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height="0.9243055555555556in"}

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

**[MEMORANDUM]{.underline}**

Date: January 18, 2006

Subject: Human Health Risk Assessment for Sulfuryl Fluoride and Fluoride
Anion Addressing the Section 3 Registration of Sulfuryl Fluoride as a
Fumigant for Foods and Food Processing Facilities. PP# 3F6573.

DP Number: 312659 Class: Fumigant

PC Code: 078003

40 CFR 180: 575 (sulfuryl fluoride)

145 (fluorine compounds)

From: Michael Doherty, Chemist

Registration Action Branch 2

Health Effects Division (7509C)

Through: Richard Loranger, Branch Senior Scientist

Registration Action Branch 2

Health Effects Division (7509C)

To: Dan Kenny/Meredith Laws

Insecticide/Rodenticide Branch

Registration Division (7505C)

Note: This risk assessment post-dates the Federal Register notice
establishing tolerances for residues of sulfuryl fluoride and fluoride
resulting from fumigation of some foods and of food processing
facilities \[Federal Register - July 15, 2005 (Volume 70, Number 135)\].
During the internal peer-review process in OPP, errors were noted in the
residue files used to estimate dietary exposure and it was found that
there were discrepancies between the assumptions made in the risk
assessment and the uses that were being allowed on the product label.
Those errors and discrepancies have been resolved. While the dietary and
aggregate exposure and risk estimates presented in this document are
slightly greater than those presented in the Federal Register notice,
HED's conclusions and regulatory recommendations remain unchanged. HED
is still recommending for a conditional registration of sulfuryl
fluoride for the sought after uses and the establishment of permanent
tolerances for residues of sulfuryl fluoride and fluoride anion.

**Table of Contents**

1.0 EXECUTIVE SUMMARY [3](#__RefHeading___Toc125354193)

2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION
[5](#__RefHeading___Toc125354194)

3.0 HAZARD CHARACTERIZATION [6](#__RefHeading___Toc125354195)

3.1 Sulfuryl Fluoride [6](#__RefHeading___Toc125354196)

3.1.1 Hazard Profile [6](#__RefHeading___Toc125354197)

3.1.2 FQPA Considerations [12](#__RefHeading___Toc125354198)

3.1.3 Dose-Response Assessment [13](#__RefHeading___Toc125354199)

3.1.4 Endocrine Disruption [17](#__RefHeading___Toc125354200)

3.2 Fluoride Anion [18](#__RefHeading___Toc125354201)

3.2.1 Hazard Profile [18](#__RefHeading___Toc125354202)

3.2.2 FQPA Considerations [19](#__RefHeading___Toc125354203)

3.2.3 Dose-Response Assessment [19](#__RefHeading___Toc125354204)

3.2.4 Endocrine Disruption [19](#__RefHeading___Toc125354205)

4.0 EXPOSURE ASSESSMENT [20](#__RefHeading___Toc125354206)

4.1 Summary of Proposed Uses [20](#__RefHeading___Toc125354207)

4.2 Dietary Exposure/Risk Pathway [21](#__RefHeading___Toc125354208)

4.2.1 Residue Profile [21](#__RefHeading___Toc125354209)

4.2.1.1 Sulfuryl Fluoride and Fluoride Residues from the use of Sulfuryl
Fluoride [21](#__RefHeading___Toc125354210)

4.2.1.5 Other Sources of Fluoride [23](#__RefHeading___Toc125354211)

4.2.2 Acute Dietary [23](#__RefHeading___Toc125354212)

4.2.3 Chronic Dietary [23](#__RefHeading___Toc125354213)

4.2.4 Cancer Dietary [25](#__RefHeading___Toc125354214)

4.3 Water Exposure/Risk Pathway [25](#__RefHeading___Toc125354215)

4.4 Residential Exposure/Risk Pathway [26](#__RefHeading___Toc125354216)

4.4.1 Other [26](#__RefHeading___Toc125354217)

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION
[27](#__RefHeading___Toc125354218)

6.0 CUMULATIVE RISK [28](#__RefHeading___Toc125354219)

7.0 OCCUPATIONAL EXPOSURE [29](#__RefHeading___Toc125354220)

8.0 DATA NEEDS AND LABEL REQUIREMENTS [30](#__RefHeading___Toc125354221)

9.0 REFERENCES [33](#__RefHeading___Toc125354222)

APPENDIX I - Risk Estimates for Development of Skeletal Fluorosis Based
on Institute of Medicine Toxicological Findings
[35](#__RefHeading___Toc125354223)

APPENDIX II - Risk Estimates for Development of Dental Fluorosis
[36](#__RefHeading___Toc125354224)

**1.0 EXECUTIVE SUMMARY**[]{#__RefHeading___Toc125354193 .anchor}

Dow AgroSciences has petitioned the Agency to register sulfuryl fluoride
for the control of numerous pests in foods and food processing
facilities. In conjunction with that petition, Dow AgroSciences has
requested the establishment of permanent tolerances for residues of
sulfuryl fluoride and of fluoride anion on a suite of commodities
related to the proposed use. Sulfuryl fluoride is a potential methyl
bromide replacement for these uses. Under the proposed use, foods and
food processing facilities will be fumigated with sulfuryl fluoride
formulated as the 99% a.i. ProFume. Fumigation may be carried out at
ambient pressures or, where practical, under vacuum conditions. Dow
AgroSciences has developed software to tailor the application rate based
on pressure, volume of the structure/chamber being fumigated, and pest
species. Maximum fumigation rates are 1500 ozhrs/1000 ft^3^ (1500
mghrs/L) at ambient pressure and 200 mghrs/L under vacuum conditions.

This assessment also addresses a revised use pattern for the previously
registered use of sulfuryl fluoride in cereal grain milling facilities.
The directions for that use have been revised to eliminate the required
blending of fumigated flour with untreated flour.

HED has reviewed the toxicology and residue chemistry data submitted to
support the petition and has examined the potential for exposures via
dietary (food and drinking water), non-dietary oral, inhalation, and
dermal routes. Residues of concern for sulfuryl fluoride are sulfuryl
fluoride, *per se*, and fluoride anion (also referred to as Afluoride@
in this document). This assessment addresses the human health risks
associated with sulfuryl fluoride and fluoride anion. Due to the
different toxicological effects elicited by these two chemicals, their
risks have been assessed separately. This risk assessment builds on the
previous human health risk assessment issued by HED (M. Doherty,
D309013, 10/12/04). Much of the detail regarding exposure estimates to
fluoride from water, background residues in food, toothpaste,
inhalation, and use of cryolite (which also results in fluoride residues
in food) can be found in that document.

*Sulfuryl Fluoride*. Based on the submitted toxicology data, taken in
conjunction with the proposed uses, and the physical-chemical properties
of sulfuryl fluoride, HED has determined that acute, short-term, and
intermediate-term assessments are not appropriate for addressing risks
to persons who are not working directly with sulfuryl fluoride. Chronic
exposure to sulfuryl fluoride may occur through dietary exposure.
Because of its chemical properties, sulfuryl fluoride is extremely
unlikely to occur in water; therefore, chronic dietary exposure would
occur only through residues in/on food. In conducting the chronic
dietary assessment, HED has assumed average residue levels based on
residue trials conducted at the maximum fumigation rate and has
incorporated estimates of the percent of commodities treated.
Additionally, we assumed that commodities might be serially fumigated,
first as part of a post-harvest and/or grain mill fumigation and then
again due to food processing facility fumigation. The actual probability
of this occurring is likely to be very small; therefore, this assumption
results in an overestimate of exposure. Even with this assumption, the
estimated dietary exposures for the general U.S. population and all
population subgroups, including those of infants and children, are less
than or equal to 8% of the chronic PAD. Generally, HED is concerned
about estimated risk levels when they exceed 100% of the PAD; therefore,
these risk estimates are well below HED=s level of concern. As noted
above, chronic dietary (food only) exposure is the only relevant
exposure pathway for inclusion in aggregate risk estimates. Aggregate
risk estimates from exposure to sulfuryl fluoride, therefore, are below
HED=s level of concern for all population subgroups.

HED has also evaluated the potential risks to workers conducting
fumigations with sulfuryl fluoride and to personnel engaged in
post-fumigation activities. The most current proposed label and use
booklet mandates that all workers must wear approved self-contained
breathing apparatus if they will be in an area where the concentration
of sulfuryl fluoride exceeds 1 ppm or is unknown. Workers not wearing
proper respiratory protection may enter a fumigated area only after the
concentration of sulfuryl fluoride has been shown to be below 1 ppm.
Based on information available to HED, short-term, intermediate-term and
chronic exposure to sulfuryl fluoride may occur for professionals
working with sulfuryl fluoride or sulfuryl fluoride fumigated
commodities. HED has estimated exposures and risks for fumigators and
tent workers based on sulfuryl fluoride data depicting exposure to
workers following structural fumigation with Vikane. The Vikane data
were collected based on a 5-ppm reentry concentration. ProFume has a
1-ppm reentry concentration. Therefore, the exposure estimates from
Vikane were reduced by 5-fold. Occupational MOEs for ProFume range from
300 to 2100. Since levels of concern are 100 for short- and
intermediate-term exposures, and 300 for long-term exposures, the risk
estimates represented by the occupational MOEs are below HEDs level of
concern.

*Fluoride Anion*. In assessing the risks associated with exposure to
fluoride, HED has relied on the toxicological assessment completed by
the Agency=s Office of Water. That assessment identified crippling
skeletal fluorosis as the endpoint of regulatory concern and determined
that a value of 8 mg/day is protective against skeletal fluorosis
without being so low as to negate the beneficial, cavity-fighting
effects of fluoride exposure. The Office of Water has acknowledged that
dental fluorosis may occur at exposures of less than 8 mg/day. At this
time, based on the information available to the Agency, EPA is not
concluding that mild to moderate dental fluorosis associated with
fluoride exposure is an adverse health effect under the Federal Food,
Drug, and Cosmetic Act (FFDCA). The current arguments that dental
fluorosis is more than a cosmetic effect are not sufficiently persuasive
to warrant regulation as an adverse health effect under the FFDCA.
Accordingly, consistent with the action taken by the Office of Water
under the Safe Drinking Water Act, 40 FR 47142 (November 14, 1985)
(WH‑FRL‑2913‑8(b)), the Agency believes that the appropriate endpoint
for regulation under the FFDCA is skeletal fluorosis. While the
tolerance safety determination under the FFDCA is a health based
standard, the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) requires the balancing of all costs, taking into account the
economic, social, and environmental effects, as well as health-based
risks, against the benefits associated with the pesticide use.
Therefore, the Agency has considered dental fluorosis in determining
whether sulfuryl fluoride meets the requisite standard under FIFRA (see
Appendix II).

OPP notes that a more recent assessment of fluoride by the National
Academy of Sciences= Institute of Medicine (IOM) identified a skeletal
fluorosis NOAEL at 10 mg/day[^1]. Their assessment of the data concluded
that no safety or uncertainty factors were needed. The IOM also notes
that high exposures for long durations (on the order of 10 years) are
required to develop skeletal fluorosis and that such a condition is not
expected to occur in children under the age of 8. Although the values of
8 mg/day and 10 mg/day are equally appropriate for use in a human health
risk assessment, OPP has used the 8-mg/day value in order to be slightly
more conservative in assessing risk. For fluoride risk assessments
addressed in this document, the 8 mg/day value has been used in a manner
analogous to a reference dose (RfD) and for ease of communication will
be referred to as such.

This assessment includes quantitative estimates of dietary exposure from
background levels of fluoride in food, fluoride in water, and fluoride
from the pesticidal food uses of cryolite and sulfuryl fluoride,
non-dietary exposure from the use of fluoridated toothpaste, and
non-dietary exposure from fluoride residues in air. For each of these
pathways of exposure, residue estimates are conservative to moderately
conservative in nature. For foods, we have assumed that all commodities
are serially fumigated (as described above for sulfuryl fluoride), with
cryolite included as a potential addition source of elevated fluoride
residues. Other potential sources of fluoride exposure have not been
included in this assessment in a quantitative manner, primarily due to
lack of demographic and/or exposure information. Non-quantified pathways
of exposure are not expected to significantly increase exposure
estimates for the various population subgroups at large.

Risk estimates for individual fluoride exposure pathways are below 100%
of the RfD for the general U.S. population and all population subgroups,
including those of infants and children. When all quantified dietary and
non-dietary exposure pathways are combined, risk estimates range from 17
to 43% of the RfD. These aggregate risk estimates are below HED=s level
of concern for all population subgroups.

HED notes that this assessment is predicated upon the removal of dried
eggs from the list of "Commodities That Can Be Fumigated" on the ProFume
Label. Dow AgroSciences recently submitted a proposed label with that
deletion.

Deficiencies in the sulfuryl fluoride data are noted in Section 8 and
HED=s recommended tolerance levels are summarized in Table 8.1. HED=s
recommendations involving the method for fluoride may impact tolerance
levels. Because of this, we are recommending that the registration, if
granted, be conditional upon receipt and evaluation of the data outlined
in Section 8. Furthermore, HED notes that the Office of Water, via the
National Academy of Sciences, is reevaluating the available information
regarding fluoride and recommends that OPP reexamine this risk
assessment once the Office of Water has completed its review.

**2.0 PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION**[]{#__RefHeading___Toc125354194 .anchor}

Sulfuryl fluoride (SO~2~F~2~) is a fumigant that is being proposed as a
methyl bromide replacement for the control of pests in food processing
facilities. Sulfuryl fluoride is a gas at standard temperature and
pressure. It has a melting point of -136°C, a boiling point of -55°C,
and a vapor pressure of 11552 mm Hg (Torr) at 20°C. Sulfuryl fluoride
rapidly breaks down to form sulfate and fluoride anion. As ProFume7 and
Vikane7, sulfuryl fluoride constitutes 99% of the product and there are
no known impurities of toxicological concern.

Fluorine has an atomic mass of 18.99, is extremely electronegative and
reactive, and occurs as the diatomic F~2~ in its elemental form. Due to
its high reactivity, fluorine does not typically exist outside of the
laboratory. In the environment, fluorine readily reacts with all other
elements except nitrogen, oxygen, and the lighter noble gases to form
various fluoride complexes. It is these fluoride complexes that govern
the behavior and bioavailability of fluoride. Due to fluorine=s ability
to readily react with other elements and molecules, fluoride has the
potential to occur in food, water, and air, and exposure to humans may
occur through any of these media.

**3.0 HAZARD CHARACTERIZATION**[]{#__RefHeading___Toc125354195 .anchor}

**3.1 Sulfuryl Fluoride**[]{#__RefHeading___Toc125354196 .anchor}

**3.1.1 Hazard Profile**[]{#__RefHeading___Toc125354197 .anchor}

+--------+--------------------+-------------+----------------+--------+
| *      |                    |             |                |        |
| *Table |                    |             |                |        |
| 3.1.1. |                    |             |                |        |
| Acute  |                    |             |                |        |
| To     |                    |             |                |        |
| xicity |                    |             |                |        |
| of     |                    |             |                |        |
| Tec    |                    |             |                |        |
| hnical |                    |             |                |        |
| Grade  |                    |             |                |        |
| Su     |                    |             |                |        |
| lfuryl |                    |             |                |        |
| Fl     |                    |             |                |        |
| uoride |                    |             |                |        |
| (99.8% |                    |             |                |        |
| active |                    |             |                |        |
| i      |                    |             |                |        |
| ngredi |                    |             |                |        |
| ent)** |                    |             |                |        |
+--------+--------------------+-------------+----------------+--------+
| Gui    | Study Type         | MRID        | Results        | Tox    |
| deline |                    |             |                |        |
| No.    |                    |             |                | Ca     |
|        |                    |             |                | tegory |
+--------+--------------------+-------------+----------------+--------+
| 870.11 | Acute Oral         | 43314       | M: LD~50~ =    | II\*   |
|        |                    |             | 100 mg/kg      |        |
|        | Rats               |             |                |        |
|        |                    |             | F: LD~50~ =    |        |
|        |                    |             | 100 mg/kg      |        |
+--------+--------------------+-------------+----------------+--------+
| 870.12 | Acute Dermal       | \-\-\-\--   | Study Waived   | IV\*\* |
|        |                    |             | \*             |        |
+--------+--------------------+-------------+----------------+--------+
| 870.13 | Acute Inhalation   | 41769101    | M: LC~50~ =    | I\*    |
|        |                    |             | 660 ppm        |        |
|        | Mice               |             |                |        |
|        |                    |             | (2.56 mg/L)    |        |
|        | (4 hour exposure)  |             |                |        |
|        |                    |             | F: LC~50~ =    |        |
|        |                    |             | 642 ppm        |        |
|        |                    |             |                |        |
|        |                    |             | (2.49 mg/L)    |        |
+--------+--------------------+-------------+----------------+--------+
| 870.13 | Acute Inhalation   | 238663      | LC~50~ = 4512  | I\*    |
|        |                    |             | ppm            |        |
|        | Rats               |             |                |        |
|        |                    |             | ( 17.5 mg/L)   |        |
|        | (1 hour exposure)  |             |                |        |
+--------+--------------------+-------------+----------------+--------+
| 870.24 | Primary Eye        | \-\-\-\--   | Study Waived   | I\*\*  |
|        | Irritation         |             | \*             |        |
+--------+--------------------+-------------+----------------+--------+
| 870.25 | Primary Skin       | \-\-\-\--   | Study Waived   | IV\*\* |
|        | Irritation         |             | \*             |        |
+--------+--------------------+-------------+----------------+--------+
| 870.26 | Dermal             | \-\-\-\--   | Study Waived   | No     |
|        | Sensitization      |             | \*             | n-Sens |
|        |                    |             |                | itizer |
|        |                    |             |                | \*\*   |
+--------+--------------------+-------------+----------------+--------+
| \-\    | Dermal Vapor       | 41712001    | No adverse     | N/A    |
| -\-\-\ |                    |             | effects at     |        |
| -\-\-- | Rats               |             | 9600 ppm       |        |
|        |                    |             |                |        |
|        | (4 hour dermal     |             | (40.3 mg/L)    |        |
|        | exposure)          |             |                |        |
+--------+--------------------+-------------+----------------+--------+

\* Memorandum by M. Lewis (SRRD) to V. Dutch (SRRD), 11/17/99, HED Doc.
No. 078003.

\*\* Assumed Toxicity Category. See memorandum by M. Lewis (above).

N/A Not applicable

+--------+---------------+---------------------------------------------+
| *      |               |                                             |
| *Table |               |                                             |
| 3.1.2. |               |                                             |
| To     |               |                                             |
| xicity |               |                                             |
| P      |               |                                             |
| rofile |               |                                             |
| of     |               |                                             |
| Tec    |               |                                             |
| hnical |               |                                             |
| Grade  |               |                                             |
| Su     |               |                                             |
| lfuryl |               |                                             |
| Fl     |               |                                             |
| uoride |               |                                             |
| (99.8% |               |                                             |
| active |               |                                             |
| i      |               |                                             |
| ngredi |               |                                             |
| ent)** |               |                                             |
+========+===============+=============================================+
| Gui    | Study Type    | Results                                     |
| deline |               |                                             |
| No.    |               |                                             |
+--------+---------------+---------------------------------------------+
| \-\    | 2-Week        | **NOAEL**: 83/89 mg/kg/day (M/F)            |
| -\-\-\ | inhalation    |                                             |
| -\-\-- | toxicity,     | **LOAEL**: 249/267 mg/kg/day (M/F): M&F =   |
|        | rats          | slightly increased kidney weights, minimal  |
| (inha  |               | histopathology in kidney.                   |
| lation | 0, 100, 300,  |                                             |
| study) | 600 ppm       | [At 498/534 mg/kg/day (M/F):]{.underline}   |
|        |               | M&F = high mortality, decreased body        |
|        | (0/0, 83/89,  | weights, severe histopathology in kidney,   |
|        | 249/267,      | gross and histopathology in many            |
|        | 498/534       | tissues/organs (secondary to kidney         |
|        | mg/kg/day)    | effects); severe inflammation of            |
|        | (M/F)         | respiratory tissues in 1 survivor. No       |
|        |               | treatment-related neurotoxicity.            |
+--------+---------------+---------------------------------------------+
| \-\    | 2-Week        | **NOAEL**: 26/27 mg/kg/day (M/F)            |
| -\-\-\ | inhalation    |                                             |
| -\-\-- | toxicity,     | **LOAEL**: 79/80 mg/kg/day (M/F): M&F =     |
|        | dogs          | intermittent tremors and tetany during      |
| (inha  |               | exposures, minimal inflammatory changes in  |
| lation | 0, 30, 100,   | upper respiratory tract, decreased body     |
| study) | 300 ppm       | weight (F only).                            |
|        |               |                                             |
|        | (0/0,         | [Note]{.underline}Bincreased serum fluoride |
|        | 7.9/8.0,      | at [\>]{.underline}26/27 mg/kg/day.         |
|        | 26/27, 79/80  |                                             |
|        | mg/kg/day)    |                                             |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| \-\    | 2-Week        | **NOAEL**: 30/30 mg/kg/day (M/F)            |
| -\-\-\ | inhalation    |                                             |
| -\-\-- | toxicity,     | **LOAEL**: 90/90 mg/kg/day (M/F): M&F =     |
|        | rabbits       | malacia (necrosis) in cerebrum, vacuolation |
| (inha  |               | of cerebrum, moderate inflammation of       |
| lation | 0, 100, 300,  | respiratory tissues.                        |
| study) | 600 ppm       |                                             |
|        |               | [At 180/180 mg/kg/day (M/F]{.underline}):   |
|        | (0/0, 30/30,  | M&F = convulsions, hyperactivity, malacia   |
|        | 90/90,        | (necrosis) in cerebrum, vacuolation of      |
|        | 180/180       | cerebrum, moderate inflammation of          |
|        | mg/kg/day)    | respiratory tissues.                        |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 90-Day        | **NOAEL**: 24/25 mg/kg/day (M/F)            |
| .3100) | inhalation    |                                             |
|        | toxicity,     | **LOAEL**: 80/83 mg/kg/day (M/F): M&F =     |
| (inha  | rats          | dental fluorosis.                           |
| lation |               |                                             |
| study) | 0, 30, 100,   | [At 240/250 mg/kg/day (M/F)]{.underline}:   |
|        | 300 ppm       | M&F = vacuolation of caudate-putamen        |
|        |               | nucleus and white fiber tracts of the       |
|        | (0/0, 24/25,  | internal capsule of the brain, decreased    |
|        | 80/83,        | body weight, inflammation of nasal          |
|        | 240/250       | passages, alveolar histiocytosis; slight    |
|        | mg/kg/day)    | hyperplasia of renal collecting ducts (F    |
|        | (M/F)         | only).                                      |
+--------+---------------+---------------------------------------------+
| (870   | 90-Day        | **NOAEL**: 38/36 mg/kg/day (M/F)            |
| .3100) | inhalation    |                                             |
|        | toxicity,     | **LOAEL**: 125/121 mg/kg/day (M/F): M&F =   |
| (inha  | mice          | microscopic lesions in caudate-putamen      |
| lation |               | nucleus and external capsule, decreased     |
| study) | 0, 10, 30,    | body weight, decreased body weight gain,    |
|        | 100 ppm       | follicular cell hypertrophy in thyroid.     |
|        |               |                                             |
|        | (0/0,         | [Note]{.underline}Bincreased serum fluoride |
|        | 12.5/12.1,    | at [\>]{.underline}38/36 mg/kg/day.         |
|        | 38/36,        |                                             |
|        | 125/121       |                                             |
|        | mg/kg/day)    |                                             |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 90-Day        | **NOAEL**: 25/26 mg/kg/day (M/F)            |
| .3150) | inhalation    |                                             |
|        | toxicity,     | **LOAEL**: 50/51 mg/kg/day (M/F): M&F =     |
| (inha  | dogs          | slight histopathology of the caudate        |
| lation |               | nucleus of the basal ganglia, decreased     |
| study) | 0, 30, 100,   | bodyweight, decreased body weight gain,     |
|        | 200 ppm       | transient neurological signs (lateral       |
|        |               | recumbancy, tremors, incoordination,        |
|        | (0/0,         | salivation, tetany, inactivity) starting at |
|        | 7.5/7.6,      | day 19 in 1 M.                              |
|        | 25/26, 50/51  |                                             |
|        | mg/kg/day)    |                                             |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 90-Day        | **NOAEL**: 8.6/8.5 mg/kg/day (M/F)          |
| .3150) | inhalation    |                                             |
|        | toxicity,     | **LOAEL**: 29/28 mg/kg/day (M/F): M&F =     |
| (inha  | rabbits       | decreased body weight, decreased liver      |
| lation |               | weight, dental fluorosis, vaculoation of    |
| study) | 0, 30, 100,   | white matter of the brain (F only).         |
|        | 600/300\* ppm |                                             |
|        |               | [At 86/85 mg/kg/day (M/F)]{.underline}: M&F |
|        | (0/0,         | = malacia (necrosis) and vacuolation of     |
|        | 8.6/8.5,      | putamen, globus pallidus and internal &     |
|        | 29/28, 86/85  | external capsules in brain, decreased body  |
|        | mg/kg/day)    | weight gain, alveolar histiocytosis,        |
|        | (M/F)         | histopathology in nasal epithelium.         |
|        |               |                                             |
|        | \* 600 ppm    | [Note]{.underline}Bincreased serum fluoride |
|        | reduced to    | at all dose levels ([\>]{.underline}8.6/8.5 |
|        | 300 ppm after | mg/kg/day).                                 |
|        | 9 exposures   |                                             |
|        | due to        |                                             |
|        | convulsions   |                                             |
|        | and hind leg  |                                             |
|        | paralysis .   |                                             |
+--------+---------------+---------------------------------------------+
| (870   | Developmental | **Maternal NOAEL**: 243 mg/kg/day (F):      |
| .3700) | toxicity      | highest dose tested.                        |
|        | inhalation    |                                             |
| (inha  | study, rats   | **Maternal LOAEL**: \>243 mg/kg/day (F).    |
| lation |               |                                             |
| study) | 0, 25, 75,    | [Note]{.underline}-significant maternal     |
|        | 225 ppm       | toxicity observed in range-finding study at |
|        |               | 300 ppm.                                    |
|        | (0, 27, 81,   |                                             |
|        | 243           | **Developmental NOAEL**: 243 mg/kg/day (F): |
|        | mg/kg/day)(F) | highest dose tested.                        |
|        |               |                                             |
|        |               | **Developmental LOAEL**: \>243 mg/kg/day    |
|        |               | (F)                                         |
+--------+---------------+---------------------------------------------+
| (870   | Developmental | **Maternal NOAEL**: 29 mg/kg/day (F)        |
| .3700) | toxicity      |                                             |
|        | inhalation    | **Maternal LOAEL**: 86 mg/kg/day (F): F =   |
| (inha  | study ,       | decreased body weight and decreased body    |
| lation | rabbits       | weight gain during treatment.               |
| study) |               |                                             |
|        | 0, 25, 75,    | [Note]{.underline}-significant maternal     |
|        | 225 ppm       | toxicity observed in range-finding study at |
|        |               | 300 ppm.                                    |
|        | (0, 9.5, 29,  |                                             |
|        | 86            | **Developmental NOAEL**: 29 mg/kg/day (F)   |
|        | mg/kg/day)(F) |                                             |
|        |               | **Developmental LOAEL**: 86 mg/kg/day (F):  |
|        |               | F = decreased fetal body weight, decreased  |
|        |               | crown-rump length, possibly increased fetal |
|        |               | liver pathology (pale liver).               |
+--------+---------------+---------------------------------------------+
| (870   | 2-Generation  | **Parental NOAEL**: 3.6/3.6 mg/kg/day (M/F) |
| .3800) | reproduction  |                                             |
|        | inhalation    | **Parental LOAEL**: 14/14 mg/kg/day (M/F):  |
| (inha  | study, rats   | M&F = pale foci in lungs, increased         |
| lation |               | alveolar macrophages in lungs.              |
| study) | 0, 5, 20, 150 |                                             |
|        | ppm           | [At 108/108 mg/kg/day (M/F)]{.underline}:   |
|        |               | M&F = vacuolation of caudate putamen tracts |
|        | (0/0,         | in brain, decreased body weight,            |
|        | 3.6/3.6,      | histopathology in lungs, dental fluorosis.  |
|        | 14/14,        |                                             |
|        | 108/108       | **Offspring NOAEL**: 14/14 mg/kg/day (M/F)  |
|        | mg/kg/day )   |                                             |
|        | (M/F)         | **Offspring LOAEL**: 108/108 (M/F):         |
|        |               | Decreased pup weights in F1 and F2          |
|        |               | generations (probably secondary to maternal |
|        |               | body weight loss).                          |
+--------+---------------+---------------------------------------------+
| 870.41 | Chronic       | See (870.4300)                              |
|        | toxicity,     |                                             |
|        | rats          |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 1-Year        | **NOAEL**: 5.0/5.1 mg/kg/day (M/F)          |
| .4100) | chronic       |                                             |
|        | inhalation    | **LOAEL**: 20/20 mg/kg/day (M/F): M&F =     |
| (inha  | toxicity,     | decreased body weight gain, increased       |
| lation | dogs          | alveolar macrophages in lungs, dental       |
| study) |               | fluorosis.                                  |
|        | 0, 20, 80,    |                                             |
|        | 200 ppm       | [At 50/51 mg/kg/day (M/F)]{.underline}: M&F |
|        |               | = increased mortality, malacia (necrosis)   |
|        | (0/0,         | in caudate nucleus of brain, follicular     |
|        | 5.0/5.1,      | cell hypertrophy in thyroid, histopathology |
|        | 20/20, 50/51  | in lung.                                    |
|        | mg/kg/day)    |                                             |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| 870.42 | Car           | See (870.4300)                              |
|        | cinogenicity, |                                             |
|        | rats          |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 18-Month      | **NOAEL**: 25/25 mg/kg/day (M/F)            |
| .4200) | car           |                                             |
|        | cino-genicity | **LOAEL**: 101/101 mg/kg/day (M/F): M&F =   |
| (inha  | inhalation    | cerebral vacuolation in brain, decreased    |
| lation | study, mice   | body weight gain; follicular cell           |
| study) |               | hypertrophy in thyroid (M only); increased  |
|        | 0, 5, 20, 80  | mortality (F only), heart thrombus (F       |
|        | ppm           | only), lung congestion (F only).            |
|        |               |                                             |
|        | (0/0,         | Negative for carcinogenicity in M and F.    |
|        | 5.3/6.3,      |                                             |
|        | 25/25,        |                                             |
|        | 101/101       |                                             |
|        | mg/kg/day)    |                                             |
|        | (M/F)         |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 2-Year        | **NOAEL (M)**: 3.5 mg/kg/day                |
| .4300) | combined      |                                             |
|        | chronic       | **LOAEL (M)**: 14 mg/kg/day: M = dental     |
| (inha  | toxicity/     | fluorosis.                                  |
| lation |               |                                             |
| study) | ca            | [At 56 mg/kg/day (M)]{.underline}: M =      |
|        | rcinogenicity | effects similar to those in F at 62         |
|        | inhalation    | mg/kg/day.                                  |
|        | study, rats   |                                             |
|        |               | **NOAEL (F)**: 16 mg/kg/day                 |
|        | 0, 5, 20, 80  |                                             |
|        | ppm           | **LOAEL (F)**: 62 mg/kg/day: F = greatly    |
|        |               | increased mortality (due mostly to severe   |
|        | (0/0,         | kidney toxicity which led to kidney         |
|        | 3.5/3.9,      | failure); histopathology in brain           |
|        | 14/16, 56/62  | (vacuolation in cerebrum and                |
|        | mg/kg/day)    | thalamus/hypothalamus), adrenal cortex,     |
|        | (M/F)         | eyes, liver, nasal tissue, and respiratory  |
|        |               | tract; dental fluorosis.                    |
|        |               |                                             |
|        |               | Negative for carcinogenicity in M and F.    |
+--------+---------------+---------------------------------------------+
| 87     | M             | Negative without and with S-9 activation.   |
| 0.5100 | utagenicity - |                                             |
|        | Reverse gene  |                                             |
|        | mutation (S.  |                                             |
|        | typhimurium)  |                                             |
+--------+---------------+---------------------------------------------+
| 87     | M             | Negative.                                   |
| 0.5395 | utagenicity - |                                             |
|        | *in vivo*     |                                             |
|        | micronucleus  |                                             |
|        | assay, mice   |                                             |
|        | (bone marrow  |                                             |
|        | cells)        |                                             |
+--------+---------------+---------------------------------------------+
| 87     | M             | Negative.                                   |
| 0.5500 | utagenicity - |                                             |
|        | unscheduled   |                                             |
|        | DNA synthesis |                                             |
|        | (primary rat  |                                             |
|        | hepatocytes)  |                                             |
+--------+---------------+---------------------------------------------+
| (870   | Acute         | **Systemic NOAEL**: 354 mg/kg/day (F):      |
| .6200) | inhalation    | highest dose tested.                        |
|        | neurotoxicity |                                             |
| (inha  | study, rats   | **Systemic LOAEL**: \>354 mg/kg/day (F).    |
| lation |               |                                             |
| study) | (special      | **Neurotoxic NOAEL**: 354 mg/kg/day (F):    |
|        | design)       | highest dose tested.                        |
|        |               |                                             |
|        | 0, 100, 300   | **Neurotoxic LOAEL**: \>354 mg/kg/day (F).  |
|        | ppm           |                                             |
|        |               | [Note]{.underline}-study included           |
|        | ( 0, 118, 354 | electrophysiological parameters, but no     |
|        | mg/kg/day) (F | microscopic pathology.                      |
|        | only)         |                                             |
+--------+---------------+---------------------------------------------+
| (870   | 90-Day        | **Systemic NOAEL**: 24/25 mg/kg/day (M/F)   |
| .6200) | inhalation    |                                             |
|        | neurotoxicity | **Systemic LOAEL**: 80/83 mg/kg/day (M/F):  |
| (inha  | study, rats   | M&F = pale foci in pleura and macrophages   |
| lation |               | in lungs, dental fluorosis                  |
| study) | (special      |                                             |
|        | design)       | [At 240/250 mg/kg/day (M/F)]{.underline}:   |
|        |               | M&F = decreased body weight, excessive      |
|        | 0, 30, 100,   | salivation, poor grooming.                  |
|        | 300 ppm       |                                             |
|        |               | **Neurotoxic NOAEL**: 24/25 mg/kg/day (M/F) |
|        | ( 0/0, 24/25, |                                             |
|        | 80/83,        | **Neurotoxic LOAEL**: 80/83 mg/kg/day       |
|        | 240/250       | (M/F): M&F = disturbances in                |
|        | mg/kg/day)    | electrophysiologic parameters (slowing of   |
|        | (M/F)         | VER and SER waveforms in F and ABR          |
|        |               | waveforms in M).                            |
|        |               |                                             |
|        |               | [At 240/250 mg/kg/day (M/F)]{.underline}:   |
|        |               | M&F = slowing of all waveforms except CNAP, |
|        |               | vacuolation of white matter in caudate      |
|        |               | putamen in cerebrum.                        |
|        |               |                                             |
|        |               | [Note]{.underline}-study included           |
|        |               | electrophysiological parameters.            |
+--------+---------------+---------------------------------------------+
| (870   | 1-Year        | **Systemic NOAEL**: 3.5/3.9 mg/kg/day (M/F) |
| .6200) | inhalation    |                                             |
|        | neurotoxicity | **Systemic LOAEL**: 14/16 mg/kg/day (M/F):  |
| (inha  | study, rats   | M&F = dental fluorosis.                     |
| lation |               |                                             |
| study) | (special      | [At 56/62 mg/kg/day (M/F)]{.underline}: M&F |
|        | design)       | = increased kidney and liver weights,       |
|        |               | progressive kidney disease, histopathology  |
|        | 0, 5, 20, 80  | in lung.                                    |
|        | ppm           |                                             |
|        |               | **Neurotoxic NOAEL**: 56/62 mg/kg/day       |
|        | ( 0/0,        | (M/F): highest dose tested.                 |
|        | 3.5/3.9,      |                                             |
|        | 14/16, 56/62  | **Neurotoxic LOAEL**: \>56/\>62 mg/kg/day   |
|        | mg/kg/day)    | (M/F).                                      |
|        | (M/F)         |                                             |
|        |               | [Note]{.underline}-study did                |
|        |               | [not]{.underline} include                   |
|        |               | electrophysiological parameters.            |
+--------+---------------+---------------------------------------------+
| 87     | Developmental | No study available. Required to be          |
| 0.6300 | n             | performed and submitted by HIARC (April 11, |
|        | eurotoxicity, | 2001 and October 21, 2003). That            |
|        | rats          | requirement has subsequently been waived    |
|        |               | (2004, see attachment)                      |
+--------+---------------+---------------------------------------------+
| 87     | Metabolism    | No study available. Study waived in         |
| 0.7485 | and           | Reregistration Eligibility Document (RED)   |
|        | phar          | published by EPA in 1993.                   |
|        | macokinetics, |                                             |
|        | rats          |                                             |
+--------+---------------+---------------------------------------------+
| 87     | Dermal        | No study available. Not required.           |
| 0.7600 | Penetration,  |                                             |
|        | rats          |                                             |
+--------+---------------+---------------------------------------------+

Technical grade sulfuryl fluoride (99.8% active ingredient) is marketed
as a liquefied gas in pressurized steel cylinders. The acute oral LD50
of sulfuryl fluoride has been estimated to be approximately 100 mg/kg in
rats (Toxicity Category II). The acute inhalation LC50 in mice (4 hour
exposure) is 660 ppm (2.56 mg/L) in males and 642 ppm (2.49 mg/L) in
females. The acute inhalation LC50 in rats (1 hour exposure) is 4512 ppm
(17.5 mg/L). Based on the use pattern for sulfuryl fluoride and several
reported incidences of human poisonings in the general toxicological
literature, the Agency has classified sulfuryl fluoride as Toxicity
Category I for acute inhalation toxicity. When released from pressurized
steel cylinders, sulfuryl fluoride causes freezing of skin and eye
tissues on contact. Therefore, no dermal studies or eye irritation
studies have been required to be submitted. The acute dermal toxicity
study (assumed Toxicity Category of IV), the primary skin irritation
study (assumed Toxicity Category of IV), the primary eye irritation
study (assumed Toxicity Category of I), and the dermal sensitization
study (assumed to be a non-sensitizer) have been waived. In a
non-guideline study in which rats were dermally exposed (with no
inhalation exposure) to vapors of sulfuryl fluoride gas at an exposure
concentration of 9600 ppm (40.3 mg/L) for 4 hours, no treatment-related
adverse effects were observed.

In 2-week inhalation studies in rats, dogs and rabbits, different target
organs were affected. In rats, the primary target organ was the kidney,
in which severe histopathological lesions were observed. These lesions
included papillary necrosis, hyperplasia of the epithelial cells of the
papillae, and degeneration/regeneration of collecting tubules and
proximal tubules. In dogs, the primary target organ was the upper
respiratory tract, in which minimal inflammation was observed.
Intermittent tremors and tetany were also noted in dogs. In rabbits, the
primary target organ was the brain, in which malacia (necrosis) and
vacuolation were observed in the cerebrum. Inflammation of the upper
respiratory tract was also noted in rabbits.

In subchronic (90-day) inhalation studies in rats, mice, dogs and
rabbits, the brain was the major target organ. Malacia and/or
vacuolation were observed in the white matter of the brain in all four
species. The portions of the brain most often affected were the
caudate-putamen nucleus in the basal ganglia, the white fiber tracts in
the internal and external capsules, and the globus pallidus of the
cerebrum. In dogs and rabbits, clinical signs of neurotoxicity
(including tremors, tetany, incoordination, convulsions and/or hind limb
paralysis) were also observed. Inflammation of the nasal passages and
histiocytosis of the lungs were observed in rats and rabbits, but not in
dogs, in which species inflammation of the upper respiratory tract was
more prominent in the 2-week study. In rats, kidney damage was also
observed. In mice, follicular cell hypertrophy was noted in the thyroid
gland. Decreased body weights and body weight gains were also observed
in rats, dogs and mice.

In chronic (1-2 year) inhalation studies in rats, dogs and mice, target
organs were the same as in the 90-day studies. In rats, severe kidney
damage caused renal failure and mortality in many animals. Additional
gross and histopathological lesions in numerous organs and tissues were
considered to be secondary to the primary effect on the kidneys. Other
treatment-related effects in rats included effects in the brain
(vacuolation of the cerebrum and thalamus/ hypothalamus) and respiratory
tract (reactive hyperplasia and inflammation of the respiratory
epithelium of the nasal turbinates, lung congestion, aggregates of
alveolar macrophages). In dogs and mice, increased mortality, malacia
and/or vacuolation in the white matter in the brain, histopathology in
the lungs, and follicular cell hypertrophy in the thyroid gland were
observed. Decreased body weights and body weight gains were also noted
in all three species. No evidence of carcinogenicity was observed in
either the combined chronic toxicity/carcinogenicity study in rats or in
the 18-month carcinogenicity study in mice.

In many subchronic and chronic inhalation studies in rats, dogs, and
rabbits, dental fluorosis was the most sensitive effect observed in the
study. In two 90-day studies in mice and rabbits, in which serum
fluoride levels were determined, an increased serum level of fluoride
anions was observed at even lower dose levels. The increased serum
fluoride levels were due to the conversion of sulfuryl fluoride to
fluoride anions in the body.

In specially designed acute and subchronic inhalation neurotoxicity
studies in rats, several electrophysiological parameters
(electroencephalograms, EEGs) were recorded in addition to observations
for clinical signs of neurotoxicity, functional observational battery
(FOB) and motor activity testing, and/or neurohistopathologic
examination. Following two exposures on consecutive days for 6 hours/day
at 300 ppm of sulfuryl fluoride (354 mg/kg/day), no treatment-related
neurotoxic effects were noted. In a 90-day study, changes in some EEG
patterns were observed at 100 ppm (80 mg/kg/day) and in several
additional patterns at 300 ppm (240 mg/kg/day). Vacuolation of the white
matter in the cerebrum was also observed at 300 ppm in this study. In a
specially designed 1-year chronic inhalation neurotoxicity study in
rats, no treatment-related neurotoxic effects were observed at 80 ppm
(56 mg/kg/day). EEGs were not recorded in this study.

In a developmental toxicity inhalation study in rats, no developmental
toxicity was observed in the pups. Although no maternal toxicity was
observed in this study at the highest dose tested (225 ppm), significant
maternal toxicity (decreased body weight, body weight gain and food
consumption; increased water consumption and kidney weights; and gross
pathological changes in the kidneys and liver) was observed in a
previously conducted range-finding study at a slightly higher dose level
(300 ppm). In a developmental toxicity inhalation study in rabbits,
decreased fetal body weights were observed in the pups. At the same dose
level, decreased body weight and body weight gain were observed in the
dams. In a 2-generation reproduction inhalation study in rats,
vacuolation of the white matter in the brain, pathology in the lungs
(pale, gray foci; increased alveolar macrophages) and decreased body
weights were observed in the parental animals. Decreased pup body
weights in the F1 and F2 generations were observed in the offspring. No
effects on reproductive parameters were noted in this study. No
quantitative or qualitative evidence of increased susceptibility of
fetuses or pups was observed in the developmental toxicity or
reproduction studies on sulfuryl fluoride.

A battery of mutagenicity studies was negative for genotoxic potential.
The studies included a reverse gene mutation assay in *Salmonella
typhimurium*, an unscheduled DNA synthesis assay in primary rat
hepatocytes, and a micronucleus assay in mouse bone marrow cells.

In carcinogenicity studies in male and female rats and in male and
female mice, sulfuryl fluoride did not demonstrate evidence of
carcinogenic potential. Sulfuryl fluoride is classified as **A**not
likely to be carcinogenic to humans@ according to the July 2, 1999 EPA
*Draft Proposed Guidelines for Carcinogen Risk Assessment*.

Poisonings and fatalities have been reported in humans following
inhalation exposure to sulfuryl fluoride. The severity of these effects
has depended on the concentration of sulfuryl fluoride and the duration
of exposure. Short-term inhalation exposure to high concentrations has
caused respiratory irritation, pulmonary edema, nausea, abdominal pain,
central nervous system depression, and numbness in the extremities[^2].
In addition, there have been two reports of deaths of persons entering
houses treated with sulfuryl fluoride. One person entered the house
illegally and was found dead the next morning. A second person died of
cardiac arrest after sleeping in a house overnight following fumigation.
A plasma fluoride level of 0.5 mg/L (10 times normal) was found in this
person following exposure[^3]. These acute poisonings in humans,
however, occurred only after label directions were grossly violated and
persons were subsequently exposed to extremely high concentrations of
sulfuryl fluoride. Prolonged chronic inhalation exposures to
concentrations of sulfuryl fluoride gas significantly above the
threshold limit value (TLV) of 5 ppm have caused fluorosis in humans
because sulfuryl fluoride is converted to fluoride anion in the body.
Fluorosis results from the binding of fluoride anion to teeth (causing
mottling of the teeth) and to bone.

**3.1.2 FQPA Considerations**[]{#__RefHeading___Toc125354198 .anchor}

On October 21, 2003, the HED Hazard Identification Assessment Review
Committee (HIARC) met to re-evaluate the potential for increased
susceptibility of infants and children from exposure to sulfuryl
fluoride, as required by the Food Quality Protection Act (FQPA) of 1996,
according to the 2002 OPP 10X Guidance Document. This re-evaluation was
conducted to update the decision which was reached on April 11, 2001
using previous OPP policy.

Based on the available evidence, HIARC reiterated its earlier
recommendation that an inhalation developmental neurotoxicity (DNT)
study in rats (Guideline No. 870.6300) be required in order to more
clearly and fully characterize the potential for neurotoxic effects in
young animals.

HIARC determined that a 10X database uncertainty factor (UF~DB~) is
needed to account for the lack of the DNT study since the available data
provide no basis to support reduction or removal of the default 10X
factor. The following points were considered in this determination:

-   The current regulatory dose for chronic dietary risk assessment is
    the NOAEL of 8.5 mg/kg/day (30 ppm; 0.13 mg/L) selected from a
    90-day inhalation toxicity study in rabbits. This dose is also used
    for intermediate- and long-term inhalation exposure risk
    assessments. The current dose for the short-term inhalation exposure
    risk assessment is the NOAEL of 30 mg/kg/day (100 ppm; 0.42 mg/L)
    from a 2-week inhalation toxicity study in rabbits.

-   After considering the dose levels used in the neurotoxicity studies
    and in the 2-generation reproduction study, it is assumed that the
    DNT study with sulfuryl fluoride will be conducted at dose levels
    similar to those used in the 2-generation reproduction study (0, 5,
    20, 150 ppm; 0, 0.02, 0.08, 0.6 mg/L). It is considered possible
    that the results of the DNT study could impact the endpoint
    selection for risk assessments because the lowest dose that may be
    tested in the DNT (5 ppm or 0.02 mg/L), based on the HIARC=s dose
    analysis, could become an effect level which would necessitate an
    additional factor resulting in doses which would then be lower than
    the current doses used for chronic dietary (8.5 mg/kg/day),
    intermediate and long-term inhalation (30 ppm or 0.13 mg/L) and
    short term inhalation (100 ppm or 0.42 mg/L) risk assessments. Given
    these circumstances, the HIARC does not have sufficient reliable
    data justifying selection of an additional safety factor for the
    protection of infants and children lower than the default value of
    10X. Therefore, a UF~DB~ of 10X will be applied to repeated dose
    exposure scenarios (i.e. chronic RfD, and residential short,
    intermediate and long term inhalation) to account for the lack of
    the DNT study with sulfuryl fluoride.

The HIARC determined that there is no need for a special FQPA safety
factor (i.e., 1X) since there are no residual uncertainties for pre-
and/or post-natal toxicity based on the following:

-   In the developmental toxicity study in rats, neither quantitative
    nor qualitative evidence of increased susceptibility of fetuses to
    *in utero* exposure to sulfuryl fluoride was observed.

-   In the developmental toxicity study in rabbits, neither quantitative
    nor qualitative evidence of increased susceptibility of fetuses to
    *in utero* exposure to sulfuryl fluoride was observed.

-   In the 2-generation reproduction toxicity study in rats, neither
    quantitative nor qualitative evidence of increased susceptibility of
    fetuses to sulfuryl fluoride was observed.

In April 2004, the Health Effects Division evaluated rational submitted
by the registrant requesting a waiver of the DNT study. HED granted the
waiver request (Attachment 1) because, given the relatively minimal
exposure to sulfuryl fluoride relative to the identified endpoints, any
lowering of the regulatory endpoints due to DNT study results would be
unlikely to affect the safety determination. However, because there
remains uncertainty with regard to the regulatory endpoints for sulfuryl
fluoride in the absence of a DNT, EPA has retained the FQPA 10X factor
in assessing the risk posed by sulfuryl fluoride.

**3.1.3 Dose-Response Assessment**[]{#__RefHeading___Toc125354199
.anchor}

The endpoint selection and rationale are provided, below and in Table
3.1.3, for the various exposure route and duration combinations.

*Acute Reference Dose (RfD):* None. No toxicological endpoint
attributable to a single exposure was identified in the available
toxicology studies on sulfuryl fluoride that would be appropriate for an
acute risk assessment and would be applicable to females (13-50 years
old) or to the general population (including infants and children).

*Chronic Reference Dose (RfD):* 0.003 mg/kg/day from the 90-Day
subchronic inhalation toxicity study in rabbits. In that study, the
LOAEL is 28 mg/kg/day based on vacuolation of white matter in the brain
of females, and decreased body weights, decreased liver weights and
dental fluorosis in males and females. The NOAEL is 8.5 mg/kg/day. The
Uncertainty Factor associated with the chronic RfD is 3000 and is based
on 10X for intraspecies variation, 10X for interspecies extrapolation,
3X Uncertainty Factor for using a subchronic (90-day) study for chronic
risk assessment (UF~S~), and 10X Database Uncertainty Factor (UF~DB~)
for lack of a DNT study. We note that a chronic dog study with an NOAEL
of 5 mg/kg/day is available. In that study, the noted effects at the
LOAEL of 20 mg/kg/day were decreased body weight gain, increased
alveolar macrophages, and dental fluorosis. This study was not selected
as the basis for the RfD because the effects from the rabbit study are
considered to be more severe. Had this dog study been used, the
resulting RfD (0.005 mg/kg/day) would have been nearly identical to that
derived from the 90-day rabbit study. A chronic rat study with an NOAEL
of 3.5 mg/kg/day is also available. In that study, the effect at the
LOAEL of 14 mg/kg/day was dental fluorosis. The effects in the rabbit
study are considered to be more severe than those in the rat study. If
this rat study had been selected, the resulting RfD (0.0035 mg/kg/day)
also would have been nearly identical to that derived from the 90-day
rabbit study. The selected chronic RfD for sulfuryl fluoride is
considered to be protective of all effects, including dental fluorosis.

For sulfuryl fluoride, the endpoint from an [inhalation]{.underline}
toxicity study was used to calculate the chronic RfD which is to be used
to perform risk assessments for [oral]{.underline} exposures. HIARC
believes this is a very conservative methodology which is supported by
the following considerations:

-   A higher and more persistent level of parent test material in the
    body may occur following inhalation exposure as compared to an oral
    exposure because the parent test material is immediately distributed
    throughout the circulatory system following inhalation, rather than
    first being directly shunted to the liver (where most metabolism
    occurs) as in the case of oral exposure.

-   In addition, for sulfuryl fluoride, the NOAEL on which the chronic
    RfD was calculated is from a study in rabbits (which is the most
    sensitive species for neurotoxic effects) and the LOAEL in this
    study was close to a threshold effect level (the effect was observed
    in only one female rabbit).

The LOAEL of 100 ppm (equivalent to 28 mg/kg/day) in the 90-day rabbit
study, which was used to calculate the chronic RfD, was considered to be
close to a threshold effect level because only one female rabbit at this
concentration had vacuolation of the white matter in the brain. The
HIARC considered applying an additional uncertainty factor to the NOAEL
in this study due to the severity of the effect at the LOAEL, but
concluded that application of an additional uncertainty factor would not
be necessary since the LOAEL was an approximate threshold effect level.

For the purpose of determining a chronic oral RfD, the HIARC believes
that an endpoint based on a well-defined morphological/pathological
effect, such as the neurological effect observed in the 90-day rabbit
study, is preferable to one based on a more equivocal and/or dubious
effect such as dental fluorosis (mottling of teeth). The HIARC also
believes that it is not appropriate to utilize an effect on the
respiratory system in an inhalation study as the basis for calculating
an oral RfD. Therefore, the NOAEL of 5 ppm (equivalent to 3.5 mg/kg/day)
for male rats in the combined 2-year chronic/carcinogenicity inhalation
study in rats (MRID 43354902) was not used to calculate the chronic RfD
because the effect observed at the LOAEL of 20 ppm (equivalent to 14
mg/kg/day) was dental fluorosis. Also, the parental NOAEL of 5 ppm
(equivalent to 3.6 mg/kg/day) in the 2-generation reproduction
inhalation study in rats (MRID 42179801) was not used because the effect
observed at the parental LOAEL of 20 ppm (equivalent to 14 mg/kg/day)
was pathological changes in the lungs. In addition, the NOAEL of 20 ppm
(equivalent to 5.0 mg/kg/day) in the 1-year chronic inhalation toxicity
study in dogs (MRID 43354901) was not used because the effect observed
at the LOAEL of 80 ppm (equivalent to 20 mg/kg/day) was decreased body
weight gain, dental fluorosis, and histopathological changes in the
lungs.

*Incidental Oral Exposure (All Durations):* None. Sulfuryl fluoride is a
gas at ordinary temperatures and pressures and because of its use
pattern as a fumigant in enclosed structures and spaces only, it is not
anticipated that toxicologically significant residues of sulfuryl
fluoride or its degradates will remain in/on the contents of residential
or other structures after the aeration period is completed.
Consequently, there is no potential for incidental ingestion by
toddlers. Therefore, HIARC did not select endpoints for this exposure
scenario.

*Dermal Exposure (All Durations):* None. No hazard was identified and
quantification of risk is not necessary.

*Inhalation - Short-term (1-30 days):* NOAEL = 30 mg/kg/day (100 ppm;
0.42 mg/L) from the 2-week inhalation toxicity study in rabbits. The
NOAEL is based on malacia (necrosis) in the cerebrum in 1 male and 1
female, vacuolation in the cerebrum in [all]{.underline} male and
females, and moderate inflammation of nasal tissues in most animals and
acute inflammation of the trachea in some animals at the LOAEL of 90
mg/kg/day (300 ppm; 1.25 mg/L). The results of this study provide the
best information available pertaining to assessment of the potential
short-term (1 - 30 days) risk via inhalation exposure.

The HIARC determined there is no need to quantify the inhalation risk
resulting from a single residential or occupational inhalation exposure
to sulfuryl fluoride. No treatment-related neurotoxic or other effects
were observed in a specially designed acute neurotoxicity inhalation
study (MRID 42772001) in which rats were exposed on two consecutive days
for 6 hours/day to concentrations up to 300 ppm of sulfuryl fluoride
(equivalent to 1.25 mg/L). Further, no appropriate endpoints resulting
from a single inhalation exposure were identified in any of the
available toxicity studies on sulfuryl fluoride. Therefore, no hazard
attributable to a single inhalation exposure was identified and
quantification of risk for single inhalation exposures was determined to
be unnecessary. The HIARC noted that poisonings and fatalities have been
reported in humans following inhalation exposure to sulfuryl fluoride.
The severity of these effects has depended on the concentration of
sulfuryl fluoride and the duration of exposure. Short-term inhalation
exposure to high concentrations has caused respiratory irritation,
pulmonary edema, nausea, abdominal pain, central nervous system
depression, and numbness in the extremities[^4]. In addition, there have
been two reports of deaths of persons entering houses treated with
sulfuryl fluoride (see end of section 3.1.1). As previously stated,
these acute poisonings in humans, however, occurred only after label
directions were grossly violated and persons were subsequently exposed
to extremely high concentrations of sulfuryl fluoride.

*Inhalation - Intermediate-term (1-6 months):* NOAEL = 8.5 mg/kg/day (30
ppm; 0.13 mg/L) from the 90-day subchronic inhalation toxicity study in
rabbits. The NOAEL is based on vacuolation of white matter in the brain
of females at the LOAEL of 28 mg/kg/day (100 ppm; 0.42 mg/L). The route
and dosing regimen of this study is appropriate for the route and
duration of exposure of concern.

*Inhalation - Long-term (several months to lifetime):* NOAEL = 8.5
mg/kg/day (30 ppm; 0.13 mg/L) from the 90-day subchronic inhalation
toxicity study in rabbits. The NOAEL is based on vacuolation of white
matter in the brain of females at the LOAEL of 28 mg/kg/day (100 ppm;
0.42 mg/L). This is the same study used to establish the chronic RfD.

+------------+-------------+---------------+-------------------------+
| **Table    |             |               |                         |
| 3.1.3.     |             |               |                         |
| Summary of |             |               |                         |
| Dose and   |             |               |                         |
| Endpoint   |             |               |                         |
| Selection  |             |               |                         |
| for use in |             |               |                         |
| Human      |             |               |                         |
| Health     |             |               |                         |
| Risk       |             |               |                         |
| A          |             |               |                         |
| ssessments |             |               |                         |
| for        |             |               |                         |
| Sulfuryl   |             |               |                         |
| F          |             |               |                         |
| luoride.** |             |               |                         |
+============+=============+===============+=========================+
| **         | **Dose Used | **Special     | **Study and             |
| Exposure** | in Risk     | FQPA SF and   | Toxicological Effects** |
|            | Assessment, | Level of      |                         |
| **         | UF**        | Concern for   |                         |
| Scenario** |             | Risk          |                         |
|            |             | Assessment**  |                         |
+------------+-------------+---------------+-------------------------+
| Acute      | None        | Not           | No toxicological        |
| Dietary    |             | applicable    | endpoint attributable   |
|            | UF = N/A    |               | to a single exposure    |
|            |             |               | was identified in the   |
|            |             |               | available toxicology    |
|            |             |               | studies on sulfuryl     |
|            |             |               | fluoride.               |
+------------+-------------+---------------+-------------------------+
| Chronic    | NOAEL= 8.5  | FQPA SF = 1X  | **90-Day Inhalation -   |
| Dietary    | mg/kg/day   |               | Rabbit**                |
|            |             | **cPAD** =    |                         |
| (All       | UF = 3000   |               | LOAEL = 28 mg/kg/day    |
| po         |             | [chronic      | based on vacuolation of |
| pulations) | **Chronic   | RfD           | white matter in the     |
|            | RfD** =     | ]{.underline} | brain of females.       |
|            |             |               |                         |
|            | **0.003**   | FQPA SF       |                         |
|            | mg/kg/day   |               |                         |
|            |             | = **0.003**   |                         |
|            |             | mg/kg/day     |                         |
+------------+-------------+---------------+-------------------------+
| Incidental | None        | Not           | Due to sulfuryl         |
| Oral       |             | applicable    | fluoride being a gas    |
|            |             |               | and pattern of use, no  |
| (All       |             |               | significant incidental  |
| durations) |             |               | oral exposure is        |
|            |             |               | anticipated.            |
+------------+-------------+---------------+-------------------------+
| Dermal     | None        | Not           | Due to sulfuryl         |
|            |             | applicable    | fluoride being a gas    |
| (All       |             |               | and pattern of use, no  |
| durations) |             |               | significant dermal      |
|            |             |               | exposure is             |
|            |             |               | anticipated. No hazard  |
|            |             |               | identified, therefore,  |
|            |             |               | no quantification is    |
|            |             |               | required.               |
+------------+-------------+---------------+-------------------------+
| Short-Term | Inhalation  | **            | **2-Week Inhalation -   |
| Inhalation | study       | Residential** | Rabbit**                |
| (1 to 30   | NOAEL=      | LOC for MOE = |                         |
| days)      | **30**      | **1000**      | LOAEL = 90 mg/kg/day    |
|            | mg/kg/day   |               | (300 ppm; 1.25 mg/L)    |
|            | (100 ppm;   | **O           | based on malacia        |
|            | 0.42 mg/L)  | ccupational** | (necrosis) and          |
|            |             | LOC for MOE = | vacuolation in brain,   |
|            |             | **100**       | inflammation of nasal   |
|            |             |               | tissues and trachea.    |
+------------+-------------+---------------+-------------------------+
| Interme    | Inhalation  | **            | **90-Day Inhalation -   |
| diate-Term | study NOAEL | Residential** | Rabbit**                |
| Inhalation | = **8.5**   | LOC for MOE = |                         |
| (1 to 6    | mg/kg/day   | **1000**      | LOAEL = 28 mg/kg/day    |
| months)    | (30 ppm;    |               | (100 ppm; 0.42 mg/L)    |
|            | 0.13 mg/L)  | **O           | based on vacuolation of |
|            |             | ccupational** | white matter in the     |
|            |             | LOC for MOE = | brain of females.       |
|            |             | **100**       |                         |
+------------+-------------+---------------+-------------------------+
| Long-Term  | Inhalation  | **            | **90-Day Inhalation -   |
| Inhalation | study NOAEL | Residential** | Rabbit**                |
| (\>6       | = **8.5**   | LOC for MOE = |                         |
| months)    | mg/kg/day   | **3000**      | LOAEL = 28 mg/kg/day    |
|            | (30 ppm;    |               | (100 ppm; 0.42 mg/L)    |
|            | 0.13 mg/L)  | **O           | based on vacuolation of |
|            |             | ccupational** | white matter in the     |
|            |             | LOC for MOE = | brain of females.       |
|            |             | **300**       |                         |
+------------+-------------+---------------+-------------------------+
| Cancer     | Classified  |               |                         |
|            | as ANot     |               |                         |
| (oral,     | likely to   |               |                         |
| dermal,    | be          |               |                         |
| i          | c           |               |                         |
| nhalation) | arcinogenic |               |                         |
|            | to humans@  |               |                         |
+------------+-------------+---------------+-------------------------+

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL =
no observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

**3.1.4 Endocrine Disruption**[]{#__RefHeading___Toc125354200 .anchor}

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) Amay have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.@
Following recommendations of its Endocrine Disruptor 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 recommendation 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 the wildlife evaluations. As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP). In the available toxicity
studies on sulfuryl fluoride, there was no toxicologically significant
evidence of endocrine disruptor effects. Follicular cell hypertrophy in
the thyroid of mice in the 90-day toxicity study and in the 18-month
carcinogenicity study, and in the thyroid of dogs in the 1-year chronic
toxicity study was observed. At the same dose levels at which these
effects were observed, however, considerably more serious effects
(microscopic lesions in the brain in mice and dogs and increased
mortality in dogs) were also observed. Consequently, there is only
minimal concern for potential endocrine disruptor effects at these dose
levels in these species. When additional appropriate screening and/or
testing protocols being considered under the Agency=s EDSP have been
developed, sulfuryl fluoride may be subjected to further screening
and/or testing to better characterize effects related to endocrine
disruption.

**3.2 Fluoride Anion**[]{#__RefHeading___Toc125354201 .anchor}

**3.2.1 Hazard Profile**[]{#__RefHeading___Toc125354202 .anchor}

A very large body of information regarding the toxicology of fluoride is
available in the open literature. A complete review or re-presentation
of that information is beyond the scope of this assessment. For a
comprehensive review of the toxicology of fluoride, the reader is
referred to publications by the World Health Organization (2002), the
Department of Health and Human Services (2001), the National Research
Council (1993), the Medical Research Council (2002), and NHS CRD (2000).
In conducting the assessment for fluoride, HED has used the
toxicological assessment conducted by the Agency=s Office of Water. The
regulatory findings in that assessment \[FR 51 (63)\] are based on a
LOAEL of 20 mg/day and a safety factor of 2.5, giving a maximum
allowable intake of 8 mg/day. The use of a safety factor of 2.5 ensures
public health criteria while still allowing sufficient concentration of
fluoride in water to realize its beneficial effects in protecting
against dental caries. The typical 100X factor used by HED to account
for inter- and intra-species variability have been removed due to the
large amounts of human epidemiological data surrounding fluoride and
skeletal fluorosis. In a more recent review of the data, the National
Academy of Sciences= Institute of Medicine (IOM) identified a skeletal
fluorosis NOAEL at 10 mg/day[^5]. Their assessment of the data concludes
that no safety or uncertainty factors are needed. The IOM also notes
that high exposures for long durations (on the order of 10 years) are
required to develop skeletal fluorosis and that such a condition is not
expected to occur in children under the age of 8. The findings of the
IOM are nearly identical with respect to upper limits of exposure as
those of the Office of Water. Although the values of 8 mg/day and 10
mg/day are essentially equivalent, OPP has used the 8-mg/day value in
order to be slightly more conservative in assessing risk. For fluoride
risk assessments addressed in this document, the 8 mg/day value has been
used in a manner analogous to a reference dose (RfD) and is referred to
as such for ease of communication. We note that the previous human
health risk assessment for sulfuryl fluoride (M. Doherty, 10/12/2004,
D309013) expressed toxicology and exposure in terms of mg/kg/day in
order to match the units used by the dietary exposure model. In this
assessment, those values are being expressed in mg/day to better
harmonize with the more typical units found in the open literature
describing fluoride exposures. In both cases, the values listed are
derived from the same toxicological data and conclusions.

The Agency is aware of concern regarding dental fluorosis. The National
Academy of Sciences has stated that \"\...dental fluorosis is accepted
as a purely cosmetic defect with no general health ramifications.
However, the most severe forms of dental fluorosis might be more than a
cosmetic defect if enough fluorotic enamel is fractured and lost to
cause pain, adversely affect food choices, compromise chewing efficiency
and require complex dental treatment.\" (NRC, 1993). The Office of Water
has established a secondary maximum contaminant level (SMCL) for
fluoride at 2.0 ppm to be protective against objectionable dental
fluorosis. The SMCL is a non-enforceable level established to be
protective against the cosmetic and aesthetic effects of a contaminant.
Appendix II of this risk assessment addresses dental fluorosis.

**3.2.2 FQPA Considerations**[]{#__RefHeading___Toc125354203 .anchor}

HED has not applied an additional FQPA safety factor to the fluoride
assessment. Skeletal fluorosis is an effect that requires chronic (10+
years) high exposures in order to be manifested. As such, infants and
children will not exhibit this effect and an additional factor to
account for potential enhanced sensitivity is not necessary.

**3.2.3 Dose-Response Assessment**[]{#__RefHeading___Toc125354204
.anchor}

*Toxicological Dose for Use in Acute Risk Assessments:* None. HED has
not identified any toxicological endpoint attributable to a single
exposure of fluoride that would be applicable to females (13-50 years
old) or to the general population (including infants and children). The
Agency is aware of cases of acute toxicity following exposure to
extremely high concentrations of fluoride in drinking water. These
incidents appear to be due to malfunctioning fluoridation equipment and
fall far outside the realm of expected exposures. As such, HED has not
tried to assess acute toxicity for fluoride.

*Toxicological Dose for Use in Non-Acute Risk Assessments:* For all
short-term, intermediate-term, and chronic assessments, HED has used the
8-mg/day value derived by the Office of Water in a manner analogous to a
chronic PAD.

*Carcinogenicity:* In its assessment of the health effects of fluoride,
the National Research Council came to the following conclusion:

> *The subcommittee concludes that the available laboratory data are
> insufficient to demonstrate a carcinogenic effect of fluoride in
> animals. The subcommittee also concludes that the weight of the
> evidence from more than 50 epidemiological studies does not support
> the hypothesis of an association between fluoride exposure and
> increased cancer risk in humans.* National Research Council, 1993.

The Agency for Toxic Substances and Disease Registry (ATSDR, 2001) and
the World Health Organization (2002) have come to similar conclusions.
Based on the findings of those bodies, HED believes that a cancer risk
assessment for fluoride is not appropriate.

**3.2.4 Endocrine Disruption**[]{#__RefHeading___Toc125354205 .anchor}

As noted in Section 3.1.4, HED is required to consider potential
endocrine effects when conducting its risk assessments. The Agency is
aware of potential endocrine effects of fluoride being noted in the open
literature. From a preliminary review of this literature (Baetcke, et
al., 2003), there does not appear to be a sufficient scientific
foundation to permit confident conclusions regarding the ability of
fluoride to produce endocrine effects. Thus, the available body of
literature does not provide a compelling basis to depart from OPP=s use
of the current Agency MCL in pesticide risk assessments at this time.
This conclusion is supported by the recent York Review (2000) and the
conclusions of the Medical Research Council (2002). The National Academy
of Sciences is currently in the process of reviewing the toxicological
data for fluoride. When their review is available, EPA will reexamine
this conclusion.

**4.0 EXPOSURE ASSESSMENT**[]{#__RefHeading___Toc125354206 .anchor}

**4.1 Summary of Proposed Uses**[]{#__RefHeading___Toc125354207 .anchor}

Sulfuryl fluoride is being proposed as a methyl bromide replacement to
control pests in food processing facilities. Sulfuryl fluoride is a
fumigant and, in the form of ProFume^J^, is formulated as 99+% active
ingredient. The fumigation rate for sulfuryl fluoride is the product of
the fumigant concentration and exposure time. The maximum target rate is
1500 mghr/L for normal atmospheric fumigations and 200 mghr/L for
vacuum fumigations. Double fumigations are recommended for insect
infestations where eggs may be present, with the second fumigation timed
to control newly hatched, immature stages. The proposed label specifies
that all food commodities be aerated for a minimum of 24 hours prior to
the foods entering commerce.

Sulfuryl fluoride is a highly volatile compound with a boiling point of
-55°C and a vapor pressure of 11552 Torr (20°C). At 20°C, sulfuryl
fluoride has a vapor density of 4.3 g/L (heavier than air) and is both
colorless and odorless. The log K~OW~ is estimated to be 0.41. Sulfuryl
fluoride has a very low solubility in water (0.075 g/100 g).
Solubilities in other solvents are 0.78 g/100 g in Wesson oil, 1.74
g/100 g in acetone, and 2.12 g/100 g in chloroform.

+----------+--------+--------+--------+----------+------+------------+
| Table    |        |        |        |          |      |            |
| 4.1.1.   |        |        |        |          |      |            |
| Summary  |        |        |        |          |      |            |
| of       |        |        |        |          |      |            |
| Di       |        |        |        |          |      |            |
| rections |        |        |        |          |      |            |
| for the  |        |        |        |          |      |            |
| Use of   |        |        |        |          |      |            |
| Sulfuryl |        |        |        |          |      |            |
| Fluoride |        |        |        |          |      |            |
| from the |        |        |        |          |      |            |
| Proposed |        |        |        |          |      |            |
| Label.   |        |        |        |          |      |            |
+----------+--------+--------+--------+----------+------+------------+
| Applic.  | Formu  | Max.   | Max.   | Max.     | Aera | Use        |
| Timing,  | lation | per    | No.    | Cu       | tion | Directions |
| Type,    |        | A      | A      | mulative |      | and        |
| and      | \[EPA  | pplic. | pplic. | Applic.  | (ho  | L          |
| Equip.   | Reg.   | Rate   | per    | Rate     | urs) | imitations |
|          | No.\]  |        | Batch  |          |      |            |
|          |        | (mg    |        | (        |      |            |
|          |        | hr/L) |        | mghr/L) |      |            |
+----------+--------+--------+--------+----------+------+------------+
| Fu       | P      | 1500   | 2      | 1500     | 24   | Food       |
| migation | roFume | (a     |        |          |      | c          |
| of foods | \      | mbient |        | (ambient |      | ommodities |
| and      | [62719 | pre    |        | p        |      | must be    |
| sealed   | -XXX\] | ssure) |        | ressure) |      | aerated    |
| food     |        |        |        |          |      | for 24     |
| pr       |        | 200    |        | 200      |      | hours      |
| ocessing |        | (      |        |          |      | prior to   |
| fa       |        | vacuum |        | (vacuum  |      | entering   |
| cilities |        | fumig  |        | fum      |      | commerce.  |
|          |        | ation) |        | igation) |      |            |
+----------+--------+--------+--------+----------+------+------------+

Provided the proposed label is amended to remove dried eggs as a
targeted commodity for food fumigations and to prohibit targeted
fumigation of edible oils, the label has sufficient information to allow
the Agency to evaluate the residue trials in light of the proposed use
patterns. Dow AgroSciences has submitted a draft label in which dried
egg has been deleted as a targeted commodity for food fumigations.

Fluoride, as a chemical species, does not have a set of registered
pesticidal uses. Pesticide chemicals that are known to increase fluoride
residues in foods above background levels are cryolite and sulfuryl
fluoride. This assessment addresses those pesticidal sources of fluoride
as well as other, non-pesticidal sources.

**4.2 Dietary Exposure/Risk Pathway**[]{#__RefHeading___Toc125354208
.anchor}

The residue chemistry databases for both sulfuryl fluoride and fluoride
anion are considered marginally adequate to set tolerances based on the
proposed use pattern. As a condition of registration, HED is
recommending that further residue data are collected to ensure that the
tolerances being recommended by HED are appropriate. Residue chemistry
data needs, including label modifications, are listed in Section 8.
Provided the label changes are made, HED is recommending a conditional
registration with the sulfuryl fluoride and fluoride anion tolerances
summarized in Table 8.1. Details regarding the dietary analyses and
residue profiles used in this assessment are provided below.

**4.2.1 Residue Profile**[]{#__RefHeading___Toc125354209 .anchor}

**4.2.1.1 Sulfuryl Fluoride and Fluoride Residues from the use of
Sulfuryl Fluoride**[]{#__RefHeading___Toc125354210 .anchor}

(M. Doherty, DP Number 317730, 7/13/05 and M. Doherty, DP Number 317731,
1/18/06)

Tolerances are currently established for sulfuryl fluoride (40 CFR
180.575) and for residues of inorganic fluoride resulting from the use
of either sulfuryl fluoride or cryolite (40 CFR 180.145). Sulfuryl
fluoride is highly reactive and breaks down to form sulfate and fluoride
anion. Parent sulfuryl fluoride and the fluoride anion are the residues
of concern for both tolerance expression and risk assessment purposes.

To support the requested uses, Dow AgroSciences has submitted residue
data for sulfuryl fluoride and fluoride anion from a number of finished
food products (chips, cookies, etc.) as well as foods considered to be
Akey@ ingredients (salt, sugar, powdered milk, etc.). Foods were
fumigated at approximately the maximum label rate (1500 mghr/L) and
allowed to aerate for 24 hours prior to residue analysis. Fumigation,
aeration, and storage were all done at 30°C in order to maximize the
potential conversion of sulfuryl fluoride to fluoride anion. For
finished foods, items were fumigated in an open configuration (i.e., a
box or other open container) as well as in their original packaging. Key
ingredients were fumigated only in the open configuration. HED has
matched the available data to the various food types in the dietary
exposure model to obtain dietary exposure estimates.

Separate analytical methods for each residue of concern are available
for most commodities; however, the data submitted to support this
petition shows that the methods are not suitable for all commodities
that may be treated. Furthermore, storage stability data for fluoride
were not submitted and there is concern that fluoride may have reacted
with food components during storage and become Abound.@ There is
evidence from previous storage stability studies with fluoride (MRID
45510302) that this may occur.

Residues of sulfuryl fluoride were highly dependent on the nature of the
fumigated material and ranged from \<0.004 ppm to approximately 2 ppm.
Similarly, fluoride residues were dependent on the commodity and ranged
from \<1 to approximately 820 ppm. Generally, commodities with higher
protein and/or fat content have higher residues of sulfuryl fluoride or
fluoride (an extreme case being powdered eggs). For a number of finished
products, the residues of sulfuryl fluoride in the packaged
configuration were greater than in the open configuration. In all such
cases, the packaging contained a polymer film, either as a bag liner or
as lined paper. The phenomena were not mirrored in the fluoride residue
levels. HED does not have a satisfactory theory to explain these
observations at this time. Method performance leaves a high degree of
uncertainty surrounding residues of sulfuryl fluoride in Oreo^7^
cookies, powdered eggs, and baking soda; and for residues of fluoride in
white cake mix, pet foods, parsley, and baking powder. Given the
transient nature of sulfuryl fluoride residues and the potential for
fluoride to serve as a marker compound, HED does not believe that the
lack of a universal method for sulfuryl fluoride warrants development of
a new sulfuryl fluoride method. HED is, however, concerned about the
lack of performance of the fluoride method for some commodities and the
fluoride storage stability issue noted above. The use of a total
fluoride analysis method would resolve both the method and the storage
stability issues and recommends that the petitioner investigate and, if
necessary, validate a total fluoride method using representative
commodities from all crop groups and animal commodities (meat, fat,
milk, eggs). Further, HED recommends that the petitioner consult with
the HED prior to the onset of any such investigation. HED is
recommending that the registration, if granted, be made conditional on
the proposal of a more universal fluoride method, acceptance of that
method by the Agency, and submission of residue data collected from
control and fumigated representative commodities. As of 1/13/06, the
Analytical Chemistry Laboratory had not received reference standards of
either sulfuryl fluoride or a suitable fluoride salt. Due to the nature
of sulfuryl fluoride, the laboratory is not requesting that a standard
be submitted at this time; however, a reference standard for fluoride
should be provided.

Based on the data available at this time, HED is recommending that the
following tolerances be established:

  ------------------------------------------- ---------------- -----------
  Commodity                                   Tolerance, ppm   

                                              Sulfuryl         Fluoride
                                              Fluoride         Ion

  All processed food commodities not          2.0              70
  otherwise listed                                             

  Cattle, meat, dried                         0.01             40

  Cheese                                      2.0              5.0

  Cocoa bean, postharvest                     0.2              20

  Coconut, postharvest                        1.0              40

  Coffee, postharvest                         1.0              15

  Cottonseed, postharvest                     0.5              70

  Eggs, dried                                 1.0              900

  Ginger, postharvest                         0.5              70

  Ham                                         0.02             20

  Herbs and Spices, Group 19, postharvest     0.5              70

  Milk, powdered                              2.0              5.0

  Nut, pine, postharvest                      0.2              20

  Peanut, postharvest                         0.5              15

  Rice, flour, postharvest                    0.05             45

  Vegetables, Legume, Group 6, postharvest    0.5              70
  ------------------------------------------- ---------------- -----------

**4.2.1.5 Other Sources of Fluoride**[]{#__RefHeading___Toc125354211
.anchor}

(M. Doherty, DP Number 309013)

This risk assessment includes quantitative estimates of fluoride
exposure from residues in foods from the use of sulfuryl fluoride and/or
cryolite, background levels in foods, and consumption of
fluoride-containing water. Also addressed quantitatively are exposure
from the use of fluoridated toothpaste and inhalation of fluoride from
the atmosphere. These sources are addressed in Section 4.4 of the
previous risk assessment. The exposure estimates are summarized in Table
4.2.3.2, below. Other known potential sources of fluoride exposure were
not addressed quantitatively either due to lack of data regarding
residues and/or data regarding the demographics of exposure. Sections
4.4 and 5 provide more information.

**4.2.2 Acute Dietary**[]{#__RefHeading___Toc125354212 .anchor}

No toxicological endpoint attributable to a single exposure was
identified in the available toxicology studies on sulfuryl fluoride or
fluoride anion. Therefore, acute dietary assessments were not conducted.

**4.2.3 Chronic Dietary**[]{#__RefHeading___Toc125354213 .anchor}

The Health Effects Division has conducted two dietary assessments to
evaluate the potential dietary exposures to sulfuryl fluoride and
fluoride anion associated with the requested uses. The first assessment
addresses food fumigations and includes use on dried fruits, stored
cereal grains, herbs and spices, dried peas and beans, tree nuts, cocoa
beans, coconut, coffee beans, cottonseed, ginger, powdered milk, cheese,
peanut, pine nut, and ham. The second analysis addresses inadvertent
residues that may occur during space fumigations of grain milling
facilities and food processing facilities. Both assessments were
conducted using the Dietary Exposure Evaluation Model (DEEM‑FCID,
Version 2.03), which uses food consumption data from the USDA\'s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994‑1996
and 1998. There is the potential for a given commodity to receive
post-harvest treatment with sulfuryl fluoride and to then be exposed to
the fumigant again as part of a space fumigation. Therefore, the dietary
exposure estimates from the food fumigation and space fumigation
analyses have been combined to give total dietary exposure estimates.
Since the likelihood of this serial treatment is highly unlikely, adding
the exposure estimates is considered to be a highly health-protective
assumption.

The Biological and Economic Analysis Division has supplied HED with
information regarding the amount of commodities that may be treated per
year. For food fumigations, estimates are 2% for stored cereal grains,
20% for tree nuts, and 40% for dried fruits. All other commodities in
the food fumigation assessments were assigned a percent crop treated
value of 100%. The space fumigation assessments include estimates of the
fraction of commodities treated. The estimates include the percentage of
facilities that may be fumigated per year as well as the amount of the
various commodities that may be exposed to sulfuryl fluoride during
fumigation. It is estimated that approximately 40% of the processing
facilities would receive sulfuryl fluoride fumigation with, on average,
2.5 fumigations per year. Approximately one day's worth of production
could be stored on-site and the facilities typically operate over 300
days per year. Combining these estimates gives a fraction of commodity
treated estimate of 0.4 × 2.5 × 1 ÷ 300 = 0.003. This estimate was
rounded up to 0.004 for the space fumigation analyses. For grain mills,
HED assumed that 40% of the facilities would be treated, that there
could be 3 fumigations per year, and 2 days worth of production exposed,
giving an estimate of 0.4 × 3 × 2 ÷ 300 = 0.008. Since cereal grain
commodities could be exposed to sulfuryl fluoride at the mill and at the
food processing facility, these two percent-commodity-treated estimates
were added together for an overall inadvertent cereal grain commodity
treated estimate of 1.1%.

The previous human health risk assessment included a 0.1X processing
factor for flour commodities to account for the practice of drawing down
grain in the mills prior to fumigation and then flushing any residual
grain/flour out of the mill with fresh material during startup and mill
equilibration. The present assessment has removed that 0.1X factor to
account for the ProFume label having been revised in 2005 to eliminate
blending of fumigated flour with untreated flour.

*Sulfuryl Fluoride*. The chronic analysis for sulfuryl fluoride used
average residue values from residue trials reflecting the maximum
proposed use. The refined chronic dietary risk estimates for all
population subgroups are less than or equal to 8% of the chronic
population‑adjusted dose (cPAD) of 0.003 mg/kg/day when combined for the
food fumigation and space fumigation uses.

  -------------- ------------- ------ ------------- ------ ------------- ------
  Table 4.2.3.1.                                                         
  Sulfuryl                                                               
  Fluoride                                                               
  Chronic                                                                
  Dietary                                                                
  Exposure and                                                           
  Risk Estimates                                                         
  for Fumigation                                                         
  of Food and                                                            
  Food                                                                   
  Processing                                                             
  Facilities                                                             
  with Sulfuryl                                                          
  Fluoride. The                                                          
  cPAD for                                                               
  sulfuryl                                                               
  fluoride is                                                            
  0.003                                                                  
  mg/kg/day for                                                          
  all population                                                         
  subgroups.                                                             

  Population     Food                 Space                Food + Space  
  Subgroup       Fumigations          Fumigations                        

                 Exposure      \%     Exposure      \%     Exposure      \%
                 Estimate,     cPAD   Estimate,     cPAD   Estimate,     cPAD
                 mg/kg/day            mg/kg/day            mg/kg/day     

  U.S. Pop.      0.000064      2      0.000017      1      0.000082      3
  (total)                                                                

  All infants    0.000041      1      0.000097      3      0.000138      5
  (\< 1 year)                                                            

  Children 1-2   0.000189      6      0.000036      1      0.000225      8
  yrs                                                                    

  Children 3-5   0.000177      6      0.000036      1      0.000213      7
  yrs                                                                    

  Children 6-12  0.000100      3      0.000026      1      0.000126      4
  yrs                                                                    

  Youth 13-19    0.000058      2      0.000017      1      0.000075      3
  yrs                                                                    

  Adults 20-49   0.000047      2      0.000014      \<1    0.000061      2
  yrs                                                                    

  Adults 50+ yrs 0.000045      2      0.000011      \<1    0.000056      2

  Females 13-49  0.000046      2      0.000013      \<1    0.000059      2
  yrs                                                                    
  -------------- ------------- ------ ------------- ------ ------------- ------

*Fluoride*. The chronic analyses for fluoride are presented in Table
4.2.3.2. The separate food-fumigation and space-fumigation risk
estimates are below HED=s level of concern for all population subgroups.
It should be noted that crippling skeletal fluorosis requires high
exposure for extended time (on the order of decades); therefore, it is
not really appropriate to include children in an assessment for this
condition. Children are included in Table 4.2.3.2, and subsequent
tables, for completeness.

Table 4.2.3.3 combines dietary exposure estimates from sulfuryl
fluoride, cryolite, background levels in food, and drinking water to
give an overall dietary exposure estimate. Note that exposure estimates
in Tables 4.2.3.2 and 4.2.3.3 are expressed in mg/day. Total dietary
risk estimates range from 13 to 38% of the RfD and are below HED's level
of concern for all population subgroups.

  -------------- ----------- ------------- -------- ----- ------------- -------- ----- ----------- -----
  Table 4.2.3.2.                                                                                   
  Fluoride                                                                                         
  Chronic                                                                                          
  Dietary                                                                                          
  Exposure and                                                                                     
  Risk Estimates                                                                                   
  for Fumigation                                                                                   
  of Food and                                                                                      
  Food                                                                                             
  Processing                                                                                       
  Facilities                                                                                       
  with Sulfuryl                                                                                    
  Fluoride. The                                                                                    
  RfD for                                                                                          
  fluoride is 8                                                                                    
  mg/day for all                                                                                   
  population                                                                                       
  subgroups.                                                                                       

  Population     NHANES      Food                         Space                        Food +      
  Subgroup       Estimated   Fumigations                  Fumigations                  Space       
                 Body                                                                              
                 Weight,                                                                           
                 kg^\*^                                                                            

                             Exposure               \%    Exposure               \%    Exposure    \%
                             Estimate,              RfD   Estimate,              RfD   Estimate,   RfD
                                                                                       mg/day      

                             mg/kg/day     mg/day         mg/kg/day     mg/day                     

  U.S. Pop.      70          0.008701      0.6091   8     0.000820      0.0574   1     0.6665      8
  (total)                                                                                          

  All infants    7           0.010972      0.0768   1     0.000876      0.0061   \<1   0.0829      1
  (\< 1 year)                                                                                      

  Children 1-2   13          0.017980      0.2337   3     0.002052      0.0267   \<1   0.2604      3
  yrs                                                                                              

  Children 3-5   22          0.019274      0.4240   5     0.002009      0.0442   1     0.4682      6
  yrs                                                                                              

  Children 6-12  40          0.012879      0.5152   6     0.001361      0.0544   1     0.5696      7
  yrs                                                                                              

  Youth 13-19    60          0.008014      0.4808   6     0.000795      0.0477   1     0.5285      7
  yrs                                                                                              

  Adults 20-49   70          0.007212      0.5048   6     0.000660      0.0462   1     0.5510      7
  yrs                                                                                              

  Adults 50+ yrs 70          0.006670      0.4669   6     0.000516      0.0361   \<1   0.5030      6

  Females 13-49  61          0.006398      0.3903   5     0.000603      0.0368   \<1   0.4271      5
  yrs                                                                                              
  -------------- ----------- ------------- -------- ----- ------------- -------- ----- ----------- -----

^\*^ National Health and Nutrition Examination Survey. U.S. EPA. 2000.
Methodology for Deriving Ambient Water Quality Criteria for the
Protection of Human Health. Office of Science and Technology, Office of
Water EPA-822-B-00-004. Washington, DC.

  ------------------ -------- ------------ ---------- ------- ------- --------- -------
  Table 4.2.3.3.                                                                
  Total Chronic                                                                 
  Exposure and Risk                                                             
  Estimates for                                                                 
  Fluoride from                                                                 
  Dietary Sources.                                                              

  Population         RfD,     Dietary                                           Risk, %
  Subgroup           mg/day   Fluoride                                          RfD
                              Anion                                             
                              Exposure                                          
                              Estimates,                                        
                              mg/day                                            

                              Sulfuryl     Cryolite   Food    Water   Total     
                              Fluoride                                Dietary   

  U.S. Population    8        0.667        0.049      0.476   1.883   3.075     38
  (total)                                                                       

  All infants (\< 1  8        0.083        0.007      0.065   0.997   1.152     14
  year)                                                                         

  Children 1-2 yrs   8        0.260        0.043      0.228   0.529   1.060     13

  Children 3-5 yrs   8        0.468        0.046      0.328   0.744   1.586     20

  Children 6-12 yrs  8        0.570        0.036      0.376   0.908   1.890     24

  Youth 13-19 yrs    8        0.529        0.018      0.372   1.056   1.975     25

  Adults 20-49 yrs   8        0.551        0.028      0.399   1.764   2.742     34

  Adults 50+ yrs     8        0.503        0.035      0.35    1.792   2.680     34

  Females 13-49 yrs  8        0.427        0.031      0.329   1.452   2.239     28
  ------------------ -------- ------------ ---------- ------- ------- --------- -------

**4.2.4 Cancer Dietary**[]{#__RefHeading___Toc125354214 .anchor}

As noted in Section 3, sulfuryl fluoride has been classified as Anot
likely to be carcinogenic to humans@ and there is no evidence showing an
increased risk of cancer following exposure to fluoride. HED has not
conducted an assessment of cancer risk from dietary exposures for either
sulfuryl fluoride or fluoride anion.

**4.3 Water Exposure/Risk Pathway**[]{#__RefHeading___Toc125354215
.anchor}

Please see the previous human health risk assessment for sulfuryl
fluoride/fluoride for a discussion of water exposures and risks (M.
Doherty, D309013, 10/12/04). This risk assessment assumed an average 2
ppm level of fluoride in drinking water (see M. Doherty 10/12/04 memo,
D309014). This level represents the 99th percentile of exposure for the
US population as presented in a 2003 Office of Water publication
("Occurrence Estimation Methodology and Occurrence Findings Report for
the Six-Year Review of Existing National Primary Drinking Water
Regulations"). The latter also concluded that a subpopulation of about
191,000 is served by drinking water sources containing average fluoride
residues greater than the MCL of 4 ppm. An additional 535,900 and 1.98
million individuals are estimated to be served by sources containing
more than 3 ppm and 2 ppm average fluoride, respectively. Public notice
regulations have been established by EPA under Chapter 40, Part 141,
Subpart Q of the Code of Federal Regulations to address situations
wherein fluoride levels exceed 2 ppm[^6]. These regulations require
operators of public water systems to inform consumers when fluoride
levels exceed the secondary MCL (SMCL) of 2 ppm or the MCL of 4 ppm.
Exceedances of the SMCL must be reported as soon as practical but within
12 months, while levels higher than the 4 ppm MCL must be reported
within 30 days. In both cases the public notices state that children
under the age of nine should be provided with an alternative source of
drinking water low in fluoride. The SMCL exceedance notice states that
older children and adults may safely drink the water, but the notice for
levels greater than the MCL advises adults and older children to consult
their dentist or doctor to determine if an alternate source of water low
in fluoride should be used. Based on the existence of this public notice
system for consumers in areas with higher fluoride levels, HED considers
the use of 2 ppm fluoride in drinking water as a reasonable upper limit
for the purposes of chronic risk assessment.

**4.4 Residential Exposure/Risk Pathway**[]{#__RefHeading___Toc125354216
.anchor}

Please see the previous human health risk assessment for sulfuryl
fluoride/fluoride for a discussion of non-dietary exposures and risks
(M. Doherty, D309013, 10/12/04). Exposure estimates for these pathways
are summarized in Table 4.4.1, below.

  ----------------------- ------------------ -------------- --------------
  Table 4.4.1. Estimated                                    
  Fluoride Exposure from                                    
  Non-Dietary Sources.                                      

  Population Subgroup     Standard           Estimated      
                          Respiration,       Exposure,      
                          m^3^/day           mg/day         

                                             Toothpaste     Air

  U.S. Population (total) 13.3               0.30           0.0420

  All infants (\< 1 year) 4.5                0.30           0.0133

  Children 1-2 yrs        8.7                0.30           0.0260

  Children 3-5 yrs        8.7                0.30           0.0264

  Children 6-12 yrs       8.7                0.30           0.0280

  Youth 13-19 yrs         13.3               0.30           0.0420

  Adults 20-49 yrs        13.3               0.30           0.0420

  Adults 50+ yrs          13.3               0.30           0.0420

  Females 13-49 yrs       11.3               0.30           0.0366
  ----------------------- ------------------ -------------- --------------

**4.4.1 Other**[]{#__RefHeading___Toc125354217 .anchor}

HED has not conducted a quantitative assessment for persons living near
fumigation activities (i.e., bystanders). Due to the rapid dissipation
of sulfuryl fluoride and the infrequency of fumigations of food
processing facilities, HED is not concerned with potential bystander
exposures associated with fumigation of those facilities. As noted in
the previous assessment, for tree nut and dried fruit fumigations, there
is more of a potential for more regular bystander exposure to sulfuryl
fluoride. Based on the properties of sulfuryl fluoride and the practices
associated with fumigation facilities, HED does not believe that there
will be significant exposure to bystanders; however, as a condition of
registration and in conjunction with the monitoring of fumigation
workers (see Section 7), HED has requested air monitoring data from
areas surrounding fumigation sites.

**5.0 AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION**[]{#__RefHeading___Toc125354218 .anchor}

*Sulfuryl Fluoride.* In estimating aggregate risks from exposure to
sulfuryl fluoride, HED has examined potential dietary and non-dietary
exposure pathways. Due to the use pattern of sulfuryl fluoride and
associated label restrictions, the potential non-dietary exposure
pathways are believed to result in negligible exposures. Therefore, HED
has not included non-dietary exposure in a quantitative aggregate
exposure assessment. Due to the use pattern and toxicology of sulfuryl
fluoride, HED has determined that a chronic aggregate assessment is
appropriate and has not calculated acute, short-term, or
intermediate-term aggregate risks. As discussed in Section 4.3, residues
of sulfuryl fluoride will not occur in drinking water. Therefore,
drinking water does not contribute to aggregate exposure, leaving
residues in or on food as the only quantifiable exposure pathway for
estimating aggregate risks. Estimated chronic dietary risks, and
therefore chronic aggregate risks, are less than or equal to 8% of the
cPAD for the U.S. population and all population subgroups (Table
4.2.3.1). These risk estimates are well below HED=s level of concern.

*Fluoride*. In estimating aggregate risks for skeletal fluorosis, HED
has examined potential dietary and non-dietary exposure pathways. Based
on the toxicology of fluoride and the behaviors associated with fluoride
exposure (e.g., brushing teeth), HED has examined only chronic aggregate
exposure scenarios. As discussed in Section 4.2.2.3, moderately
conservative estimates of dietary exposure were quantified based on
fluoride residues coming from the pesticidal uses of sulfuryl fluoride
and cryolite, from background residue levels in food, and the fluoride
content of drinking water. Non-dietary sources for which sufficient
information was available to quantitate exposure were toothpaste and
air. As noted in Section 4.4, the exposure estimates from these sources
are considered to be conservative. Aggregate exposures are summarized in
Table 5.1 for the representative population subgroups addressed in the
chronic exposure module of the DEEM-FCID software (the general U.S.
population, all infants (\<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old) . The aggregate risks for those populations are also
presented in Table 5.1 as a percentage of the RfD. The aggregate risk
estimates for the representative subgroups in DEEM-FCID range from 17%
(children 1-2 year of age) to 43% (general U.S. population) of the RfD.
The aggregate risk estimates for the U.S. population and all subgroups,
including those of infants and children, are below HED=s level of
concern. Risk estimates based on toxicological findings of the Institute
of Medicine (1997) are presented in Appendix I. Risk estimates
associated with dental fluorosis are presented in Appendix II.

  ----------------- --------- ----------- ------------ -------- ------- -------
  Table 5.1.                                                            
  Aggregate                                                             
  Exposure and Risk                                                     
  Estimates for                                                         
  Skeletal                                                              
  Fluorosis.                                                            

  Population        RfD,      Estimated                                 Risk, %
  Subgroup          mg/day    Fluoride                                  of RfD
                              Exposure by                               
                              Source,                                   
                              mg/day                                    

                              Dietary     Toothpaste   Air      Total   

  U.S. Population   8         3.075       0.3          0.0420   3.417   43
  (total)                                                               

  All infants (\< 1 8         1.152       0.3          0.0133   1.465   18
  year)                                                                 

  Children 1-2 yrs  8         1.060       0.3          0.0260   1.386   17

  Children 3-5 yrs  8         1.586       0.3          0.0264   1.912   24

  Children 6-12 yrs 8         1.890       0.3          0.0280   2.218   28

  Youth 13-19 yrs   8         1.975       0.3          0.0420   2.317   29

  Adults 20-49 yrs  8         2.742       0.3          0.0420   3.084   39

  Adults 50+ yrs    8         2.680       0.3          0.0420   3.022   38

  Females 13-49 yrs 8         2.239       0.3          0.0366   2.576   32
  ----------------- --------- ----------- ------------ -------- ------- -------

In developing the exposure estimates for fluoride from water, HED has
used the national median fluoride concentration of 0.4 ppm for non-tap
water (i.e., food-based water, commercially processed water, and bottled
water). While we believe that the median value is a reasonable estimate
given that such water, as a whole, will come from various sources, we
acknowledge that certain water within that designation may come from a
fairly localized region and therefore fluoride levels may be
underestimated by use of a national median. In order to ascertain the
impact of using the 0.4-ppm value on the aggregate exposure estimates,
HED has also estimated fluoride exposure from water using the 2-ppm
concentration for all water sources. Using the 2-ppm value results in
total dietary fluoride exposure estimates that range from 20% to 67% of
the RfD, giving a maximum aggregate risk estimate of approximately 71%
of the RfD (details not shown). Although HED believes that this risk
estimate is based on unreasonably high exposure levels, it still falls
below our level of concern.

*Other Sources of Fluoride Exposure*. HED is aware that exposure to
fluoride may come from sources other than those quantified above.
Although those sources have not been incorporated directly in the
aggregate risk assessment, HED believes that the assessment is
sufficiently conservative to ensure that it does not underestimate
actual fluoride exposures experienced by members of the U.S. population.

**6.0 CUMULATIVE RISK**[]{#__RefHeading___Toc125354219 .anchor}

The Food Quality Protection Act (1996) 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.

HED did not perform a cumulative risk assessment as part of this risk
assessment for sulfuryl fluoride because HED has not yet initiated a
review to determine if there are any other chemical substances that have
a mechanism of toxicity common with that of sulfuryl fluoride. For
purposes of this petition, EPA has assumed that sulfuryl fluoride does
not have a common mechanism of toxicity with other substances.

On this basis, the petitioner must submit, upon EPA=s request and
according to a schedule determined by the Agency, such information as
the Agency directs to be submitted in order to evaluate issues related
to whether sulfuryl fluoride shares a common mechanism of toxicity with
any other substance and, if so, whether any tolerances for sulfuryl
fluoride need to be modified or revoked. If HED identifies other
substances that share a common mechanism of toxicity with sulfuryl
fluoride, HED will perform aggregate exposure assessments on each
chemical, and will begin to conduct a cumulative risk assessment.

HED has recently finalized its guidance for conducting cumulative risk
assessments on substances that have a common mechanism of toxicity. This
guidance will be available from the OPP Website
(http://www.epa.gov/pesticides). In the guidance, it is stated that a
cumulative risk assessment of substances that cause a common toxic
effect by a common mechanism will not be conducted until an aggregate
exposure assessment of each substance has been completed.

Before undertaking a cumulative risk assessment, HED will follow
procedures for identifying chemicals that have a common mechanism of
toxicity as set forth in the *Guidance for Identifying Pesticide
Chemicals and Other Substances that Have a Common Mechanism of Toxicity*
(64 FR 5795-5796, February 5, 1999).

**7.0 OCCUPATIONAL EXPOSURE**[]{#__RefHeading___Toc125354220 .anchor}

The proposed use of sulfuryl fluoride is identical with respect to
occupational exposure to the previously assessed uses. Please see the
previous human health risk assessment for a discussion of occupational
exposure (M. Doherty, D309013, 10/12/04). For convenience, the estimates
from that assessment have been reproduced in Table 7.1, below.

+---------+---------+---------+---------+---------+---------+---------+
| Table   |         |         |         |         |         |         |
| 7.1.    |         |         |         |         |         |         |
| Occup   |         |         |         |         |         |         |
| ational |         |         |         |         |         |         |
| E       |         |         |         |         |         |         |
| xposure |         |         |         |         |         |         |
| MOEs    |         |         |         |         |         |         |
| for     |         |         |         |         |         |         |
| P       |         |         |         |         |         |         |
| roFume. |         |         |         |         |         |         |
| MOEs    |         |         |         |         |         |         |
| assume  |         |         |         |         |         |         |
| one     |         |         |         |         |         |         |
| fifth   |         |         |         |         |         |         |
| the     |         |         |         |         |         |         |
| ge      |         |         |         |         |         |         |
| ometric |         |         |         |         |         |         |
| mean    |         |         |         |         |         |         |
| e       |         |         |         |         |         |         |
| xposure |         |         |         |         |         |         |
| concent |         |         |         |         |         |         |
| rations |         |         |         |         |         |         |
| of 0.08 |         |         |         |         |         |         |
| ppm     |         |         |         |         |         |         |
| (fumi   |         |         |         |         |         |         |
| gators) |         |         |         |         |         |         |
| and     |         |         |         |         |         |         |
| 0.17    |         |         |         |         |         |         |
| ppm     |         |         |         |         |         |         |
| (tent   |         |         |         |         |         |         |
| w       |         |         |         |         |         |         |
| orkers) |         |         |         |         |         |         |
| det     |         |         |         |         |         |         |
| ermined |         |         |         |         |         |         |
| from    |         |         |         |         |         |         |
| str     |         |         |         |         |         |         |
| uctural |         |         |         |         |         |         |
| fum     |         |         |         |         |         |         |
| igation |         |         |         |         |         |         |
| studies |         |         |         |         |         |         |
| with    |         |         |         |         |         |         |
| Vikane, |         |         |         |         |         |         |
| and an  |         |         |         |         |         |         |
| A       |         |         |         |         |         |         |
| ctivity |         |         |         |         |         |         |
| Factor  |         |         |         |         |         |         |
| of 2.   |         |         |         |         |         |         |
| The     |         |         |         |         |         |         |
| 5-fold  |         |         |         |         |         |         |
| re      |         |         |         |         |         |         |
| duction |         |         |         |         |         |         |
| factor  |         |         |         |         |         |         |
| is due  |         |         |         |         |         |         |
| to      |         |         |         |         |         |         |
| diff    |         |         |         |         |         |         |
| erences |         |         |         |         |         |         |
| in      |         |         |         |         |         |         |
| reentry |         |         |         |         |         |         |
| concent |         |         |         |         |         |         |
| rations |         |         |         |         |         |         |
| (5 ppm  |         |         |         |         |         |         |
| for     |         |         |         |         |         |         |
| Vikane  |         |         |         |         |         |         |
| vs. 1   |         |         |         |         |         |         |
| ppm for |         |         |         |         |         |         |
| Pr      |         |         |         |         |         |         |
| oFume). |         |         |         |         |         |         |
| MOEs    |         |         |         |         |         |         |
| are     |         |         |         |         |         |         |
| rounded |         |         |         |         |         |         |
| down to |         |         |         |         |         |         |
| 2       |         |         |         |         |         |         |
| sign    |         |         |         |         |         |         |
| ificant |         |         |         |         |         |         |
| f       |         |         |         |         |         |         |
| igures. |         |         |         |         |         |         |
| Values  |         |         |         |         |         |         |
| from M. |         |         |         |         |         |         |
| D       |         |         |         |         |         |         |
| oherty, |         |         |         |         |         |         |
| D       |         |         |         |         |         |         |
| 309013, |         |         |         |         |         |         |
| 10      |         |         |         |         |         |         |
| /12/04. |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Work    | Sho     |         | Int     |         | Lo      |         |
| A       | rt-Term |         | ermedia |         | ng-Term |         |
| ctivity |         |         | te-Term |         |         |         |
|         | (NOAEL  |         |         |         | (NOAEL  |         |
|         | = 100   |         | (NOAEL  |         | = 30    |         |
|         | ppm)    |         | = 30    |         | ppm)    |         |
|         |         |         | ppm)    |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
|         | Target  | Es      | Target  | Es      | Target  | Es      |
|         | MOE     | timated | MOE     | timated | MOE     | timated |
|         |         | MOE     |         | MOE     |         | MOE     |
+---------+---------+---------+---------+---------+---------+---------+
| Fu      | 100     | 2100    | 100     | 650     | 300     | 650     |
| migator |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+
| Tent    | 100     | 1000    | 100     | 300     | 300     | 300     |
| Worker  |         |         |         |         |         |         |
+---------+---------+---------+---------+---------+---------+---------+

MOE = \[NOAEL  Animal Exposure Duration (6 hrs/day)  Animal Activity
Factor (1)\]  \[ Human Exposure Concentration  Human Exposure Duration
(8.6 hrs/day)  Human Activity Factor (2)\]

**8.0 DATA NEEDS AND LABEL REQUIREMENTS**[]{#__RefHeading___Toc125354221
.anchor}

**Toxicology**

-   None associated with this petition.

**Residue Chemistry Deficiencies**

-   HED believes that a total fluoride analysis method would resolve the
    method performance and the storage stability issues that came to
    light as a result of this and the previous petition, and recommends
    that the petitioner investigate and validate a total fluoride method
    using control and fumigated representative commodities from all crop
    groups and animal commodities (meat, fat, milk, eggs). HED further
    recommends that the petitioner consult with the Agency prior to
    initiating any such validation.

-   HED has not included dried eggs in dietary exposure and risk
    estimates associated with food fumigations, and is recommending that
    food fumigation of dried eggs be removed from the label section
    titled "Commodities That Can Be Fumigated." Dow AgroSciences has
    submitted a draft label making that change. Incidental treatment of
    dried eggs resulting from space fumigations may be permitted.

-   HED has not included edible oils in dietary exposure and risk
    estimates associated with food fumigations, and is recommending that
    the label be modified to state that edible oils may not be directly
    fumigated. Incidental treatment of edible oils resulting from space
    fumigations may be permitted.

-   As of 1/13/06, the Analytical Chemistry Laboratory had not received
    reference standards of either sulfuryl fluoride or a suitable
    fluoride salt. Due to the nature of sulfuryl fluoride, the
    laboratory is not requesting that a standard be submitted at this
    time; however, a suitable reference standard of a fluoride salt
    should be provided.

-   The previous risk assessment requested information regarding the
    transfer of fluoride from feedstuffs into livestock commodities. To
    date, HED has not received any such information.

-   The previous risk assessment also requested that the label be
    modified to specify that active aeration of at least 24 hours at not
    less than 1 chamber volume/min shall occur for all commodities prior
    to their entering commerce.

**Occupational and Residential Exposure**

-   None associated with this petition. Air monitoring data around
    fumigation sites have been received by the Agency but have not yet
    been reviewed.

  ------------------------------------------------------------------------------
  Table 8.1. Tolerance Summary for                              
  Sulfuryl Fluoride                                             
  ----------------------------------- ----------- ------------- ----------------
  Commodity                           Proposed    Recommended   Comments
                                      Tolerance   Tolerance     (correct
                                      (ppm)       (ppm)         commodity
                                                                definition)

  Flavorings, leavening agents        0.05        None          Covered under
  (except yeast), dry garlic, dry                               AAll processed
  onion, dry pepper, baking powder,                             food commodities
  baking soda                                                   not otherwise
                                                                listed.@

  Other herbs, spices, chili pepper   0.3         0.5           Herbs and
                                                                spices, group
                                                                19, postharvest

  Salt, sugars, high-fructose corn    0.02        None          Covered under
  syrup                                                         AAll processed
                                                                food commodities
                                                                not otherwise
                                                                listed.@

  Peanuts                             0.2         0.5           Peanut,
                                                                postharvest

  Coffee, cocoa beans                 0.8         See below     Separate
                                                                listings should
                                                                be made for
                                                                Coffee,
                                                                postharvest and
                                                                Cocoa bean,
                                                                postharvest

  Cocoa beans, postharvest            0.8         0.2           

  Coffee, postharvest                 0.8         1.0           

  Dried legume vegetables (beans,     0.02        0.5           Vegetables,
  peas, soybean, etc.)                                          legume, group
                                                                19, postharvest

  Powdered milk, powdered cheese      1.5         See below     Separate
                                                                listings should
                                                                be made for
                                                                milk, powdered
                                                                and cheese

  Cheese                              1.5         2.0           

  Milk, powdered                      1.5         2.0           

  All other processed foods           1.2         2.0           All processed
                                                                food commodities
                                                                not otherwise
                                                                listed

  Cattle, meat, dried                 0.01        0.01          

  Coconut, postharvest                1.0         1.0           

  Egg                                 0.7         1.0           Eggs, dried

  Ginger, postharvest                 0.2         0.5           

  Ham                                 0.01        0.02          

  Nut, pine, postharvest              3.0         0.2           

  Rice, flour, postharvest            0.08        0.05          

  Grain, cereal forage, fodder, and   2.0         None          No data to
  straw, group 16, postharvest                                  support
                                                                tolerance

  Grass, forage, fodder, and hay,     2.0         None          No data to
  group 17, postharvest                                         support
                                                                tolerance

  Animal Feed                         2.0         None          Covered under
                                                                AAll processed
                                                                food commodities
                                                                not otherwise
                                                                listed.@
  ------------------------------------------------------------------------------

  ------------------------------------------------------------------------------
  Table 8.2. Tolerance Summary for                              
  Fluoride                                                      
  ----------------------------------- ----------- ------------- ----------------
  Commodity                           Proposed    Recommended   Comments
                                      Tolerance   Tolerance     (correct
                                      (ppm)       (ppm)         commodity
                                                                definition)

  Flavorings, leavening agents        8           None          Covered under
  (except yeast), dry garlic, dry                               AAll processed
  onion, dry pepper, baking powder,                             food commodities
  baking soda                                                   not otherwise
                                                                listed.@

  Other herbs, spices, chili pepper   70          70            Herbs and
                                                                spices, group
                                                                19, postharvest

  Salt, sugars, high-fructose corn    2           None          Covered under
  syrup                                                         AAll processed
                                                                food commodities
                                                                not otherwise
                                                                listed.@

  Peanuts                             13          15            Peanut,
                                                                postharvest

  Coffee, cocoa beans                 12          See below     Separate
                                                                listings should
                                                                be made for
                                                                Coffee,
                                                                postharvest and
                                                                Cocoa bean,
                                                                postharvest

  Cocoa beans, postharvest            12          20            

  Coffee, postharvest                 12          15            

  Dried legume vegetables (beans,     6           70            Vegetables,
  peas, soybean, etc.)                                          legume, group
                                                                19, postharvest

  Powdered milk, powdered cheese      3           See below     Separate
                                                                listings should
                                                                be made for
                                                                milk, powdered
                                                                and cheese

  Cheese                              3           5.0           

  Milk, powdered                      3           5.0           

  All other processed foods           70          70            All processed
                                                                food commodities
                                                                not otherwise
                                                                listed

  Cattle, meat, dried                 40          40            

  Coconut, postharvest                40          40            

  Egg                                 850         900           Eggs, dried

  Ginger, postharvest                 13          70            

  Ham                                 20          20            

  Nut, pine, postharvest              10          20            

  Rice, flour, postharvest            98          45            

  Grain, cereal forage, fodder, and   130         None          No data to
  straw, group 16, postharvest                                  support
                                                                tolerance

  Grass, forage, fodder, and hay,     130         None          No data to
  group 17, postharvest                                         support
                                                                tolerance

  Animal Feed                         130         None          Covered under
                                                                AAll processed
                                                                food commodities
                                                                not otherwise
                                                                listed.@
  ------------------------------------------------------------------------------

**9.0 REFERENCES**[]{#__RefHeading___Toc125354222 .anchor}

**OPP Documents**

Baetcke, K., Blondell, J., Burnam, W., Dellarco, V. L., Donohue, J., and
Hill, R. 11/18/2003. A Preliminary Evaluation of Articles Related to
Fluoride Cited by the Fluoride Action Network (FAN) as Objections to the
Sulfruryl Fluoride Pesticide Tolerance Rule.

Daiss, B. D274960. 5/15/01. Residential Risk from Dissipation of
Sulfuryl Fluoride after Structural Fumigation (62719-EUP-45).

Doherty, M. D309013. 10/12/04. Corrected Human Health Risk Assessment
for Sulfuryl Fluoride and Fluoride Anion Addressing the Section 3
Registration of Sulfuryl Fluoride Post-Harvest Fumigation of Stored
Cereal Grains, Dried Fruits and Tree Nuts and Pest Control in Grain
Processing Facilities. PP# 1F6312.

Doherty, M. D309015. 10/12/04. PP#1F06312 B Sulfuryl Fluoride. Section 3
Registration for the Post-harvest Fumigation of Stored Cereal Grains,
Dried Fruits, and Tree Nuts, and Fumigation of Grain Milling
Establishments. Corrected Summary of Analytical Chemistry and Residue
Data.

Doherty, M. D309014. 10/12/04. Corrected Chronic Dietary Exposure
Assessments for Sulfuryl Fluoride and Fluoride Anion, Addressing the
Section 3 Registration of Sulfuryl Fluoride on Stored Cereal Grains,
Grain Processing Facilities, Dried Fruits, and Tree Nuts. PP# 1F6312.

Doherty, M. D317730. 7/13/05. Sulfuryl Fluoride. Evaluation of the
Proposed Fumigation of Food Processing Establishments. Summary of
Analytical Chemistry and Residue Data. Petition Number 3F6573.

Doherty, M. D317731. 1/18/06. Sulfuryl Fluoride and Fluoride Chronic
Dietary Exposure Assessments for the Section 3 Registration of Sulfuryl
Fluoride as a Fumigant for Food Processing Facilities.

Kidwell, J. TXR No. 0052208. 10/31/03. Sulfuryl Fluoride - Second Report
of the Hazard Identification Assessment Review Committee.

**Open Literature**

CDC. 2001. Recommendations for Using Fluoride to Prevent and Control
Dental Caries in the United States. Centers for Disease Control and
Prevention, Recommendations and Reports. August 17, 2001 /
50(RR14);1‑42.

Institute of Medicine. 1997. Dietary Reference Intakes for Calcium,
Phosphorous, Magnesium, Vitamin D, and Fluoride. Institute of Medicine.
National Academy of Sciences. National Academy Press. Washington, DC.

IRIS Database. Fluorine (soluble fluoride). Entry No. 0053. Search Date:
12/9/03 http://www.epa.gov/iris/subst/0053.htm

Medical Research Council. 2002. *Water fluoridation and health*. Medical
Research Council, London.

National Research Council. 1993. *Health Effects of Ingested Fluoride*.
National Academy Press, Washington D.C.

NHS CRD. 2000. A Systematic Review of Public Water Fluoridation (CRD
Report No. 18). NHS Centre for Review and Dissemination, University of
York, York, UK. Available at http://www.york.ac.uk/inst/crd/fluorid.htm

U.S. Dept. of Health and Human Services, Agency for Toxic Substances and
Disease Registry. 2002. *Toxicological Profile for Fluorides*. U.S.
Government. Printing Office.

World Health Organization. 2002. *Fluorides. Environmental Health
Criteria 227.* World Health Organization, Geneva.

cc: M. Doherty (RAB2)

Attachments: Waiver of Rat Developmental Neurotoxicity Study with
Sulfuryl Fluoride.

**APPENDIX I - Risk Estimates for Development of Skeletal Fluorosis
Based on Institute of Medicine Toxicological
Findings**[]{#__RefHeading___Toc125354223 .anchor}

The Institute of Medicine of the National Academies (IOM) published, in
1997, dietary reference intakes for calcium, phosphorus, magnesium,
vitamin D, and fluoride. Their examination of the available data
identified a NOAEL of 10 mg/day as relates to fluoride intake and
skeletal fluorosis. They further point out that exposures of 10 or more
years are required to develop this condition and focus their attention
on people greater than 8 years of age. OPP has included all age groups
in its assessment for the sake of completeness. The IOM analysis results
in a tolerable upper intake level of 10 mg/day for children (\> 8 years
old) and adults, including pregnant or lactating females. In deriving
their recommended upper limit for exposure, the Institute used an
uncertainty factor of 1, noting that the NOAEL is derived from human
studies and that symptomatic skeletal fluorosis is not observed at
intakes of 10 mg/day. As noted in the general discussion of fluoride
toxicity, the FQPA safety factor can be reduced to 1X; therefore, the
cPAD for skeletal fluorosis based on the IOM analysis is 10 mg/day. Due
to the constraints of the chronic dietary exposure model output, HED has
included children aged 6-12 in this assessment even though such a group
includes people too young to develop skeletal fluorosis.

When the dietary and non-dietary exposure estimates summarized in
Section 5 are compared to the IOM-based toxicological threshold, the
risk estimates are slightly less (ranging from 14 to 33% cPAD; Table
I-2) than those that are based on the RfD (17 to 41% RfD; Table 5.1).

  ----------------- --------- ----------- ------------ -------- ------- -------
  Table I-2.                                                            
  Aggregate                                                             
  Exposure and Risk                                                     
  Estimates for                                                         
  Skeletal                                                              
  Fluorosis Based                                                       
  on Analysis by                                                        
  the Institute of                                                      
  Medicine of the                                                       
  National                                                              
  Academies.                                                            

  Population        RfD,      Estimated                                 Risk, %
  Subgroup          mg/day    Fluoride                                  of RfD
                              Exposure by                               
                              Source,                                   
                              mg/day                                    

                              Dietary     Toothpaste   Air      Total   

  U.S. Population   10        3.075       0.3          0.0420   3.417   34
  (total)                                                               

  All infants (\< 1 10        1.152       0.3          0.0133   1.465   15
  year)                                                                 

  Children 1-2 yrs  10        1.060       0.3          0.0260   1.386   14

  Children 3-5 yrs  10        1.586       0.3          0.0264   1.912   19

  Children 6-12 yrs 10        1.890       0.3          0.0280   2.218   22

  Youth 13-19 yrs   10        1.975       0.3          0.0420   2.317   23

  Adults 20-49 yrs  10        2.742       0.3          0.0420   3.084   31

  Adults 50+ yrs    10        2.680       0.3          0.0420   3.022   30

  Females 13-49 yrs 10        2.239       0.3          0.0366   2.576   26
  ----------------- --------- ----------- ------------ -------- ------- -------

**APPENDIX II - Risk Estimates for Development of Dental
Fluorosis**[]{#__RefHeading___Toc125354224 .anchor}

At this time, based on the information available to the Agency, EPA is
not concluding that dental fluorosis associated with fluoride exposure
is an adverse health effect under the FFDCA. The current arguments that
dental fluorosis is more than a cosmetic effect are not sufficiently
persuasive to warrant regulation as an adverse health effect under the
FFDCA. Accordingly, consistent with the action taken by the Office of
Water under the Safe Drinking Water Act, 40 FR 47142 (November 14, 1985)
(WH‑FRL‑2913‑8(b)), the Agency believes that the appropriate endpoint
for regulation under the FFDCA is skeletal fluorosis.

While the tolerance safety determination under the FFDCA is a health
based standard, FIFRA requires the balancing of all costs, taking into
account the economic, social, and environmental effects as well as
health based risks, against the benefits associated with the pesticide
use. Therefore, the Agency will consider dental fluorosis in determining
whether sulfuryl fluoride meets the requisite standard under FIFRA.

The Agency, through the Office of Water, has set a Secondary MCL (SMCL)
for fluoride at 2 ppm. This SMCL is set to be protective against
moderate to severe dental fluorosis. Therefore, at exposures from 2 ppm
fluoride in water, and assuming a source contribution of 100% from
water, dental fluorosis in the moderate-to-severe category is not
expected to occur; dental fluorosis in the mild-to-moderate category may
occur. HED notes that the EPA=s Integrated Risk Information System
(IRIS) lists an oral RfD of 1 ppm fluoride in water for dental fluorosis
(IRIS Database). That RfD is based on a NOEL of 1 ppm with an LOEL of 2
ppm and no modifying or uncertainty factors since the effect was noted
in a sensitive population and the duration of exposure was appropriate
for the effect and the population. The information in IRIS supports the
SMCL of 2 ppm given that mild dental fluorosis is a cosmetic effect. In
addition to findings by the Agency, the Institute of Medicine of the
National Academies (IOM) has published Tolerable Upper Intakes for
fluoride as relates to dental fluorosis. The Agency=s SMCL and the IOM
values are presented on a mg/day basis in Table II-1.

  ------------------------- ----------------- ----------- ----------------
  Table II-1. Reference                                   
  Exposure Levels used to                                 
  Estimate Risk of                                        
  Developing Dental                                       
  Fluorosis.                                              

  Population Subgroup       Water             SMCL,       Tolerable Upper
                            Consumption,      mg/day\*    Intake, mg/dayH
                            L/day                         

  All Infants (\<1 year)    1                 2           0.7

  Children 1-2 years        1                 2           1.3

  Children 3-5 years        1                 2           1.9

  Children 6-12 years       1                 2           2.2
  ------------------------- ----------------- ----------- ----------------

\* SMCL (mg/day) = SMCL (mg/L)  Water Consumption (L/day).

H Tolerable Upper Intake from Institute of Medicine, Food and Nutrition
Board. Dietary reference intakes for calcium, phosphorus, magnesium,
vitamin D and fluoride. Report of the Standing Committee on the
Scientific Evaluation of Dietary Reference Intakes. Washington, DC:
National Academy Press, 1997. Values have been matched to the listed age
groups using a weighted average.

HED has not estimated risks for dental fluorosis for population
subgroups greater than 12 years of age. Dental fluorosis is an effect
that occurs prior to eruption of the teeth, at the time that the tooth
enamel is being formed. In evaluating dental fluorosis, the National
Academy of Sciences and the Office of Water use age cutoffs of 8 years
and 9 years, respectively, as ages above which it is not appropriate to
assess this effect. In this assessment, HED has used a maximum age of 12
years due to the population grouping of the exposure modeling software.

The risk estimates for dental fluorosis are presented in Table II-2.
They are based on the aggregate exposure assessment discussed in Section
5 of this document. The use of both the SMCL and the Tolerable Upper
Intake values provides a range of risk estimates for each population
subgroup. Both estimates should be considered when looking at the
potential for fluoride exposures to result in dental fluorosis.

+--------------+-------------+-------+----------+---------+----------+
| Table II-2.  |             |       |          |         |          |
| Aggregate    |             |       |          |         |          |
| Exposure and |             |       |          |         |          |
| Risk         |             |       |          |         |          |
| Estimates    |             |       |          |         |          |
| for Dental   |             |       |          |         |          |
| Fluorosis.   |             |       |          |         |          |
+--------------+-------------+-------+----------+---------+----------+
| Population   | Aggregate   | SMCL, | \% of    | To      | \% of    |
| Subgroup     | Exposure,   | m     | SMCL     | lerable | T        |
|              | mg/day      | g/day |          | Upper   | olerable |
|              |             |       | (without | Intake, | Upper    |
|              | (without    |       | too      | mg/day  | Intake   |
|              | toothpaste) |       | thpaste) |         |          |
|              |             |       |          |         | (without |
|              |             |       |          |         | too      |
|              |             |       |          |         | thpaste) |
+--------------+-------------+-------+----------+---------+----------+
| All infants  | 1.465       | 2     | 73 (58)  | 0.70    | 209      |
| (\< 1 year)  | (1.165)     |       |          |         | (166)    |
+--------------+-------------+-------+----------+---------+----------+
| Children 1-2 | 1.386       | 2     | 69 (54)  | 1.30    | 107 (84) |
| yrs          | (1.086)     |       |          |         |          |
+--------------+-------------+-------+----------+---------+----------+
| Children 3-5 | 1.912       | 2     | 96       | 1.90    | 101      |
| yrs          |             |       |          |         |          |
+--------------+-------------+-------+----------+---------+----------+
| Children     | 2.218       | 2     | 111      | 2.20    | 101      |
| 6-12 yrs     |             |       |          |         |          |
+--------------+-------------+-------+----------+---------+----------+

Based on the SMCL values, risks slightly exceed HED=s level of concern
for children aged 6 to 12 years old. When risk estimates are based on
the Institute of Medicine=s Tolerable Upper Intake values, those
estimates indicate that there may be concern for infants. The exposure
estimates for the Aall infants@ group includes exposure from fluoridated
toothpaste. Provided parents follow the recommendations of the American
Academy of Pediatric Dentistry that fluoridated toothpaste not be
introduced into oral hygiene until children are at a minimum of 2 years
old, the aggregate exposure estimates presented in Table II-2 represent
an overestimate of exposure. Exposure and risk estimates without
toothpaste are included parenthetically in the table for populations
less than 2 years old. We note that dental fluorosis which occurs in the
infant population subgroup will be to their deciduous teeth[^7].
Therefore, the risk estimate of 209% (166% without toothpaste) of the
Tolerable Upper Intake does not pertain to fluorosis of the permanent
teeth. Given the assumptions in the exposure assessments and the range
of numbers presented in Table II-2, HED does not believe that these risk
estimates warrant critical concern regarding development of
objectionable dental fluorosis.

Attachment 1. Waiver of Rat Developmental Neurotoxicity Study with
Sulfuryl Fluoride.

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

April 22, 2004

MEMORANDUM

SUBJECT: Waiver Justification of Inhalation Rat Developmental
Neurotoxicity Study

With Sulfuryl Fluoride

FROM: Vicki L. Dellarco, Ph.D., Senior Science Advisor

Karl Baetcke, Ph.D., Senior Scientist

Health Effects Division

Office of Pesticide Programs

THRU: Margaret Stasikowski, Director

Health Effects Division

Office of Pesticide Programs

TO: Lois Rossi, Director

Registration Division

Office of Pesticide Programs

We have conducted a review of the waiver justification submitted by Dow
AgroSciences for the sulfuryl fluoride inhalation rat developmental
neurotoxicity study (DNT). DOW requested this waiver on the basis of:

-   Essentially no chronic dietary exposure

-   Minimal potential inhalation exposures or short duration (1-2 days)

-   Animal welfare concerns (1500 to 4000 animals)

-   Potentially confounded scientific and technical aspects of
    conducting an inhalation DNT

Also, Dow indicated in their waiver justification that they recently
conducted a rat metabolism study that showed sulfuryl fluoride is
rapidly release to fluoride. Thus, given the known toxicology of
fluoride coupled with the minimal inhalation exposure to humans,
neurotoxicity to the adult or developmental neurotoxicity would be
highly unlikely.

It is important to evaluate the merit of this rat DNT study from a risk
perspective that considers realistic circumstances of human exposure.
Therefore, we are in agreement with Dow's scientific arguments
concerning the minimal potential for human exposure and the unlikelihood
that neurotoxicity or developmental neurotoxicity would occur due to
dietary exposure or inhalation exposure to sulfuryl fluoride.
Furthermore, a composite uncertainty factor (UF) of 1000 (rather than
the standard 100X) is applied and will be retained to account for
uncertainties inherent in the extrapolation from laboratory animal data
to humans (10X), variations in sensitivity among members of the human
population (10X), and for the lack of a DNT (10X) in the sulfuryl
fluoride risk assessment. Thus, there is an ample level of protection
built into the risk assessment.

cc: Michael Doherty

Dennis McNeilly

Jess Rowland

Karen Whitby

[^1]: Dietary reference intakes for calcium, phosphorus, magnesium,
    vitamin D and fluoride. Report of the Standing Committee on the
    Scientific Evaluation of Dietary Reference Intakes. Washington, DC:
    National Academy Press, 1997.

[^2]: U.S.EPA, Structural fumigation using sulfuryl fluoride:
    DowElanco=s Vikane ^TM^ Gas Fumigant, Methyl bromide alternative
    case study, Part of EPA 430-R-021, 10 Case studies, volume 2,
    December 1996, p. 3. Available at
    http://www.epa.gov/spdpublc/mbr/sulfury2.html.

[^3]: U.S.EPA, Reregistration Eligibility Decision (RED); Sulfuryl
    fluoride, 1993, p. 9.

[^4]: U.S. EPA, Structural fumigation using sulfuryl fluoride:
    DowElanco=s Vikane ^TM^ Gas Fumigant, Methyl bromide alternative
    case study, Part of EPA 430-R-021, 10 Case studies, volume 2,
    December 1996, p. 3. Available at
    http://www.epa.gov/spdpublc/mbr/sulfury2.html.

[^5]: Dietary reference intakes for calcium, phosphorus, magnesium,
    vitamin D and fluoride. Report of the Standing Committee on the
    Scientific Evaluation of Dietary Reference Intakes. Washington, DC:
    National Academy Press, 1997.

[^6]: For guidance on the public notice regulations, the reader is
    referred to the "Public Notification Handbook" at
    [www.epa.gov/safewater/pws/pn/handbook.pdf](http://www.epa.gov/safewater/pws/pn/handbook.pdf).

[^7]: Centers for Disease Control. \"Recommendations for Using Fluoride
    to Prevent and Control Dental Caries in the United States\".
    http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5014a1.htm.