paper
500 tons paper	No data	2,300

Oil systems	Open pour	0.069	2.8	NA	6,900

	5.6

3,500

Swimming Pools and Aquatic Areas

Retention ponds/fountain	Liquid pour	0.00001	10,000	No data	670

Swimming pools (public)	Solid place	1.8E-5	200,000	5	120

HVAC Systems

HVAC	Airless sprayer	0.007	5	140	NA

	Fogger (liquid pour)

0.25	2,000	NA

a	Baseline Dermal:  Long-sleeve shirt, long pants, no gloves.

b	PPE Dermal with gloves: baseline dermal plus chemical-resistant
gloves.

c	MOE = NOAEL  (mg/kg/day) / Daily Dose [Where short-and
intermediate-term NOAEL = 3 mg/kg/day for dermal exposure]. Target MOE
is 100 for dermal exposure.

	

	7.2	Occupational Post Application Exposure

7.2.1 Dermal Post Application Exposure

	No information is available to assess post application/bystander dermal
exposure to uses in agricultural premises as well as food handling,
commercial/institutional and medical premises; human drinking water
facilities; industrial processes; and retention ponds.  However, dermal
post application exposure to chlorine dioxide is expected to be less
than that of the dermal contact of children playing on treated floor
surfaces.  Therefore, the dermal exposure route is not believed to be of
concern in these industries.  

		7.2.2	Inhalation Post Application Exposure

Non-Fogging Uses

	There is the potential for the off gassing of chlorine dioxide during
some applications that are not totally enclosed (e.g., spray aqueous
solution, mopping, pouring, etc).  Although no occupational air
monitoring data have been submitted to assess the inhalation route, EPA
has obtained air concentration measurements from OSHA.  OSHA maintains a
data base known as the Integrated Management Information System (IMIS). 
The IMIS entries for chlorine dioxide are available for 7 industry
Standard Industrial Classification (SIC) codes.  Specific uses such as
applicators, bystanders and the activities involved are not available. 
The SIC codes representing the chlorine dioxide data in IMIS used in
this assessment include:  

SIC 0723  Crop preparation services for market;

SIC 1629  Heavy construction;

SIC 2611  Pulp mills;

SIC 2621  Paper mills;

SIC 2819  Industrial inorganic chemicals;

SIC 2836  Biological products; and

SIC 3999 Manufacturing industries.  

	The data selected for this analysis include only those samples that are
reported as 8-hour TWA measurements from personal air samplers.  Other
samples, such as peak concentrations and/or area monitors, have been
omitted.  The chlorine dioxide sampling and analytical procedures used
in the collection of the data in IMIS are available at   HYPERLINK
"http://www.osha.gov/dts/sltc/methods/inorganic/id202/id202.html" 
http://www.osha.gov/dts/sltc/methods/inorganic/id202/id202.html .  The
quantitative LOD from this method is 0.004 ppm for a 4-hour sample (the
recommended sampling time).  The reported full 8-hour work shift
samples are based on two 4-hour samples collected in sequence.  The
inhalation endpoint selected by EPA is 0.003 ppm, just below the OSHA
LOD for an 8-hour TWA air sample [i.e., (0.5 x 0.004 ppm per 4 hrs) +
(0.5 x 0.004 ppm per 4 hrs)=0.004 ppm per 8 hours].

	The summary results of the 33 observations taken from 8-hour TWA
personal air samplers for chlorine dioxide are above the EPA selected
inhalation reference concentration (RfC) of 0.003 ppm, and therefore,
are of concern.  Of the 33 TWA measurements available, 21 of those
measurements were below the LOD of 0.004 ppm.  In addition, of the 33
TWA measurements, only 3 were at or above the OSHA PEL of 0.1 ppm.  

Fogging Uses

	The fogging use of chlorine dioxide is unique such that no persons are
present during the actual application/fogging.  There is also a greater
potential for chlorine dioxide gas formation from fogging then an
aqueous-based application such as mopping.  Therefore, a separate
assessment was developed for foggers that indicate potential inhalation
exposure and reentry recommendations.  The air concentration in a fogged
area should be below the occupational RfC of 0.003 ppm before the room
is entered by persons not wearing respiratory protection.  EPA Reg. No.
74602-2 was used to illustrate potential air concentrations.  

	Concentrations of chlorine dioxide were estimated for buildings after
fogging applications.  Air concentrations were calculated using the
Multi-Chamber Concentration and Exposure Model (MCCEM v1.2).   MCCEM
estimates average and peak indoor air concentrations of chemicals
released from products or materials in houses, apartments, townhouses,
or other residences. Although the data libraries contained in MCCEM are
limited to residential settings, the model can be used to assess other
indoor environments.  MCCEM has the capability to estimate inhalation
exposures to chemicals, calculated as single day doses, chronic average
daily doses, or lifetime average daily doses.

	The product, EPA Reg # 74602-2 (sodium chlorite with a 5% chlorine
dioxide equivalent) has a maximum application rate for egg houses of
0.0083 lb ai/gal (1000 ppm chlorine dioxide treatment solution).  This
particular product specifically lists a Dramm fogger for the application
(i.e., ultra low volume (ULV)).  According to the registrant, the Dramm
fogger for chlorine dioxide applications uses 2.5 ounces of the diluted
product per 225,000 cubic feet (USEPA 2006), and the label states to run
the fogger for five minutes.  Note:  This labeled rate should be added
to all chlorine dioxide fogger uses.  If other registrants require a
higher application rate, these rates need to be brought to EPA’s
attention during the development of the chlorine dioxide RED.  

	Using an air exchange rate (air changes per hour or ACH) of 0.18, an
8-hr TWA of less than 0.003 ppm (0.0084 mg/m3) is expected with no REI. 
Although there appears to be no inhalation risks of concern, a 1-hour
REI would be prudent.

	In a second fogging example, EPA Reg. No. 21164-3 allows chlorine
dioxide fogging and misting applications while workers are in the room
if the level of chlorine dioxide does not exceed the TLV-TWA of 0.1 ppm.
 The use directions are as follows:

“…may be added to the plant misting or fogging systems to deodorize
and to control odor causing bacteria, mold and mildew in food processing
plants, dairies, bottling plants, poultry, meat and fish plants and
animal facilities such as poultry houses, swine pens, calf barns and
kennels.  If the TLV-TWA is to be exceeded, turn off air handlers and
vacate people and livestock from the rooms to be fogged or misted. 
Ventilate for 15 minutes prior to reentry.  Note – Be careful not to
add concentrated acid solutions to undiluted DURA KLOR as high
concentrations of chlorine dioxide gas may evolve.  The concentration of
chlorine dioxide in the diluted DURA KLOR solution should not be allowed
to exceed 0.5 ppm…”

	The occupational RfC of 0.003 ppm could be exceeded based on these use
directions (i.e., workers do not need to leave treatment area unless the
TLV-TWA of 0.1 ppm is exceeded).

EPA’s Risk-based RfC versus OSHA PEL

	It is also important to note that the OSHA PEL for chlorine dioxide is
0.1 ppm.  Air concentrations above the PEL are assumed to be mitigated
at each facility.  Facilities using chlorine dioxide are not required to
mitigate inhalation exposures until the air concentration reaches 0.1
ppm.  Based on the occupational inhalation toxicological endpoint
selected for chlorine dioxide (i.e., RfC of 0.003 ppm), levels at or
near the PEL are of concern.  In fact, the capability (i.e., LOD) of the
OSHA sampling method is insufficient for the occupational RfC presented
in this document.  Reconciliation of the EPA risk-based RfC and the
current OSHA standards will be made during the regulatory decision phase
of the Reregistration Eligibility Decision (RED) for chlorine dioxide. 
The various cited chlorine dioxide levels from other organizations are
reported below for review by regulatory managers.

Table 16.  Chlorine Dioxide Regulatory and/or Recommended Air
Concentrations

Organization	Time/Duration	Description	Air Concentration (ppm)

OSHA	8-hour TWA	PEL	0.1

ACGIH	8-hour TWA	TLV	0.1

	15-minutes	STEL	0.3

NIOSH	10-hour TWA	REL	0.1

	30-minutes (escape)	IDLH	5

EPA	8-hour TWA	RfC - Occupational	0.003

	“Short-term”	RfC – Residential for single exposures	0.05

	Continuous (24/7)	RfC – Residential 	0.00007

   

8.0	INCIDENT REPORT ASSESSMENT	

	A detailed summary of the human incident data is presented in the
document “Chlorine Dioxide Incident Reports.”  Below is a brief
summary of this information.    SEQ CHAPTER \h \r 1 The Agency consulted
the following databases for poisoning incident data for chlorine dioxide
and other similar compounds:

OPP Incident Data System (IDS) - The Incident Data System of The Office
of Pesticide Programs (OPP) of the Environmental Protection Agency (EPA)
contains reports of incidents from various sources, including
registrants, other federal and state health and environmental agencies
and individual consumers, submitted to OPP since 1992.  Reports
submitted to the Incident Data System represent anecdotal reports or
allegations only, unless otherwise stated.  Typically no conclusions can
be drawn implicating the pesticide as a cause of any of the reported
health effects. Nevertheless, with enough cases and/or enough
documentation, risk mitigation measures may be suggested.

Poison Control Centers - as a result of a data purchase by EPA, OPP
received Poison Control Center data covering the years 1993 through 2003
for all pesticides.  Most of the national Poison Control Centers (PCCs)
participate in a national data collection system, the Toxic Exposure
Surveillance System, which obtains data from about 65-70 centers at
hospitals and universities.  PCCs provide telephone consultation for
individuals and health care providers on suspected poisonings, involving
drugs, household products, pesticides, etc.

California Department of Pesticide Regulation - California has collected
uniform data on suspected pesticide poisonings since 1982.  Physicians
are required, by statute, to report to their local health officer all
occurrences of illness suspected of being related to exposure to
pesticides.  The majority of the incidents involve workers.  Information
on exposure (worker activity), type of illness (systemic, eye, skin,
eye/skin and respiratory), likelihood of a causal relationship, and
number of days off work and in the hospital are provided.

National Pesticide Telecommunications Network (NPTN) - NPTN is a
toll-free information service supported by OPP.  A ranking of the top
200 active ingredients for which telephone calls were received during
calendar years 1984-1991, inclusive, has been prepared.  The total
number of calls was tabulated for the categories human incidents, animal
incidents, calls for information, and others.

Published Incident Reports - Some incident reports associated with
chlorine dioxide related human health hazards are published in the
scientific literature.

	  SEQ CHAPTER \h \r 1 There are no significant health effects
associated with chlorine dioxide in published scientific literature;
however there are some reported incidents associated with exposure to
end-use products containing chlorine dioxide.  Inhalation is the primary
route of exposure.  Most of the incidents are related to irritation
reaction..

9.0	ECOTOXICOLOGY ASSESSMENT tc "

9.0	ECOTOXICOLOGY ASSESSMENT" 

	A detailed ecotoxicology risk assessment for chlorine dioxide is
provided in the Environmental Hazard and Risk Assessment Chapter.  The
summary of the exposures and risks are presented below.

Environmental Modeling/Exposure

	The Probabilistic Distribution Model version 4 (PDM4) was used to
estimate exposure from once-through cooling tower uses.  This
screening-level model was used to provide the percentage of days per
year various concentrations are exceeded for several different flow,
application, and dosing scenarios.  The details of this model can be
found in the Environmental Modeling Chapter.

Three different flow regimes were considered: high flow [power plants
with average stream flow rates of 1000±50 million gallons per day
(MGD)]; medium flow (power plants with average stream flow rates of
500±50 MGD); and low flow (power plants with average stream flow rates
of 100±10 MGD).  Two pesticide application scenarios, continuous feed
and intermittent feed, were used in the modeling, based on label
instructions.  For continuous feed use, the label rates ranged from 0.10
ppm to 2.0 ppm chlorine dioxide/sodium chlorite in the water.  For
intermittent use, the label rates ranged from 0.10 ppm to 25 ppm
chlorine dioxide/sodium chlorite in the water.  A single label contained
the rate of 800 ppm chlorine dioxide/sodium chlorite and did not specify
whether this was for continuous or intermittent use.  It is believed
that this label with the 800 ppm dose rate will be either cancelled or
amended by the registrant to delete this dose.  The concentrations (the
“concentrations of concern,” or COC) used in the model were
endpoints from aquatic organism toxicity studies with sodium chlorite.

Exceedance values for average and worst-case situations were modeled. 
The average values were calculated by averaging all of the values for a
given flow category.  The worst-case values were calculated by averaging
the highest (peak) values for a given flow category.  Since the modeling
for chlorine dioxide/sodium chlorite provides results as percent days
per year a particular concentration is exceeded, Risk Quotients were not
used in the usual way to provide numeric estimates of risk.  Instead,
the endpoints from various toxicity studies were adjusted to determine
the numeric Level of Concern (LOC) for each taxa for both acute and
chronic effects.  The adjustment factor is the same as the one used with
the RQ method, e.g. 0.5 * LC50 or EC50 for acute effects, and 0.05 *
LC50 or EC50 for acute endangered species risks.  The chronic LOC needs
no adjustment.  The modeling results provided the percentage of days
concentrations were exceeded for a range encompassing the numeric LOCs. 
When a specific LOC was not listed in the modeling output tables, the
percent days exceeded for the LOC was interpolated from the closest
numbers above and below the specific LOC.  The percentage of days was
then multiplied by 365 to provide the number of days per year the LOC is
exceeded.  

For terrestrial organisms, there is no model available to estimate
exposure and risk from discharge of once-through cooling system
effluents into surface waters.  The rapid degradation of the chemicals,
coupled with the generally low toxicity of chlorine dioxide and sodium
chlorite to birds and mammals, make risk to these organisms unlikely. 
The very limited data available to assess the phytotoxicity of chlorine
dioxide/sodium chlorite make it difficult to determine the risk to
terrestrial/semi-aquatic plants.

	Acute risk to aquatic organisms may occur from the use of chlorine
dioxide/sodium chlorite in once-through cooling towers based on the
screening level assessment conducted.  At the highest doses, the model
shows risk to freshwater and marine/estuarine fish and invertebrates and
aquatic plants, and at the lowest doses the model shows risk only to
freshwater invertebrates.  Chronic risk to aquatic organisms cannot be
assessed at this time due to the lack of chronic toxicity endpoints for
fish and aquatic invertebrates.  When the required aquatic chronic
toxicity testing described above is submitted, chronic risk to these
organisms will be assessed.

.

Ecological Hazard and Risk

	Studies have been submitted, which fulfill the requirements of several
EPA ecotoxicity guidelines.  For terrestrial animals, the results of
studies to examine the toxicity of chlorine dioxide/sodium chlorite to
birds indicate these chemicals range from slightly to highly toxic to
birds on an acute oral basis and from slightly toxic to practically
non-toxic on a subacute dietary basis.  For freshwater aquatic animals,
the results of studies examining the toxicity of chlorine dioxide/sodium
chlorite to freshwater fish indicate these chemicals range from slightly
toxic to practically non-toxic on an acute basis.  For aquatic
invertebrates, the studies indicate that chlorine dioxide and sodium
chlorite range from very highly toxic for technical grade sodium
chlorite a.i. to practically non-toxic for the formulated product on an
acute basis.  Results of toxicity studies indicate that chlorine
dioxide/sodium chlorite are slightly toxic to estuarine/marine fish on
an acute basis and range from highly toxic to slightly toxic to
estuarine/marine invertebrates on an acute basis.  

For terrestrial plants, results of toxicity studies indicate that
chlorine dioxide/sodium chlorite are moderately toxic to terrestrial
plants.  However, since the maximum label rate for many of the chlorine
dioxide/sodium chlorite once-through cooling labels was not used in
these tests, it is necessary to conduct Tier II testing with rice.  For
aquatic plants, toxicity study results indicate that chlorine
dioxide/sodium chlorite are moderately toxic to aquatic plants.  The
once-through cooling tower use of chlorine dioxide/sodium chlorite
requires that 5 aquatic plant tests be conducted due to the algaecidal
nature of the chemical and the likelihood of exposure to aquatic plants
in surface waters receiving industrial facility outfall from the cooling
system; however, only one study (1 species) under this topic has been
submitted and 5 are required.  The following aquatic plant studies are
still required: blue-green cyanobacteria (Anabaena flos-aquae),
freshwater diatom (Navicula pelliculosa), marine diatom (Skeletonema
costatum) and floating macrophyte (Lemna gibba).  

Data is still required for the following guideline requirements:  (1) a
freshwater fish early life-stage test using the technical grade of the
active ingredient, (2) a freshwater aquatic invertebrate life-cycle test
using the technical grade of the active ingredient, (3) an
estuarine/marine invertebrate life-cycle toxicity test is required due
to the high acute toxicity of sodium chlorite to estuarine/marine
invertebrates; however, freshwater invertebrates tend to be more
sensitive than estuarine/marine invertebrates to sodium chlorite on an
acute basis, and, therefore, freshwater life-cycle endpoints will
suffice for assessing risk to estuarine/marine invertebrate species. 

Table 17.

  Acute Oral Toxicity of Chlorine Dioxide and Sodium Chlorite to Birds

Substance/%

Active Ingredient

(AI)	Organism	Endpoints/Results

(mg/kg)

(95% conf. interval)	Reference	Study Classification

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	LD50 = 382 (300-520)

NOEL = 175	Robaidek, 1985

ACC # 259373	acceptable

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	LD50 = 390 (310-490)

NOEL = N.R.	Robaidek and Johnson, 1985

ACC # 257341	acceptable

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	LD50 = 395 (272-573)

NOEL = N.R.	Fletcher, 1984

ACC # 253378	acceptable

Sodium Chlorite/83%	Northern bobwhite

(Colinus virginianus)	LD50 = 660 (540-810)	Fletcher, 1973

MRID # 31610	acceptable

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	LD50 = 467 (372-585)	Beavers, 1984

ACC # 254177	acceptable

Sodium Chlorite/80%	Mallard Duck (Anas platyrhynchos)	LD50 > 31.25
Beavers, 1984

ACC # 254176	supplemental

Sodium Chlorite/25%	Northern bobwhite

(Colinus virginianus

	LD50 = 797(420-2594)

NOEL= 125	MBA Laboratories, 1984

ACC# 252854	acceptable

Table 18.  Acute Ecotoxicity of Chlorine Dioxide and Sodium Chlorite 

Substance/%

Active Ingredient

(AI)	Organism	Endpoints/Results

(ppm)

(95% conf. interval)	Reference	Study Classification

Freshwater fish

Sodium Chlorite/80%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 360
(216-600)

NOEC = 216	Barrows, 1984

MRID # 94068007	acceptable

Sodium Chlorite/80%	Bluegill

(Lepomis macrochirus)	LC50 = 244 (196-304)

NOEC = 108	Larkin, 1984

ACC # 254181	acceptable

Sodium Chlorite/80%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 360
(216-600)

NOEC = 216	Larkin, 1984

ACC # 254180	acceptable

Sodium Chlorite/80.25%	Bluegill

(Lepomis macrochirus)	LC50 = 265 (231-309)

NOEC = 130	EG&G, Bionomics, 1978

ACC #  69809	supplemental

Sodium Chlorite/79%	Bluegill

(Lepomis macrochirus)	LC 50 = 208 (165-262)

NOEC = N.R.	Sleight III, 1971

MRID # 131351	supplemental

Sodium Chlorite/79%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 50.6
(38-65.8)

NOEC = 32	Sleight III, 1971

MRID # 131351	supplemental

Sodium Chlorite/80%	Rainbow trout (Oncorhynchus mykiss)	LC50 >100

NOEC = N.R.	McMillen, 1984

ACC # 253743	supplemental

Sodium Chlorite/80%	Bluegill (Lepomis macrochirus)	LC50 >100

NOEC = N.R.	McMillen, 1984

ACC # 253743	supplemental

Sodium Chlorite/25%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 203
(175-236)

NOEC = 100	MBA Laboratories, 1984

ACC # 252854	acceptable

Sodium Chlorite/25%	Bluegill (Lepomis macrochirus)	LC50 = 222 (207-237)

NOEC = 186	MBA Laboratories, 1983

ACC # 252854	supplemental

Sodium Chlorite/81.5%	Bluegill (Lepomis macrochirus)	LC50 = 310
(270-350)

NOEC = 220	Sousa, 1981

ACC # 245697	acceptable

Sodium Chlorite/80.25%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 290
(250-340)

NOEC = 70	EG&G, Bionomics, 1979

ACC # 69810	acceptable

Sodium Chlorite/80%	Rainbow trout (Oncorhynchus mykiss)	LC50 = 340
(220-600)

NOEC = N.R.	Sousa and Surprenant, 1984

ACC # 253379	acceptable

Sodium Chlorite/80%	Bluegill (Lepomis macrochirus)	LC50 = 420 (220-600)

NOEC = N.R.	Sousa and Surprenant, 1984

MRID # 94068006	acceptable

Freshwater Invertebrates

Sodium Chlorite/80%	Daphnia magna	EC50 = 0.027 (0.021-0.031)

NOEC = 0.003	Barrows, 1984

MRID # 146162	acceptable

Sodium Chlorite/80%	Daphnia magna	EC50 = 0.39 (0.32-0.54)

NOEC =N.R.	Hoberg and Surprenant, 1984

MRID # 141149	acceptable

Sodium Chlorite/79%	Daphnia magna	LC50 = 0.29

(0.25-0.33)

NOEC = 0.10	Vilkas, 1976

MRID # 131350	acceptable

Sodium Chlorite/80%	Daphnia magna	LC50 = 0.08

(0.06-0.10)

NOEC = 0.06	Larkin, 1984

ACC # 254182	acceptable

Sodium Chlorite/80%	Daphnia magna	LC50 = 0.146

(0.12 - 0.18)

NOEC = 0.06	Nachrord, 1984

MRID # 94068009	acceptable

Sodium Chlorite/25%	Daphnia magna	LC50 = 1.4 (1.0-1.9 )

NOEC = 0.4	MBA Laboratories, 1984

ACC # 252854	supplemental

Estuarine/Marine Fish

Sodium Chlorite/79%	Sheepshead minnow

(Cyprinodon variegatus)	LC50 = 75 (62.6-89.8)

NOAEC = 13.9	Yurk and Overman, 1994

MRID # 43259401	acceptable

Estuarine/Marine Invertebrates

Sodium Chlorite/79%	Eastern oyster

(Crassostrea virginica)	96 hour LC50/EC50 = 21.4 (14.3-27.1)

NOEC = 14.3	Yurk and Overman, 1994

MRID # 43259403	acceptable

Sodium Chlorite/79%	Mysid

(Mysidopsis bahia)	96 hour LC50/EC50 = 0.576 (0.44-0.75)

NOEC= N.R.	Yurk and Overman, 1994

MRID # 43259402	acceptable

Terrestrial/Semi-aquatic Plants

Sodium Chlorite/80%	Monocots & Dicots (10 Species)	EC25 = >3.5	Backus et
al., 1990

MRID # 41843101	acceptable

Sodium Chlorite/80%	Monocots & Dicots (10 Species)	EC25 = >3.5	Backus et
al., 1990

MRID # 41843102	acceptable

Sodium Chlorite/80%	Buckwheat (Polygonum convolvulus)	EC25 = <3.5	Backus
et al., 1990

MRID # 41843102	acceptable

Aquatic Plants

Sodium Chlorite/80%	Green Algae (Selenastrum capricornutum)	EC50 = 1.32
(1.18-1.47)

NOEC = < 0.62	Ward and Boeri, 1991

MRID # 41880403	supplemental

Table 19.  Avian Subacute Dietary Toxicity of Chlorine Dioxide and
Sodium Chlorite

Substance/% AI	

Organism	LC50

(ppm)

(95 % c.i.)	

NOAEC

(ppm)	Reference	Study Classification

Sodium Chlorite/80%	Mallard Duck (Anas platyrhynchos)	>5000	5000
Johnson, 1984

MRID # 94068008	acceptable

Sodium Chlorite/80%	Northern bobwhite (Colinus virginianus)	> 5000	N.R.
Fletcher, 1984

ACC # 253378	acceptable

Sodium Chlorite/80%	Mallard Duck (Anas platyrhynchos)	> 5000	N.R.
Fletcher, 1984

ACC # 253378	acceptable

Sodium Chlorite/80%	Northern bobwhite (Colinus virginianus)	> 5000	N.R.
Johnson, 1984

MRID # 94068005	acceptable

Sodium Chlorite/80%	Mallard Duck (Anas platyrhynchos)	> 5620	N.R.
Beavers, 1984

ACC # 254178	acceptable

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	> 5620	N.R.	Beavers, 1984

ACC # 254179	acceptable

Sodium Chlorite/80%	Northern bobwhite

(Colinus virginianus)	>10,000	N.R.	Fink, 1977

MRID # 130649	acceptable

Sodium Chlorite/80%	Mallard Duck (Anas platyrhynchos)	>10,000	N.R.	Fink,
1977

MRID # 130650	acceptable

Sodium Chlorite/25%	Mallard Duck (Anas platyrhynchos)	18686
(8186-109184)	1250	MBA Laboratories, 1983

ACC # 252854	acceptable

Sodium Chlorite/25%	Northern bobwhite (Colinus virginianus)
2031(1226-3903)	417	MBA Laboratories, 1984

ACC #252854	acceptable

Listed Species Consideration

	Section 7 of the Endangered Species Act, 16 U.S.C. Section 1536(a)(2),
requires all federal agencies to consult with the National Marine
Fisheries Service (NMFS) for marine and anadromous listed species, or
the United States Fish and Wildlife Services (FWS) for listed wildlife
and freshwater organisms, if they are proposing an “action” that may
affect listed species or their designated habitat.  Each federal agency
is required under the Act to insure that any action they authorize,
fund, or carry out is not likely to jeopardize the continued existence
of a listed species or result in the destruction or adverse modification
of designated critical habitat.  To jeopardize the continued existence
of a listed species means “to engage in an action that reasonably
would be expected, directly or indirectly, to reduce appreciably the
likelihood of both the survival and recovery of a listed species in the
wild by reducing the reproduction, numbers, or distribution of the
species.” 50 C.F.R. § 402.02.

To facilitate compliance with the requirements of the Endangered Species
Act subsection (a)(2) the Environmental Protection Agency, Office of
Pesticide Programs has established procedures to evaluate whether a
proposed registration action may directly or indirectly reduce
appreciably the likelihood of both the survival and recovery of a listed
species in the wild by reducing the reproduction, numbers, or
distribution of any listed species (U.S. EPA, 2004).  After the
Agency’s screening-level risk assessment is performed, if any of the
Agency’s Listed Species LOC Criteria are exceeded for either direct or
indirect effects, a determination is made to identify if any listed or
candidate species may co-occur in the area of the proposed pesticide
use.  If determined that listed or candidate species may be present in
the proposed use areas, further biological assessment is undertaken. 
The extent to which listed species may be at risk then determines the
need for the development of a more comprehensive consultation package as
required by the Endangered Species Act.

Acute risks to listed birds and mammals are not anticipated from the use
of chlorine dioxide and sodium chlorite products due to low exposure and
low toxicity.  The screening level model used in this assessment
indicates that there may be acute risks to listed aquatic organisms from
the once through cooling tower use of chlorine dioxide/sodium chlorite. 
Further, potential indirect effects on any species dependent upon a
species that experiences effects from use of chlorine dioxide/sodium
chlorite cannot be precluded based on the screening level ecological
risk assessment.  These findings are based solely on EPA’s screening
level assessment and do not constitute “may effect” findings under
the Endangered Species Act.

Chronic risks to listed aquatic organisms cannot be assessed at this
time; this risk will be assessed when required chronic toxicity data are
submitted to and evaluated by the Agency.  

.  

						

10.0	REFERENCES

Abdel-Rahman, et al. (1984): The kinetics of chlorite and chlorate in
the rat.  J Am Coll Toxicol 3:261-267.

ACC 245697.  Sousa, J.V.  1981.  Acute Toxicity of Sodium Chlorite to
Bluegill (Lepomis macrochirus).  Unpublished Data.  Conducted by EG&G,
Bionomics for Olin Chemicals.

ACC 252854.  1984.  96-Hour LC50 in Juvenile Rainbow Trout.  Unpublished
Data.  Conducted by Microbiological and Biochemical Assay Laboratories
for Magna Corporation.

ACC 252854.  1983.  96-Hour LC50 in Bluegill Perch.  Unpublished Data. 
Conducted by Microbiological and Biochemical Assay Laboratories for
Magna Corporation.

ACC 252854.  1984.  48-Hour LC50 in Daphnia magna.  Unpublished Data. 
Conducted by Microbiological and Biochemical Assay Laboratories for
Magna Corporation.

ACC 252854.  1984.  Avian Dietary LC50 in Bob White Quail.  Unpublished
Data.  Conducted by Microbiological and Biochemical Assay Laboratories
for Magna Corporation.

ACC 252854.  1983.  Avian Dietary LC50 in Mallard Ducks.  Unpublished
Data.  Conducted by Microbiological and Biochemical Assay Laboratories
for Magna Corporation.

ACC 252854.  1984.  Avian Single-Dose Oral LD50 in Bobwhite Quail. 
Unpublished Data.  Conducted by Microbiological and Biochemical Assay
Laboratories for Magna Corporation.

ACC 253378. Fletcher, D.  1984.  8-Day Dietary LC50 Study with Sodium
Chlorite in Mallard Ducklings.  Unpublished Data.  Conducted by Bio-Life
Associates, Ltd. for Calgon Corporation.

ACC 253378. Fletcher, D.  1984.  8-Day Dietary LC50 Study with Sodium
Chlorite in Bobwhite Quail.  Unpublished Data.  Conducted by Bio-Life
Associates, Ltd. for Calgon Corporation.

ACC 253378. Fletcher, D.  1984.  Acute Oral Toxicity Study with Sodium
Chlorite in Bobwhite Quail.  Unpublished Data.  Conducted by Bio-Life
Associates, Ltd. for Calgon Corporation.

ACC 253379.  Sousa, J.V. and D.C. Surprenant.  1984.  Acute Toxicity of
AC-66 to Rainbow Trout (Salmo gairdneri).  Unpublished Data.  Conducted
by Springborn Bionomics, Inc. for Calgon Corporation.

ACC 253743.  McMillen, C.  1984.  Static Bioassay on Sodium Chlorite to
Rainbow Trout and Bluegill Sunfish.  Unpublished Data.  Conducted by
Environmental Research Group, Inc. for Rio Linda Chemical Company, Inc.

ACC 254176.  Beavers, 1984.  An Acute Oral Toxicity Study in the Mallard
with Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for TR America Chemicals, Inc.

ACC 254177.  Beavers, 1984.  An Acute Oral Toxicity Study in the
Bobwhite with Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for TR America Chemicals, Inc.

ACC 254178.  Beavers, 1984.  A Dietary LC50 Study in the Mallard Duck
with Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for TR America Chemicals, Inc.

ACC 254179.  Beavers, 1984.  A Dietary LC50 Study in the Bobwhite with
Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for TR America Chemicals, Inc.

ACC 254180.  Larkin, J.  1984.  The Acute Toxicity of Sodium Chlorite to
Rainbow Trout (Salmo gairdneri).  Unpublished Data.  Conducted by
Biospherics Incorporated for TR America Chemicals, Inc.

ACC 254181.  Larkin, J.  1984.  The Acute Toxicity of Sodium Chlorite to
Bluegill Sunfish (Lepomis macrochirus).  Unpublished Data.  Conducted by
Biospherics Incorporated for TR America Chemicals, Inc.  

ACC 254182.  Larkin, J.  1984.  Acute Toxicity of Sodium Chlorite to
Daphnia magna Strauss.  Unpublished Data.  Conducted by Biospherics
Incorporated for TR America Chemicals, Inc.

ACC 257341. Robaidek and Johnson, 1985. Avian Single-dose Oral LD50: Bob
White Quail (Colinus virginianus).  Unpublished Data.   Conducted by
Hazleton Laboratories America, Inc. for Rio Linda Chemical Company.

ACC 259373.  Robaidek, E.  1985.  Avian Single-Dose Oral LD50 Bobwhite
Quail.  Unpublished Data.  Conducted by Hazleton Laboratories America,
Inc. for Degussa Corporation.

ACC 265867.  1994.  Mutagenicity Evaluation of Chlorine Dioxide in the
Mouse Lymphoma Foreword Mutation Assay.  Litton Bionetics, Kensington,
MD, LBI Project No. 20989, March 1984.

BCI (2002).   HVAC air monitoring study.

CMA (1996): Sodium Chlorite: Drinking Water Rat Two-Generation
Reproductive Toxicity Study.  Chemical Manufacturers Association. 
Quintiles Report Ref. CMA/17/96.MRID 4535809.

Gill, M.T. et.al.(2000), Two-generation Reproduction and Developmental
Neurotoxicity Study with Sodium Chlorite in the Rat. J. Appl.
Toxicol.20, 291-303.

Dalhamn, T. (1957): Chlorine Dioxide: Toxicity in Animal Experiments and
Industrial Risks. Arch. Ind. Health 15: 101-107. 

Daniel, F.B., et al. (1990): Comparative subchronic toxicity studies of
three disinfectants.  J Am Water Works Assoc 82:61-69.

FDA. 1994.   Memo: FAP: 4A4433, 1994). FDA extensively reviewed the
efficacy and the analytical chemistry data on the residues – full
reference not found in documents

Haag, H.B. (1949): The effect on rats of chronic administration of
sodium chlorite and chlorine dioxide in the drinking water.  Report to
the Mathieson Alkali Works from H.B. Haag of the Medical College of
Virginia.  February 7, 1949. 

Harrington, R.M., et al. (1995): Subchronic toxicity of sodium chlorite
in the rat.  J Am Coll Toxicol 14:21-33.

42301601 Ridgway, P.(1992) 13 Week Oral(Gavage) Toxicity Study in the
Rat: Lab Project Number:CMA/13/R:CD-6.0-Tox.Unpublished study prepared
by Toxicol Labs Ltd for the CMA/Chlorine Dioxide Panel.329p.

Kurokawa, Y., et al. (1984): Studies on the promoting and complete
carcinogenic activities of some oxidizing chemicals in skin
carcinogenesis.  Cancer Lett 24:299-304.

Meier, J.R., et al. (1985): Evaluation of chemicals used for drinking
water disinfection for production of chromosomal damage and sperm-head
abnormalities in mice.  Environ Mutagen 7:201-211. 

Miller, R.G., et al. (1986): Results of toxicological testing of
Jefferson Parish pilot plant samples.  Environ Health Perspect
69:129-139. 

MRID 31610.  Fletcher, D. 1973.  Acute Oral Toxicity Study with Sodium
Chlorite in Bobwhite Quail.  Unpublished Data.  Conducted by Industrial
BIO-TEST Laboratories, Inc. for Olin Corporation.

MRID 69809.  1978.  Acute Toxicity of Sodium Chlorite to Bluegill
(Lepomis macrochirus).  Unpublished Data.  Conducted by EG&G, Bionomics,
Aquatic Toxicology Laboratory for Olin Chemicals.

MRID 69810.  1979.  Acute Toxicity of Sodium Chlorite to Rainbow Trout
(Salmo gairdneri).  Unpublished Data.  Conducted by EG&G, Bionomics,
Aquatic Toxicology Laboratory for Olin Chemicals.

MRID 130649.  Fink, R.  1977.  Eight-day Dietary LC50 - Bobwhite Quail
– Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for Olin Corporation.

MRID 130650.  Fink, R.  1977.  Eight-day Dietary LC50 – Mallard Duck
– Sodium Chlorite.  Unpublished Data.  Conducted by Wildlife
International, Ltd. for Olin Corporation.

MRID 131350.  Vilkas, A.G.  1976.  Acute Toxicity of Textone to the
Water Flea Daphnia magna Strauss.  Unpublished Data.  Conducted by
Aquatic Environmental Sciences for Olin Corporation. 

MRID 131351.  Sleight III, B.H.  1971.  Acute Toxicity of Sodium
Chlorite to Bluegill (Lepomis macrochirus) and Rainbow Trout (Salmo
gairdneri).  Unpublished Data.  Conducted by Bionomics, Inc.

 

MRID 141149.  Hoberg, J.R. and D.C. Surprenant.  1984.  Acute Toxicity
of AC-66 to Daphnids (Daphnia magna).  Unpublished Data.  Conducted by
Springborn Bionomics, Inc. for Calgon Corporation.

MRID 146162.  Barrows, 1984.  The Acute Toxicity of Sodium Chlorite
Technical to the Water Flea, Daphnia magna in a Static Test System. 
Unpublished Data.  Conducted by Biospherics Incorporated for Degussa
Corporation.      

MRID 40168704.  1985.  Acute Dermal LD50 on Rabbit – Sodium Chlorite
Powder, Lot #110984-15.  Gibraltar Biological Lab, Inc. (Fairfield, NJ),
Internaltional Dioxcide, Inc. Study Number GBL 024065, April 23, 1985.

MRID 41843101.  Backus, P., K.E. Crosby and L.J. Powers.  1990.  Effect
of Sodium Chlorite on Vegetative Vigor of Plants (Tier I).  Unpublished
Data.  Conducted by Ricerca, Inc. for the Sodium Chlorite Reregistration
Task Force.

MRID 41843102.  Backus, P., K.E. Crosby and L.J. Powers.  1990.  Effect
of Sodium Chlorite on Seed Germination/Seedling Emergence (Tier I). 
Unpublished Data.  Conducted by Ricerca, Inc. for the Sodium Chlorite
Reregistration Task Force.

MRID 41880403.  Ward, T.J. and R.L. Boeri.  1991.  Static Acute Toxicity
of Sodium Chlorite to the Freshwater Alga, Selenastrum capricornutum. 
Unpublished Data.  Conducted by EnviroSystems Division, Resource
Analysis, Inc. for the Sodium Chlorite Reregistration Task Force.

MRID 42587501.  Popendorf, W.; Selim, M.; Kross, B. 1992. Chemical
Manufacturers Association Antimicrobial Exposure Assessment Study:
Second Replacement to MRID 41761201: Lab Project Number: Q626.
Unpublished study prepared by The University of Iowa.

MRID 43259401.  Yurk, J.J. and M.A. Overman.  1994.  Acute Toxicity of
Sodium Chlorite to the Sheepshead Minnow (Cyprinodon variegatus). 
Conducted by Environmental Science & Engineering, Inc. for the Chemical
Manufacturers Association.

MRID 43259402.  Yurk, J.J. and M.A. Overman.  1994.  Acute Toxicity of
Sodium Chlorite to Mysid Shrimp.  Conducted by Environmental Science &
Engineering, Inc. for the Chemical Manufacturers Association.

MRID 43259403.  Yurk, J.J. and M.A. Overman.  1994.  Effect of Sodium
Chlorite on New Shell Growth in Eastern Oyster (Crassostrea virginica). 
Conducted by Environmental Science & Engineering, Inc. for the Chemical
Manufacturers Association.

MRID 94068005.  Johnson, G.  1984.  Avian Dietary LC50 Bobwhite Quail
(Colinus virginianus).  Unpublished Data.  Conducted by Hazleton
Laboratories America, Inc. for Degussa Corporation.

MRID 94068006.  Sousa and Surprenant, 1984.  Acute Toxicity of A-66
(Technical Sodium Chlorite) to Bluegill (Lepomis macrochirus). 
Unpublished Data.  Conducted by Springborn Binomics, Inc for Calgon
Corporation.

MRID 94068007.  Barrows, B. 1984.  The Acute Toxicity of Sodium Chlorite
Technical to the Rainbow Trout, Salmo gairdneri, in a Static Test
System.  Unpublished Data.  Conducted by Biospherics Incorporated for
Degussa Corporation.

MRID 94068008.  Johnson, G.  1984.  Avian Dietary LC50 Mallard Duck
(Anas platyrhynchos).  Unpublished Data.  Conducted by Hazleton
Laboratories America, Inc. for Degussa Corporation.

MRID 94068009.  Nachrord, S.  1984.  Daphnia LC50 Bioassay.  Unpublished
Data.  Conducted by Anater Tesconi Circle for Rio Linda Chemical
Company, Inc.

MRID 41715701.  Irvine, Lorraine F.  Sodium Chlorite:  Rabbit Teratology
Study (Drinking Water Administration).  Toxicol. Labs, Ltd., Ledbury,
UK, Study Number CMA/3/R, September 21, 1990.

MRID 42484101.  Acute Inhalation Toxicity Evaluation in Rats. 
International Research and Development Corporation (IRDC), Mattawan, MI.
 Lab. Project No. 632-001, August 14, 1992.

MRID 43441903.  Primary Eye Irritation Study in Rabbits.  Stillmeadow,
Inc., Sugar Land, TX, Lab. Project No. 1441-94, October 11, 1994.

MRID 43558601.  Abdel-Rahman, et al., “Toxicity of Alcide,”
published in J. Appl. Toxicol. 2(3): 160-164, 1982.

Orme, J., et al. (1985): Effects of chlorine dioxide on thyroid function
in neonatal rats. J Toxicol Environ Health 15:315-322.

Paulet G and S. Desbrousses (1970): On the action of ClO2 at low
concentrations on laboratory animals.  Arch Mal Prof 31:97-106.

Paulet G and S. Desbrousses (1972): On the toxicology of chlorine
dioxide.  Arch Mal Prof 33:59-61.

Paulet G and S. Desbrousses (1974): Action of a discontinuous exposure
to chlorine dioxide (ClO2) on the rat.  Arch Mal Prof 35:797-804.

PHED Surrogate Exposure Guide.  1998.   Estimates of Worker Exposure
from the Pesticide Handler Exposure Database
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USEPA.  2000a. Toxicological Review of Chlorine Dioxide and Chlorite,
Integrated Risk information System (IRIS).

USEPA.  2000b. Residential SOPs.  EPA Office of Pesticide
Programs–Human Health Division. Dated April 5, 2000.

USEPA. 1998.  AD Memo by Tim McMahon and A. Najm Shamim to Norm Cook,
March, 1998.

Page   PAGE  36  of   NUMPAGES  51