Chlorothalonil Response to Comments DP# 402499

Page 3 of 21 Syngenta Comment: As previously noted, all Tuffcide products (antimicrobial uses) have been requested to be cancelled: Tuffcide 404 (EPA Reg No. 50534

- 115), Tuffcide 404 MUP (EPA Reg No. 50534

- 228), Tuffcide 500 (EPA Reg No. 50534

- 197), Tuffcide 960 (EPA Reg No.
50534

- 114)

, and Tuffcide 960 MUP (EPA Reg No. 50534

- 227).

HED’s Response: As noted above, during Registration Review, all registered uses of chlorothalonil will be reviewed. The Agency is aware that GB Bioscienc es is in the process of removing antimicrobial uses from their technical formulations. A final review of currently registered labels/end

- use products will be performed during Registration Review. These use patterns may still be included in the final asse ssment since there are other technical and end

- use registrants with antimicrobial uses of chlorothalonil.

Comments Related to Hazard Assessment

Comment #

4 from CA Rural Legal Assistance Foundation Concerning the Inhalation Toxicity Endpoint, Uncertainty Factors, and Required Studies:
We concur with the conclusion of RAB1 and the HED Science Advisory Board that using an oral endpoint may underestimate health risk by the inhalation route and that instead the lowest
observed adverse effect level from the acu te inhalation toxicology study should be used with appropriate uncertainty factors to assess acute, short

- term and intermediate term inhalation risks until valid short and intermediate toxicity studies are obtained. Because of this uncertainty regarding i nhalation toxicity, there is an urgent need for the Agency to set the FQPA safety
factors at 3X for acute and 30X for repeat exposures for both residential and occupational

exposures. Acute neurotoxicity, immunotoxicity, endocrine disruption, and reproduc tive health studies should also be required and additional uncertainty factors should be utilized in the
interim.

HED’s Response: The Agency did use interim FQPA safety factors of 3X and 30X for acute and repeated inhalation exposure scenarios, respective ly, in addressing the uncertainty associated with extrapolating toxicity findings from an acute toxicity study to longer exposure durations. Similar database uncertainty factors were applied to anticipated occupational scenarios. The toxicity database fo r chlorothalonil via the oral route of exposure is considered adequate and thus
additional uncertainty factors are not warranted. The database includes multiple developmental
and multi

- generation reproductive toxicity studies. Further, the pending data r equirements consisting of acute neurotoxicity and immunotoxicity studies are not expected to impact the current risk assessment based on what is known about the toxicology and mode of action of
chlorothalonil via the oral route of administration. Moreover , the uncertainty regarding inhalation toxicity does not necessarily translate to uncertainty via other routes of exposure such as oral or dermal, particularly because the toxicity via the inhalation route is based on portal of entry effects. It should al so be noted that the primary r egistrant for chlorothalonil has recently submitted to the Agency an immunotoxicity study and is actively working on addressing the current data gaps in the toxicity database, including the repeated inhalation exposure toxicit y study. In regards to endocrine disruption, chlorothalonil was among the group of pesticide active ingredients on the initial list to be screened under the Endocrine Disruptor Screening Program (EDSP) . The Agency will review all the available scientific ally relevant information for chlorothalonil during the registration review process.

Comment #

5 from PANNA Concerning the Inhalation Route of Exposure, Uncertainty Factors, and Required Studies: The Agency is currently considering updates in risk assessment that will improve the ability toChlorothalonil Response to Comments DP# 402499

Page 4 of 21 accurately assess the potential for harm, which is a promising direction. We urge the Agency to consider the “on the ground” evidence collected by citizen scie ntists and submitted in the
PAN NA report Pesticide Drift Monitoring in Minnesota. In our report, the air monitoring data indicates that residents living adjacent to areas of chlorothalonil application were exposed to low doses of chlorothalonil vapor in t he air over extended periods of time throughout the summer. Using evidence from oral ingestion studies for risk assessment of chlorothalonil is likely to result in underestimating health risk by inhalation, as absorption occurs differently through these t wo routes of exposure. The current studies used for risk assessment take into account oral ingestion endpoints or acute inhalation exposure, but do not account for the low

- dose exposure that residents in our report seem likely to encounter. Further, the studies utilized for inhalation risk assessment are based on inhalation of chlorothalonil as a dust or aerosol, which is inhaled less deeply than vapor. As the effects of long

- term, low

- dose exposure to chlorothalonil in vapor form are not known, our repo rt provides on the ground evidence of an exposure route that is not currently considered in risk assessment.

The lowest observed adverse effect level should be used with uncertainty factors that take into account acute, short

- term, and intermediate inhala tion risks until further studies are obtained. We encourage the Agency to also consider using uncertainty factors for long

- term, low

- dose exposures to chlorothalonil vapor, as that is the type of exposure Minnesota residents encountered in our report. As the toxicity of inhaled chlorothalonil has not been accurately assessed, we urge the Agency to set the FQPA safety factors at 3X for acute and 30X for repeat exposures for residential and occupational exposures. Workers may also be exposed to long

term low doses via inhalation during their workday. Additional uncertainty factors should be used until further studies are obtained for acute neurotoxicity, immunotoxicity, endocrine disruption, and reproductive health studies.

HED’s Response: In characteriz ing inhalation risk associated with chlorothalonil, the Agency used measurements of air concentrations available from several air monitoring studies that are
considered a good representation of actual human exposures to chlorothalonil. These air

concentra tions were used to assess acute (1 day), short

- term (1

- 30 days), and intermediate

- term (1

- 6 months) exposures. Average air concentrations were used for the intermediate

- term assessment; making a health

- protective assumption that a person could be exposed to the same air concentration every day for up to 6 months. Furthermore, different human equivalent
inhalation concentrations were estimated from the same animal acute inhalation point of departure that account for different conservative daily and weekly exposure duration adjustments (e.g., 24 hours/day, 7 days/week exposures was assumed for bystanders)

. Because of the conservative nature of the assumptions made in the hazard and exposure databases regarding inhalation exposures to chlorothalonil , no addi tional uncertainty factors are warranted at this
time

. The toxicity database for chlorothalonil via the oral route of exposure is considered adequate and the pending database requirements are not expected to impact the current risk
assessment based on wha t is known about the toxicology and mode of action of chlorothalonil via the oral route of exposure.

Comment #

6 from Syngenta Concerning the Inhalation Acute Toxicity Category: On Page 1 and 2, EPA states : “Based on acute toxicity studies, chlorothalonil is highly toxic via the inhalation route of exposure (Category I). There was a high level of lethality reported in the critical acute inhalation toxicity study (LC50 = 0.032 [M] and 0.013 [F] mg/L).”

Syn genta Comment: Syngenta would like to point out that prior to the 23

- Dec 2010 Draft HED Human Health Risk Assessment (Memo, G. Kramer et al., 12/23/10, D370486), chlorothalonilChlorothalonil Response to Comments DP# 402499

Page 5 of 21 was categorized by EPA as an acute inhalation toxicity Category II. The refer ence to chlorothalonil as an acute inhalation toxicity Category I is based on a single study conducted in 1993 (Holbert, 1993) with a reported LC50 of <0.05 mg/L. The material used in this study was a
chlorothalonil technical material that was milled into very fine particles (>30% were <1.1 micron) at the lowest exposure level, maximizing particle respiration well beyond what could
occur in actual use scenarios. An extremely wide range of LC50 values have been reported in acute inhalation toxicity studies on chlorothalonil technical materials including 2.32 mg/L (Doig, 2011), >0.09 mg/L (Shults, 1981 and Shults, 1993), which would result in acute inhalation toxicity Categories of III and II, respectively. The primary purpose of the acute inhalation
toxici ty test is to estimate a lethal concentration (LC50) value of a substance. The Holbert (1993) study included four concentration levels in male and female rats as part of the method of calculating an LC50 value. It was part of the study design to intentio nally produce test atmospheres with 25% of the particle mass consisting of particles less than 1 micron diameter. The study also reported observational information (clinical signs and gross necropsy findings) which are not typically col lected in a consiste nt or well

- standardized way in this type of study. The Holbert 1993 study cannot be considered as representative of the acute inhalation toxicity
database for chlorothalonil. Syngenta believes that it is inaccurate to refer to chlorothalonil as a Categor y I based on the results of a single study with results that have not been reproduced and that there is no reason why this study (Holbert, 1993) should be considered as “the critical acute inhalation toxicity study” for chlorothalonil.

HED’s Response: The Agency compiled all the available acute inhalation toxicity studies for chlorothalonil and used a weight

- of

- evidence approach before re

- evaluating the acute inhalation toxicity category. The compiled acute inhalation toxicity studies were performed with either the milled/unmilled technical product or diluted/undiluted end

- use product formulations. The Holbert 1993 study was selected on the basis that it meets all of the guideline requirements for an acute inhalation toxicity study, produced a well

- define d dose response relationship, tested the lowest inhalation concentrations of chlorothalonil from the available inhalation studies, and was in line with the findings noted in the other acute inhalation toxicity studies.

Comment # 7 from Syngenta Concerning the Inhalation Acute Toxicity Studies: On Page 1, paragraph 2, EPA states : “The lack of a no

- observed adverse

- effect level (NOAEL) in several acute inhalation toxicity studies carried out with technical

- grade chlorothalonil or end

use product formulations is also a concern.”

Syngenta Comment: Syngenta would like to point out that a large degree of variation exists among acute inhalation toxicity studies, which are typically used for calculating lethal
concentrations of chemical substances and have wide ly ranging reporting styles and content for nonlethal acute toxicity data. Chlorothalonil has irritant properties, indicating the ability to react on contact with sulfhydryl groups in mucosal tissues. For substances with contact irritant properties, it w ould be expected that it may be difficult to find a concentration that would not produce any irritation whatsoever. It is not appropriate to use acute inhalation toxicity studies to identify a NOAEL based on non

- lethal toxicity endpoints, which are not ev aluated consistently or using specific guidelines in these tests. It is even less appropriate to use an acute inhalation toxicity study, to determine a NOAEL for a substance with severe irritation properties because exposure levels typically selected in t hese studies are expected to be above the maximum
tol erated dose (MTD) or perilethal. The variable collection of data and qualitative nature of the reported observations (clinical signs) do not make this study suitable for reproducible evaluation
of non

- l ethality toxicity endpoints, especially at low exposure concentrations.Chlorothalonil Response to Comments DP# 402499

Page 6 of 21 HED’s Response: The Agency evaluated the totality of the toxicity information available for chlorothalonil and noted that only a route

- specific inhalation study would be adequate for risk characterization via the inhalation route of exposure. The Agency is fully aware that an acute toxicity study is not ideal for extrapolating findings to longer durations or establishing a NOAEL. However, in the absence of an appropriate study, the Agency used the best available information with appropriate uncertainty factors to account for deficiencies including extrapolation to longer exposure durations. The clinical signs reported in the Holbert 1993 study
are consistent with other acute inhalat ion toxicity studies available for chlorothalonil. The qualitative nature of the reported clinical signs is not a basis for discounting the study since there
is a robust dose

- related dependency in severity and incidence rate , ultimately resulting in
letha lity.

Comment #

8 from Syngenta Concerning the Effects Noted in the Inhalation Acute Toxicity
Studies: On Page 1, paragraph 2, EPA states : “ Cli n i cal s i g ns cons i s t e n t wi t h r es pi r a t ory

- t r a c t i r r it ati o n ( i

. e

. , p o r t a l

- o f

- e n tr y e ff e c t s) i nc l u di ng n as a l d i sch a r g e, g as pi n g , d e c r e a sed a c t i v i t y , ptos i s, a n d
l e t h a r g y , w ere r e p o rt ed at a l l e x p o sure co n ce nt r ati o ns t ested acr o ss se v eral a c ute i n h a l ati o n

to x i c i t y s t u di es .”

Syngenta Comment: Syngenta would like to point out the error in this statement. In the cited study (Holbert, 1993), the reported clinical signs varied at each exposure concentration. At the lowest concentration tested, 0.00208 mg/L, the reported clinica l signs in males and females were piloerection (slight), activity decrease (slight), ptosis (slight), and respiratory gurgle (very slight). Nasal discharge and gasping were only reported beginning at the 0. 0226

- mg/L exposure
concentration.

HED’s Response : Because of the absence and/or “slight” nature of the clinical signs, the LOAEL from the Holbert 1993 study was classified as “minimal,” and only a 3X uncertainty factor was applied for extrapolating a NOAEL from a LOAEL. During registration review, the Agency will attempt to be clearer regarding the clinical signs observed at each inhalation exposure concentration tested.

Comment #

9 from Syngenta Concerning the Inhalation Endpoint Selection: On Page 1, paragraph 2, EPA states : “The effects of short

- and intermediate

- term inhalation exposures (portal

- of

- entry or systemic) have not been studied. In the absence of such information, HED recommends that the lowest

- observed adverse

- effect level (LOAEL) from the
critical acute inhalat ion toxicity study with appropriate uncertainty factors (UFs) be used as the point of departure (POD) to assess inhalation risks (acute, short

- , and intermediate

- term).”

Syngenta Comment: Syngenta does not agree that the Holbert, 1993 study is the critic al acute inhalation study, as discussed above. Syngenta does not believe that this study should be used as the POD to assess inhalation exposure risk in humans. However, if this study is to be used temporarily for a POD, in the absence of an appropriate toxicological endpoint for an inhalation exposure risk assessment, Syngenta believes that the clinical effects (piloerection, activity decrease, ptosis, very slight respiratory gurgle) observed at the lowest concentration (containing >30 % particles of <1. 1 micron diameter) were of such slight degree of severity that the addition
of an UF for lack of NOAEL is not warranted.

HED’s Response: The Agency selected the Holbert 1993 study to derive a temporary POD for inhalation exposures because there was no re peated inhalation exposure toxicity study availableChlorothalonil Response to Comments DP# 402499

Page 7 of 21 for chlorothalonil. When an appropriate inhalation study is submitted and reviewed by the Agency, the POD may change according to the findings of the study. For the Agency, the
addition of a 3X uncertai nty for lack of a NOAEL factor is warranted due to the high incidence rate of the clinical signs reported at the lowest concentration tested in both genders and the relative narrow gap between the lowest tested inhalation concentration (i.e., LOAEL) and th e LC50. The lowest concentration tested of 0.00208 mg/L is only 6.25

- fold less than the fitted LC50 of 0.013 mg/L for female rats, indicative of a potentially steep dose response curve from mild clinical signs to lethality. This steepness of the dose res ponse curve is also evident by gross pathology findings in the lungs suggesting pulmonary edema (increased weights and purple appearance) at the mid and high

- exposure levels tested. Some of the clinical signs seen at the
lowest concentration lasted for 1 day post

- exposure suggesting that repeated exposures may lead
to cumulative effects.

Comment #

10 from Syngenta Concerning the Inhalation Endpoint Selection: On Page 1, paragraph 2, EPA states : “ At this LOAEL, there were no deaths (male or female)
and the very slight to slight (severity) clinical signs of respiratory distress resolved after two days
post

- exposure. The use of this LOAEL that is based on mild portal

- of

- entry effects is likely to be protective against any systemic toxicity through the inhala tion route of exposure.”

Syngenta Comment: As stated above, if this study is to be used temporarily for a POD, in the absence of an appropriate toxicological endpoint for an inhalation exposure risk assessment, Syngenta believes that the clinical effects (piloerection, activity decrease, ptosis, very slight respiratory gurgle) observed at the lowest concentration (containing >30 % particles of <1.1 micron diameter) were of such slight degree (severity) that the addition of an UF for lack of
NOAEL is not w arranted. Furthermore, by taking this approach in order to protect against portal of entry effects, a new standard is set for acceptable risk that would be analogous to using an acute eye or skin irritation test as a POD for an exposure risk assessment, with additional uncertainty factors for not having a NOAEL. By taking this approach, the method of protecting against systemic toxicity is to lower exposure concentrations to levels that would not be expected to produce local irritation. This is not an approach to risk assessment that has been tested or
validated.

HED’s Response: In contrast to eye and skin irritation, which may not be related to systemic toxicity, the respiratory tract effects noted after inhalation exposure to chlorothalonil in the Holbert 1993 study (and other acute inhalation studies) seem to be directly related to lethality. This is evident by the increase in incidence and severity of the clinical signs with increasing levels of exposure and the relative short distance on the dose response curve between the lowest
concentration tested and th e estimated LC50, particularly in females (see above). Therefore, it is reasonable to assume that a POD based on the respiratory tract clinical signs would be protective of any potential systemic toxicity.

Comment #1 1 from Syngenta Concerning Submission of an Inhalation Study: On Page 1, paragraph 2, EPA states : “ If the registrant submits a subchronic inhalation study, with a subset of animals designed to identify the NOAEL for acute inhalation toxicity (i.e., after one day of exposure), then the current UFs may be reduced accordingly

. Therefore, HED
believes that the submission of a 90

- day inhalation study (with acute toxicity measurements) is
needed to refine the current residential risk assessments. Based on the lack of incident data
related to inhal ation effects and the fact that an acute inhalation toxicity study is being used to
assess short and intermediate

- term risk, the risk assessment can be characterized as
conservative.”Chlorothalonil Response to Comments DP# 402499

Page 8 of 21 Syngenta Comment: Syngenta agrees with Agency regarding the lack of in cident data and highly conservative risk assessment. Syngenta, on behalf of the chlorothalonil EDSP consortium, has expanded its role and presented a multi

- staged investigation of the acute inhalation toxicity potential of chlorothalonil that will be used to reduce the uncertainties in the
hazard database. EPA has agreed to this proposal and will receive a presentation of the preliminary data along with a protocol for a definitive inhalation study, anticipated to be available in 3Q 2012. Given that the c hlorothalonil consortium (EDSP) is currently developing data with a scientifically

- driven step

- wise proposal that will require iterative design and technical approaches, it should be reflected in the scoping document that the studies are under way to
devel op the toxicology data needed for the inhalation exposure risk assessment.

HED’s Response: The Agency acknowledges that Syngenta, the primary Registrant of chlorothalonil, is currently working to address the data needs for a more refined inhalation risk assessment associated with the uses of chlorothalonil as pesticide. All available data submitted to the Agency will be considered during Registration Review.

Comment #1 2 from Syngenta Concerning Dermal Sensitization: On Page 3, paragraph 3, EPA states : “ In the previous risk assessment, chlorothalonil was classified as not being a dermal sensitizer. However, a published literature study in mice and guinea pig ranks chlorothalonil as an extremely potent contact allergen, inducing sensitization using only topical exposures on intact skin.”

Syngenta Comment: Syngenta would like to point out that chlorothalonil technical material is not a dermal sensitizer according to standard tests; however, several Syngenta formulation products have tested positively as dermal sensitizers and are appropriately labeled in accordance with the safety testing.

HED’s Response: During the registration review process, the Agency will consider all of the available information including studies published in the peer review liter ature. A weight

- of

evidence approach will be used in any re

- evaluation of the current dermal sensitizing
classification.

Comment #1 3 from Syngenta Concerning Acute Inhalation Studies and Uncertainty Factors: On Page 4, paragraph 1, EPA states : “ There ar e only acute inhalation studies available for
chlorothalonil. Its classification for acute inhalation toxicity is Category I (combined LC50 = 0.020 mg/L). The non

- lethal effects reported in acute studies even at the lowest concentration tested (i.e., no NOAEL attained) consist of clinical signs indicative of respiratory

- tract effects including nasal discharge, gasping/difficulty breathing, decreased activity/lethargy, respiratory rates/gurgle, ptosis, and piloerection. The effects of short

- and intermedi ate

- term inhalation exposures (portal

- of

- entry or systemic) have not been studied and justify retaining the FQPA SF at 10X for repeated exposure scenarios. Since there is no NOAEL available for any of the available acute inhalation studies, but the report ed portal

- of

- entry effects were relatively mild at the LOAEL for the critical study, an additional 3X factor should be added to all exposure scenarios, resulting in an overall FQPA SF of 3X and 30X for acute and repeated inhalation exposures, respectively. ”

Syngenta Comment: As stated above, Syngenta does not feel that it is appropriate to classify chlorothalonil technical as Category I acute inhalation toxicity based on there being a wide range of reported LC50 values among chlorothalonil technical material acute inhalation toxicity studies that have been accepted by EPA. The Category I is based on a single study conducted in 1993Chlorothalonil Response to Comments DP# 402499

Page 9 of 21 (Holbert, 1993) with a reported LC50 of <0.05 mg/L. The material used in this study was a
chlorothalonil tec hnical material that was milled into very fine particles (>30% were <1.1 micron) at the lowest exposure level, maximizing particle respiration well beyond what could occur in actual use scenarios. Also, Syngenta would like to point out the error in this s tatement. In the study that is referred to (Holbert, 1993), the reported clinical signs varied at each exposure concentration. At the lowest concentration tested, 0.00208 mg/L, the reported clinical signs in males and females were piloerection (slight), activity decrease (slight), ptosis (slight), and respiratory gurgle (very slight). Nasal discharge and gasping were only reported beginning at the 0.0226 mg/L exposure concentration. Syngenta does not agree that the Holbert, 1993 study is
the critical ac ute inhalation study, as discussed above, and Syngenta does not believe that this study should be used to assess inhalation exposure risk in humans. However, if this study is to be used temporarily, in the absence of an appropriate toxicological endpoint for an inhalation exposure risk assessment, Syngenta believes that the clinical effects (piloerection, activity decrease, ptosis, very slight respiratory gurgle) observed at the lowest concentration (containing >30 % particles of <1.1 micron diameter) were of such slight degree (severity) that the addition of an UF for lack of NOAEL is not warranted. Furthermore, by setting the bar this low to protect against portal of entry effects with compounds that are known to produce acute irritation on

contact, a ne w standard is set on an acceptable hazard profile that would be analogous to using an acute eye or skin irritation test to set a LOAEL with additional UFs for an exposure risk assessment. By taking this approach, the method of protecting against systemic toxicity is to lower exposure concentrations to levels that would not be expected to product local irritation. This is not an approach to risk assessment that has been tested or validated.

HED’s Response: As noted in comment #10 above, in contrast to ey e and skin irritation, which may not be related to systemic toxicity, the respiratory tract effects noted after inhalation exposure to chlorothalonil in the Holbert 1993 study (and other acute inhalation studies) seem to be directly related to lethality. This is evident by the increase in incidence and severity of the clinical signs with increasing levels of exposure and the relative short distance on the dose response curve between the lowest concentration tested and the estimated LC50, particularly in
fe males (see above). Therefore, it is reasonable to assume that a POD based on the respiratory tract clinical signs would be protective of any potential systemic toxicity.

Comment #1 4 from Syngenta Concerning Immunotoxicity Study Requirement: On Page 10, E PA states : “ An immunotoxicity study is required as a part of new data requirements in the 40 CFR Part 158 for conventional pesticide registration.”

Syngenta Comment: Syngenta, on behalf of the chlorothalonil EDSP consortium, submitted the
chlorothalonil immunotoxicity study April 3, 2012. In this study, groups of CD

- 1 mice were exposed to chlorothalonil for 28

- days at dietary concentrations of 50, 750

, and 2000 ppm. At the highest dose tested (equivalent to 345 mg/kg/day), there was no evidence of an
i mmunosuppressive effect of chlorothalonil. The results of this study do not impact current risk

assessments.

HED’s Response: The Agency has received, but not reviewed the immunotoxicity study with chlorothalonil. During registration review, the Agency will include the findings of this and other pending studies submitted to the Agency.

Comment #1 5 from Syngenta Concerning Endocrine Disruption Study Requirement: On Page 11, EPA states : “ However, as required by FFDCA section 408(p), chlorothalonil is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP)

. ”Chlorothalonil Response to Comments DP# 402499

Page 10 of 21 Syngenta Comment: Syngenta, on behalf of the chlorothalonil EDSP consortium, has already submitted all of the mammalian EDSP studies, all of which have shown no endocrine effects. The remaining two EDSP tier 1 assays (AMA and FSTRA) are scheduled to be completed by October 3, 2012 (as per an approved time

- extension request).

HED’s Response: The Agency has received the EDSP Tier 1 mammalian assays. Once all th e data (mammalian and ecological) have been received and reviewed, the POD s and SF s used for risk assessment purposes will be examined and a new risk assessment performed if necessary. For further information on the status of the EDSP, the policies and pr ocedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website: http://www.epa.gov/endo/

.

Comments Related to Incident Reporting

Comment #1 6 from CA Rural Legal Assistance Foundation Concerning Analysis of Incident Reporting: We recommend further analysis of frequency and severity of human health incidents during registration review and note that the California pesticide illness database (Cal

- PIQ) includes 55 cases of possible to definite pesticide illness involving exposure to only chlorothalonil between 1992 and 2009. Several cases in this database add further support to the need to reconsider
chlorothalonil's dermal sensitization classification as illustrated in the attached table of California Chlorothalonil Pesticide Illnesses Involving Rashes. However, the many obstacles to reporting of pesticide illnesses, particularly among farmworkers, must be considered in interpreting a "lack
of inciden t data related to inhalation effects" alluded to in this proposal. In their 2008 study of pesticide illnes s incidence, Dr. Geoffrey Calvel i and other researchers delineated the many factors contributing to underreporting, including failure of affected wor kers to get medical care, seeking medical care in Mexico outside the U.S. surveillance system, misdiagnosis, and health provider lack of knowledge of symptoms of occupational exposure and their neglect of the duty to report, in the 30 states where reportin g is required (AJIM 2008: 51:883

- 898). They also note
that 76% of farmworker illnesses in Washington and 34% in California, the states with the most established surveillance systems, were identified through the workers' compensation system, and that Oreg on (7%) and Texas (4%) were the only other states identifying pesticide illnesses through workers' compensation. These researchers observed that in the NAWS 1999 survey, 1.4% of farmworkers interviewed attributed health effects to pesticide exposure from drift, spills, or cleaning and repair of pesticide equipment and containers, suggesting a rate of illness 20

- fold higher than found through surveillance.

HED’s Response: EPA agrees with CA Rural Legal Assistance Foundation that there should be
further an alysis of the frequency and severity of human

- health incidents during registration
review. As stated in the incident memo for chlorothal onil (S. Recore, 1/12/12, 2012,D397570), based on the frequency and severity of incident cases and AHS results, for chl orothalonil , these incident data may warrant further analysis in the preliminary risk assessment phase of Registration Review. As part of the further analysis for registration review other databases will be analyzed, including California’s Pesticide Illne ss Surveillance Program and NIOSH
SENSOR.

EPA understands that under

- reporting does occur and the incidents reviewed likely do not represent all exposures. However, incident information can be an important source of feedback to the Agency

– incidents of severe outcome, or a suggested pattern or trend among less severe incidents, can signal the Agency to further investigate a particular chemical or product.Chlorothalonil Response to Comments DP# 402499

Page 11 of 21 Comments Related to Residue Chemistry and Dietary Exposure Assessment

Comment #1 7 from Syngenta Concerning Dietary Exposure: On Page 4, EPA states: “ The most recent dietary exposure assessment was performed in conjunction with the December 2010 human

- health risk assessment conducted by HED in conjunction with a registration request fo r use on low

- growing berry subgroup 13

- 07G; bushberry subgroup 13

- 07B; onion, bulb subgroup 3

- 07A; and onion, green subgroup 3

- 07B (D370486, G. Kramer, et al.; 23

- Dec

- 2010). HED was unable to make a safety finding due to inhalation risks and the proposed uses were subsequently withdrawn.”

Syngenta Comment: Please note that because the IR

- 4 petition was withdrawn, the December 2010 assessment was neither finalized nor posted for public comment and therefore we believe it
should be referred to as a draft a ssessment. The most recent finalized dietary exposure assessment was completed in September 2008 (D353241, G. Kramer, et al.; 4

- Sept

- 2008).

HED’s Response: The 2010 risk assessment was finalized ( D370486, G. Kramer, et al .; 23

- DEC

- 2010)

.

Comment #1 8 from Syngenta Concerning Residue Chemistry and Tolerances: On Page 5, EPA states: “ The residue chemistry database is sufficient to support the current registrations. The following data requirement remains outstanding: multiresidue method recovery data fo r the 4

- hydroxy metabolite.

Syngenta Comment: In 1993, analytical and independent lab validation (ILV) methods for parent and the 4

- hydroxy metabolite were submitted to EPA (before the 1999 RED was issued). The MRID Number for the analytical method is 4 2875908 and for the ILV is 42875909.

HED’s Response: The studies cited by Syngenta address GLN 860.1340. The data gap cited by

HED concerns multiresidue method testing as specified in GLN 860.1360.

Comment #1 9 from Syngenta Concerning Residue Chemist ry Data Requirements: On Page 12, EPA states: “ The database does not contain any information for the 4

- hydroxy
metabolite. In the Chlorothalonil Residue Chemistry RED Chapter, the multiresidue method recovery data for chlorothalonil trichloro impurity we re incorrectly attributed to the 4

- hydroxy metabolite; see DP# 228522, W. Smith. Multiresidue method recovery data for the 4

- hydroxy metabolite thus remain outstanding. ”

Syngenta Comment: In 1993, analytical and independent lab validation methods for parent and
the 4

- hydroxy metabolite were submitted to EPA (before the 1999 RED was issued). The MRID Number for the analytical method is 42875908 and for the ILV is 42875909

.

HED’s Response: The studies cited by Syngenta address GLN 860.1340. The data gap cited by

HED concerns multiresidue method testing as specified in GLN 860.1360.

Comment #

20 from Syngenta Concerning Dietary Exposure Assessment: On Page 13, EPA states: “ The most recent dietary exposure and risk assessment was performed in conjunction with the December 2010 human

- health risk assessment conducted by HED (D370486 , G. Kramer, et al.; 23

- DEC

- 2010 ).”

Syngenta Comment: As previously noted, due to the IR

- 4 petition

- withdrawal, the HEDChlorothalonil Response to Comments DP# 402499

Page 12 of 21 December 2010 assessment was neither finalized nor posted for public comment and should therefore be referred to as a draft assessment. The most recent finalized dietary exposure assessment was completed in September 200 8 (D353241, G. Kramer, et al.; 4

- Sept

- 2008).

HED’s Response: The 2010 risk assessment was finalized ( D370486, G. Kramer, et al .; 23

- DEC

- 2010)

.

Comments Related to Residential Exposure Assessment

Comment #2 1 from Syngenta Concerning Residential Exposure and Current Use Pattern: On Page 5, EPA states : “ ....In the most recent risk assessment, inhalation risk concerns for the
short

- /intermediate

- term exposure durations were identified for residential handlers using treated paint, post

- application exp osure from inhaling vapors from treated paint, and for bystander volatilization inhalation exposure. ...With regard to the antimicrobial uses, there is potential for dermal and incidental oral exposure to pressure

- treated wood that is used in residential st ructures such as porches and steps.... It will also be necessary to reassess the paint uses and determine if the precautionary labeling strategy required by the RED is still valid or if paints containing
chlorothalonil should have labeling that can only be accomplished by having separate registrations for each paint product.”

Syngenta Comment: As noted previously, Syngenta (representative of GB Biosciences) has requested cancellation of all of their antimicrobial uses of chlorothalonil including uses in pa int formulations or in pressure

- treated wood.

HED’s Response: As noted above, during Registration Review, all registered uses of chlorothalonil will be reviewed. The Agency is aware that GB Biosciences is in the process of removing antimicrobial uses fr om their technical formulations. A final review of currently registered labels/end

- use products will be performed during Registration Review. These use patterns may still be included in the final assessment since there are other technical and end

- use
reg istrants with antimicrobial uses of chlorothalonil.

Comment #2 2 from Syngenta Concerning Residential Post

- application Inhalation Exposure for Golfers: On Page 14, paragraph 2, EPA states : “ Post

- application inhalation exposure was also identified
as a pote ntial exposure pathway for golfers on treated courses, but the residential bystander assessment was expected to cover those potential exposures.”

Syngenta Comment: The residential bystander assessment assumes that an individual is exposed
to the same air concentration for 24 hours per day. This is inconsistent with the exposure durations for residential golfers in the 2012 Residential SOPs which lists an exposure time of 4 hours per day for greens, tees and fairways for adults (2 hours per day for 5

- year old children) and 1 hour per day for greens and tees for adults. Although these duration assumptions are specifically listed for dermal exposure, the duration of inhalation exposure should be identical. Syngenta would also like to point out that there i s published air monitoring data available that specifically addresses chlorothalonil use on golf course turf; i.e.

, “Environmental fate of metalaxyl and chlorothalonil applied to a bentgrass putting green under southern California
climatic conditions

, ” L. Wu, et al

. , Pest. Manag. Sci., Vol 58, 2002, pg 33 5

- 342, and “Inhalation
health risk to golfers from turfgrass pesticides at three north

- eastern U.S. S tates, ” R. R. Murphy and D. A. Haith, Environ. Sci. Technol., Vol. 41, 2007, pg 1038

- 1043. Additional ai r monitoring
data for turf re

- entry workers is also available from the Agricultural Re

- entry Task ForceChlorothalonil Response to Comments DP# 402499

Page 13 of 21 ( ARTF ) study ARF057 for workers involved in high contact activities with chlorothalonil

- treated golf course turf. The potential exposure of residential golfers to air concentrations of chlorothalonil would be expected to be significantly less than that of golf course maintenance workers. Please see Appendix 3 for references to Syngenta’s comments on residential bystander
post

- application exposure.

HED’ s Response: The Agency acknowledges that the post

- application inhalation exposure
duration for golfers to chlorothalonil may be less than that assumed for residential bystanders. The Agency note s the references provided, and will review these as necessar y during Registration Review. The Agency is also aware of the ARTF data related to maintenance worker exposure on golf courses and will incorporate this data, as appropriate, during Registration
Review for chlorothalonil.

Comment #2 3 from Syngenta Concer ning Residential Exposure to Paints: On Page 14, EPA states : “ The residential exposure assessment included inhalation risk estimates for residential handlers using treated paint (Table A5.I), post

- application inhalation risk
estimates for residents from exposure to treated paint (Table A5.2), post

- application incidental oral risk estimates for incidental ingestion of paint chips by children (Table A5.3), and a residential bystander assessment to address potential volatilization of chlorothalonil from trea ted fields (Table A5.4). In that assessment, dermal risk was not quantified since no hazard was
identified via the dermal route for chlorothalonil.”

Syngenta Comment: Because Syngenta (representative of GB Biosciences) has requested
cancellation of the antimicrobial uses, there are no Syngenta products that would provide a potential for residential handler and post

- application dermal or inhalation exposure from antimicrobial uses of chlorothalonil including the use in treated paints.

HED’s Response: As noted above, during Registration Review, all registered uses of chlorothalonil will be reviewed. The Agency is aware that GB Biosciences is in the process of removing antimicrobial uses from their technical formulations. A final review of currently regi stered labels/end

- use products will be performed during Registration Review. These use patterns may still be included in the final assessment since there are other technical and end

- use registrants with antimicrobial uses of chlorothalonil.

Comment #2 4 from Syngenta Concerning Residential Post

- application Exposure to Pressure

Treated Wood: On Page 15, EPA states : “ There are three products (1022

- 584, 50534

- 115, 71581

- 2) that allow pressure treatment of wood.”

Syngenta Comment: As previously noted, Syng enta (representative of GB Biosciences) has requested the cancellation of antimicrobial uses of chlorothalonil including Tuffcide 404 (EPA Reg No. 50534

- 115). There are therefore no Syngenta products that would provide a potential
for dermal or incidental oral exposure to pressure

- treated wood that is used in residential structures such as porches and steps.

HED’s Response: As noted above, during Registration Review, all registered uses of chlorothalonil will be reviewed. The Agency is aware that GB Bio sciences is in the process of removing antimicrobial uses from their technical formulations. A final review of currently registered labels/end

- use products will be performed during Registration Review. These use patterns may still be included in the fina l assessment since there are other technical and end

- useChlorothalonil Response to Comments DP# 402499

Page 14 of 21 registrants with antimicrobial uses of chlorothalonil.

Comment #2 5 from Syngenta Concerning Residential Bystander Post

- application Inhalation Exposure: On Page 15, EPA states : “ The Agency developed a preliminary bystander volatilization inhalation exposure assessment for chlorothalonil utilizing currently available inhalation toxicity and air monitoring data. The chlorothalonil bystander volatilization inhalation exposure assessment compared the ma ximum air concentration detected in each of the monitoring studies to the acute HEC for residential bystanders. This comparison was done to represent a potential resident who lives next to a treated field and may be exposed to the peak concentration of
ch lorothalonil volatilizing off the field over a 24

- hour period. In addition, the arithmetic mean chlorothalonil air concentration from each study was compared to the short

- /intermediate

- term HEC for residential bystanders. This comparison was done to repr esent a potential seasonal

exposure. None of the air concentrations results in acute risks of concern; however, there were a couple of average air concentrations from some sites that resulted in short

- /intermediate

- term risks of concern.”

Syngenta Comment: Chlorothalonil is classified

, based on its vapor pressure

, as a low to moderately low volatile pesticide. Residues of chlorothalonil that remain in the air post application are much more likely to be due to contaminated particulates than true vo latiles. Air monitoring data that is used to calculate potential residential bystander exposure should be based on samples collected with filtered sampling tubes to ensure that the calculations are based on potentially respirable residues. If filtered sa mpling tubes are not utilized, then the sampling zone should be sufficiently above the ground surface so as to not capture coarse heavy particulates
that are non

- respirable. There is a significant body of published air monitoring data much of
which was no t considered in the residential bystander inhalation exposure assessment including peer reviewed publications and studies done under Good Laboratory Practice (GLP) such as CA

DPR and CA

- ARS studies and USGS surveys. A summary of the study results are list ed below.

Environmental Setting Reported Range of Air Concentrations (ng/m3) Reference

Outdoor agricultural area, CA 92 samples; <7.0 CA

- ARB, Fresno County 1989 Outdoor agricultural area, CA 120 samples; <4

– 4.6 CA

- ARB, Ventura County 1990
Outdoor agricultural area, ND 13 samples, <0.006

– 7.8* (mean 1.4) Hawthorne, et al., JEQ, 1993 Sierra Nevada mountains, CA 12 samples; <0.0015

– 1.9 (mean 0.6) LeNoir, et al., ETC, 1999 Outdoor agricultural area, CA 160 samples; <4.3 (mean 1.3) CA

- DPR, Lompoc 2 000 Outdoor agricultural area, Franklin Field

Airport, CA 117 samples; <0.1

– 76.4 (mean 1.2) Majewski, USGS survey 2002

Outdoor agricultural area, Sacramento

Int. Airport, CA 117; <0.1

– 52.8 (mean 1.0) Majewski, USGS survey 2002

Outdoor urban area, Sacramento Metro

Airport, CA 115 samples; <0.1

– 10.2 (mean 0.3) Majewski, USGS survey 2002

Outdoor agricultural and urban areas,

CA 121 samples; <0.45

– 14 (mean 1.3) CA

- EPA, Fresno County 2002

Cambridge, MD 27 samples; 0.036

– 2.5 (mean 0.23) McConnell, et al., JEQ 2003

Cheeka Peak, WA 16 samples; <0.00167

– 0.052 (mean 0.012) Killin, et al., JGR, 2004

Outdoor agricultural area, CA 153 samples; <13.7

– 53.2 (mean 13.2) CA

- DPR, (Ben) Parlier 2006 Outdoor agricultural area, CA 153 samples; <13 .7

– 53.2 (mean 13.8) CA

- DPR, (Cha) Parlier 2006 Outdoor agricultural area, CA 153 samples; <13.7

– 53.2 (mean 15.0) CA

- DPR, (Mar) Parlier 2006 Outdoor agricultural area, PEI, Canada

(2003) 18 samples: filter: 6

– 414 (mean 54)
PUF: 8

– 95 (mean 26) Garron, PMS 2011

Outdoor agricultural area, PEI, Canada

(2004) 17 samples; filter: 6

– 78 (mean 31)
PUF: <1

– 36 (mean 15) Garron, PMS 2011

Outdoor agricultural area, PEI, Canada

(2005) 9 samples; filter: 4

– 40 (mean 16) PUF:
4

– 179 (mean 41) Garron, P MS 2011Chlorothalonil Response to Comments DP# 402499

Page 15 of 21 *All chlorothalonil detects were found on the 50 micron quartz fiber filter only

. **Glass fiber filter with 1.6 micron cut

- off; PUF residues <1.6 micron

.

In the draft 2010 human

- health risk assessment, the EPA utilized ambient air monitoring data from the Pesticide Action Network of North America (PANNA) that was neither published in a

peer

- reviewed journal nor performed under GLP. One of the PANNA reports, “Pesticide drift
monit oring in Minnesota June 13, 2006

– August 13, 2009,” was not publically available until May 2012, yet preliminary summary data from this study was utilized by EPA/HED in the draft
December 2010 human

- health risk assessment. The air monitoring data from th e other PANNA report “Air monitoring in Hastings, Florida October 1

– December 6, 2007” and the majority of the data from the Minnesota PANNA study were collected at a height of 1

- 2 meters off the ground, using PANNA drift catchers with unfiltered sampling tubes. Therefore, an evaluation of the PANNA residue data cannot be made in terms of respirable particles that contain chlorothalonil. Syngenta would like to point out that only one sampling point (Site A, Pine Point, MN) from either of the PANNA report s appears to meet the U.S. EPA ambient air siting
criteria.

Syngenta would also like to point out that there are multiple layers of conservatism built into this preliminary bystander exposure assessment, including the following:

T here is an inherent assum ption that chlorothalonil residues are volatilized off the site of application

.

o Chlorothalonil has a vapo r pressure of 5.7 x 10 - 7 mmHg at 25 C. This places chlorothalonil into the category of “low volatility pesticide” (VP ≤ 1 x 10
- 6 mmHg

at te mperatures ranging from 20

- 30 ° C).

o Therefore, airborne residues of chlorothalonil would be due either to drift or to particulates

. T he acute and short

- /intermediate

- term HEC calculations assume a daily duration of exposure of 24 hours for the residential bystander tim es either one day (acute) or seven days (short

- /intermediate

- term ).

o Syngenta believes that it is highly unlikely that any individual would be outside and exposed to the same air concentration for 24 hours

.

o P opulations move from site to site on a daily basi s such as going to work or
school and back to home

.

o T here is a lack of incident data related to inhalation effects from chlorothalonil

.

o As stated earlier, there are data available for air monitoring of workers re

- entering

areas following treatment with chl orothalonil and this data shows that there were no reports of incidents or illnesses from any of these workers related to inhalation
effects.

HED’s Response: The Agency acknowledges the issue regarding the phase of chlorothalonil during bystan der exposure (i.e., particulate versus vapor phase). This issue impacts the toxicological /hazard characterization side of the risk assessment

, as well as the exposure side

, as noted in the above comment. During Registration Review, the Agency will review the available monitoring studies to ensure transparency regarding the methods utilized in collecting the data and characterize as best as possible the applicability and limitations of the available data

. In the 2010 risk assessment, t he Agency use d the avail able air

- monitoring data in an attempt to provide a preliminary approach to estimating potential bystander exposure . This approach was based on advice and input from the FIFRA Scientific Advisory Panel (SAP) in December 2009. The risk
assessment included characterization of the bystander risk estimates, including identification of several limitations and assumptions (some of which are mentioned in the above comment). TheChlorothalonil Response to Comments DP# 402499

Page 16 of 21 Agency notes the information provided in the above comment regarding the additional air monitoring data

, and encourages the Registrant to submit any additional information it may have

, which the Agency will consider and review during Registration Review.

Comments Related to Occupational Exposure Assessment

Comment #2 6 from CA Rural Legal Assistance Foundation Concerning Environmental
Justice: As a result of the 1999 registration review of chlorothalonil, registrants agreed to prohibition of residential turf uses to protect residential handlers and their children, while heavy use in

a griculture that exposes applicators and fieldworkers has been allowed to continue. Children and other family members of workers and rural residents in turn suffer take

- home exposure through residues brought home on clothes and drift exposure if the family lives near agricultural fields. This disproportionately impacts low

- income, minority farmworkers and rural agricultural families, placing those with the least access to any or adequate health care services at increased risk of impacts to their health.

H ED’s Response: The Agency has a firm commitment to promoting environmental justice in this country. 1 In fact, environmental justice is one of the seven priorities that the EPA Administrator established for the Agency’s future. 2 EPA's risk assessments an d ri sk management decisions for chlorothalonil have been developed in a manner that is consistent with this goal. Previous chlorothalonil risk assessments are, and the future Registration Review risk

assessment will be, universally protective of all peopl e regardless of race, color, national origin, culture, education

, or income. With respect to take

- home exposures, the Agency has undertaken numerous steps to ensure that it is adequately protecting farm children, including initiating data gathering on exp osure of children in agricultural areas to pesticides. During Registration Review, EPA will review ongoing research, as it pertains to chlorothalonil, and take appropriate steps, as necessary, to address any exposure concerns regarding children. In addit ion, as noted in the response to Comment #1 above, the Agency acknowledges that spray drift is a potential source of exposure to residents and has been actively engaged in a number of initiatives to help prevent such exposure. These initiatives include: ( 1) broadening our understanding of the science and predictability of pesticide drift based on many new studies, (2) improving the clarity and enforceability of product label use directions and drift restrictions, (3) facilitating the use of drift reducing application technologies and best management practices to minimize drift, and (4) promoting applicator education and training programs. The Agency developed and issued for public comment a draft PR Notice on Pesticide Drift Labeling in 2009. The purpose of the draft PR Notice is to provide guidance to registrants and applicants for registration on labeling statements concerning pesticide drift, and to inform the public of EPA’s policies with regard to pesticide drift. Along with the development of the dr aft PR Notice, the Agency is taking a number of other actions to address pesticide drift, including facilitating adoption of drift

reducing technologies by applicators, providing access to information on best management practices to reduce drift, and suppo rting education and training programs.

Comment #2 7 from CA Rural Legal Assistance Foundation Concerning Restricted Entry
Intervals: Current chlorothalonil product labels, which allow workers to reenter a field only 12 hours after application if an eye was h is provided for workers, defy logic and are a glaring environmental

1 http://www.epa.gov/environmentaljustice/ and http://www.epa.gov/osp/ej.htm

2 http://blog.epa.gov/administrator/20 10/01/12/seven

- priorities

- for

- epas

- future/Chlorothalonil Response to Comments DP# 402499

Page 17 of 21 injustice, because incident data show that eye irritation can occur more than 48 hours after application. During re- registration, restricted entry intervals must be reevaluated and increased to adequately prevent adverse eye effects, cancer

, and any other acute and chronic health effects.

HED’s Response: Chlorothalonil is classified as Toxicity Category I for eye irritation, which

, under the Worker Protection Standard

, necessitate s a 48

- hour REI. During the previous re

registration process for chlorothalonil , the Agency acknowledged that residue data for chlorothalonil did not indicate that residues dissipated to a level where eye irritation is no longer
a concern at the end of the 48

- hour interval. Depending on plant growth, rainfall, and the timing and type of irrigation, residues of eye irritation concern might exist for seven days or more following application. Due to the uncertainties in determining a set time interval when e ye irritation from residues are no longer a concern, the Agency requir ed that, for at least seven days following the application of chlorothalonil , (1) eye wash containers be made available to workers and (2) workers were orally informed of the fact that t he residues could be highly irritating to their eyes, the precautions to avoid getting residues in their eyes, and the actions they should take if they got residues in their eyes. During Registration Review, exposures to residues of
chlorothalonil from al l routes will be re

- examined and the restricted entry interval will be re

visited.

Comment #2 8 from CA Rural Legal Assistance Foundation Concerning Dermal Exposure
Contribution to Cancer Risk: According to Agency review, chlorothalonil has been classified as a likely human carcinogen based on all routes of exposure due to elevated incidence of kidney tumors. Dermal exposure to chlorothalonil by handlers, irrigators and workers performing hand labor in treated fields, thus, needs to be assessed, because th e amount of chlorothalonil absorbed dermally contributes to cancer risk. Agricultural workers have among the highest reported rates of occupational skin disorders, so the rate of absorption needs to be adjusted to take into account enhanced absorption
thr ough skin irritated by exposure to chlorothalonil, other pesticides, irritating crop plants such as tomato, sunlight and other factors. California Department of Pesticide Regulation has previously used an absorption rate of 13% for intact skin.

HED’s Res

ponse : The Agency has reviewed an in vitro dermal penetration study based on human skin that shows that a majority (89.1

- 97.5%) of radiolabeled chlorothalonil remains in the skin, and does not appear to become systemically available with time. Further, t he Agency has
reviewed two 21

- day dermal toxicity studies in rats where there were no systemic effects identified; the effects reported consisted of dermal irritation/effects. Therefore, the likelihood that dermal exposures would contribute significantly to systemic effects such as kidney tumors is
low. D uring Registration Review, the Agency will review all available data as it relates to exposure and potential for adverse effects.

Comment #2 9 from CA Rural Legal Assistance Foundation Concerning Surrogat e Data and Assumptions used in Occupational Exposure Assessment: We do not agree with the statement that the ORETF, AHETF

, and ARTF data are more reliable
than the PHED databases. The PHED contains 1700 replicates of worker exposure, several times

more than the other databases, and the PHED data are not proprietary. The proprietary industry databases (ORETF, AHETF

, and ARTF) incorporate a number of problematic assumptions and procedures:

1. Fewer than 15 events per scenario provide insufficient stat istical power and cannot adequately re present the full range of the distribution. This greatly limits the database'sChlorothalonil Response to Comments DP# 402499

Page 18 of 21 ability to adequately describe inter

- worker variation, as well as its applicability to the larger worker populations (consisting of hundre ds of thousands of workers nationwide).
2. Hand rinses and face and neck wipes underestimate exposure because they fail to capture pesticide residues absorbed through the skin du ring the time between exposure and data
collection. Researchers have found that some pesticide residues are quick ly absorbed through the skin (Fenske R and Lu C (1994). Dete rmination of Handwash Removal Efficiency: Incomplete Removal of the Pesticide Ch lorpyrifos from Skin by Standard Handwash Techniques. American Ind ustrial Hygiene Association Journal 55:425

- 32). Any delay in collecting the rinses or wipes, therefore, increases the exposure
underestimate. In a different s tudy, hand wipes produced a 10

- fold und erestimate of exposure (Fenske R, et al . (1999). Comparison of Three Me thods for Assessment of Hand Exposure to Azinphos

- methyl (Guthion) During Apple Thinning. Applied Occupational & Environmental Hygiene 14:618

- 33).
3. Those who know they are being studied will obviously be particularly careful as they engage in mixing and lo ading tasks. The spills and splashes of real life will occur less frequently during studies. Moreover, protective clothing and equipment provided in AHETF studies will undoubtedly be well

- maintained and they will fit properly. This is quite regularly no t the case in the real world.
4. The ART F methodology used to develop their generic agricultural re

- entry exposure database assumes that occupational exposure to a pesticide is based on the degree of contact that a worker has with the foliage of a particular crop. Rather than testing each type of crop, the ARTF establishes transfer coef ficients to reflect the worker pesticide exposure from categories of activities. The ARTF "transfer coefficients" measure the amount of pesticide residue readily transferred f rom the foliage of a crop to the worker's skin during the course of certain activities, such as thinning or pruning. The ARTF data are not based on actual data pe r taining to particular pesticide uses.

Dermal a nd inhalation exposure studies should not hav e been waived in 2006 and should be required at this time. We also strongly object to moving away from risk calculations designed to protect the maximally exposed workers by assuming maximum application rates and maximum treated acres per day. In fact, the Agency's assumption that agricultural workers are only exposed to pesticides eight hours a day, five days a week does not reflect real life situations where agricultural workers often labor for 10 or 12 hours per day, six days a week, travel l ong distances to reach their residences, and lack resources to wear a clean set of clothing to work each day.

HED’s Response: Current Agency guidance recommends the use of unit exposure values derived from a number of sources. For some scenarios, this s till does include PHED. PHED houses the majority of occupational pesticide handler exposure data the Agency uses in occupational handler exposure assessments, however, the Agency has recognized and acknowledged the limitations with the existing data. In recent years, the Agency and stakeholders have expressed a desire to augment or replace this database with one that has as its foundation a more contemporary dataset and one whose exposure monitoring followed a more robust, consistent, and statistically

- dr iven sampling design. In January 2007, the Agency presented to a FIFRA SAP both the limitations to existing data and the proposed development of new data by an industry consortium, the AHETF. With joint input by Health Canada’s PMRA
and California’s DPR throughout the data development processes, the Agency believes that the AHETF and ORETF data are superior, and that use of these data will result in more reliable and scientifically defensible exposure assessments. Additionally, the Agency considers expos ure data submitted by registrants outside of the AHETF or ORETF, to be the most appropriate dataChlorothalonil Response to Comments DP# 402499

Page 19 of 21 for some scenarios and are used in a similar fashion. In response to the specific issues identified
in the above comment regarding the task force data:

1. The t ask force monitoring data does contain at least 15 events per scenario; in most studies, 25 monitoring units were included. Overall, small samples is not specific to the task force studies and pertains to other exposure databases, including some of the sa mple
sets in PHED.
2. The Agency has acknowledged the potential inefficiency of the hand rinses and face/neck wipes monitoring methods. This particular issue was addressed at the HSRB and a method was agreed upon by which to account for the uncertainty assoc iated with these sampling methods in an attempt to avoid potentially underestimating exposure.
3. The Agency agrees that studies should not reflect workers acting in ways they otherwise wouldn't (i.e., being particularly careful). The task force studies moni tor real workers in real situations. No attempt is made to provide additional protective clothing or equipment. Workers are monitored in the clothing they would normally wear, and with protective equipment normally worn depending on the use/activity. In addition, the AHETF studies are actually designed to ensure exposure measurements

, and may include having workers engage in additional activities (e.g., mix/load more than once). In this respect, exposure may be inflated compared to typical behaviors.
4. Ideally, transfer coefficients studies would be submitted for each type of crop. As a wide range of crop

- specific hand labor tasks occur in production agriculture, generating data and transfer coefficients for each crop

- activity combination would be prohi bitively expensive and unnecessary given the reasonable similarities between crops and activities. The “clustering” approach taken by ARTF, developed in consultation with regulatory agencies, is based on monitoring of selected activities used to represent similar types of activities as defined by the crop, the ergonomics of the post

- application activity, and the potential for contact with pesticide residues. Development of ARTF data and its subsequent use in this “clustering” fashion was favorably reviewe d at a 2008 FIFRA SAP (December 2

- 5, 2008: Scientific Issues Associated with Worker Reentry Exposure Assessment).

The Agency has not made changes to its use of maximum application rates and high

- end acres treated in risk assessments, and will use those values, as ap propriate, in the Registration Review

process.

Comment #

30 from CA Rural Legal Assistance Foundation Concerning Respiratory
Protection: We are puzzled as to how the need for respirato ry protection could be reduced if a m or e health

protective inhalation reference dose is adopted.

HED’s Response: Because there is no inhalation study of appropriate length available to assess
short

- and intermediate

- term exposures, HED relied upon an acute study (in which no NOAEL was achieved) to assess short

- and intermediate

- term exposure. Additional UFs were a pplied for
both the lack of a NOAEL and the lack of a subchronic inhalation study. Therefore, HED has requested a 90

- day inhalation study for chlorothalonil that will provide toxicological data more relevant to the potential exposure scenarios. If the re gistrant submits a subchronic inhalation study, with a subset of animals designed to identify the NOAEL for acute inhalation toxicity (i.e., after one day of exposure), then the current UFs may be reduced accordingly. Using a NOAEL from a relevant study, with potentially lower uncertainty factors, may result in
estimated risks being not of concern with less personal protective equipment.Chlorothalonil Response to Comments DP# 402499

Page 20 of 21 Comment #3 1 from CA Rural Legal Assistance Foundation Concerning Occupational Post

application Inhalation Exposure:
Occ upational post application inhalation exposure may be higher than bystander inhalation exposure because workers within a field are closer to the source of volatilized drift and may have additional exposure to suspended dust containing chlorothalonil. In a ddition, such inhalation exposure is more extensive, since workers remain in the fields for long periods of time, unlike bystanders. Occupational post

- application inhalation exposure should therefore be evaluated separately.

HED’s Response: Th e Agency acknowledges that there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and

re suspension of dusts and/or particulates that contain pesticides, as noted in the above comment. The Agency sought expert advice and input on issues related to volatilization of pesticides from a FIFRA SAP in December 2009. As policies and procedures are developed to assess occupational post

- application inhalation exposure , these will be incorporated

, as appropriate

, into the risk assessment for chlorothalonil during Registration Review.

Comment #3 2 from Syngenta Concerning Occupational Exposure and th e Current Use
Pattern: On Page 6, EPA states : “ With respect to the antimicrobial uses, the occupational handler exposures that occur from the use of chlorothalonil for material preservation were assessed in the RED; however, these assessments may also have to be repeated during registration review to

a ccount for changes in the toxicological PODs. In particular, the handler exposures from the open pouring of wettable powder will have to be reassessed because the antimicrobial wettable powder products are not packaged in water

- soluble packaging as requir ed by the RED. In addition, exposures that occur from the use of chlorothalonil as a wood preservative may have to be assessed because they were not assessed previously. ”

Syngenta Comment: As noted previously, Syngenta (representative of GB Biosciences) has requested cancellation of all of their antimicrobial uses of chlorothalonil including uses during sapstain treatment and pressure treatment of wood.

HED’s Response: As noted above, during Registration Review, all registered uses of
chlorothalonil wi ll be reviewed. The Agency is aware that GB Biosciences is in the process of removing antimicrobial uses from their technical formulations. A final review of currently registered labels/end

- use products will be performed during Registration Review. Thes e use patterns may still be included in the final assessment since there are other technical and end

- use registrants with antimicrobial uses of chlorothalonil.

Comment #3 3 from Syngenta Concerning Occupational Exposure and the Current Use

Pattern: On Page 17, EPA states : “ There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use pattern of chlorothalonil.”

Syngenta Comment: Because Syngenta (agent of GB Biosciences) has requested cancellation of all of its antimicrobial use products, there are therefore no Syngenta or GB Biosciences products that would provide a potential for occupational handler and post

- application dermal or inhalation exposure from antimicrobial uses of chlorothalonil, includi ng the use in treated paints.Chlorothalonil Response to Comments DP# 402499

Page 21 of 21 HED’s Response: As noted above, during Registration Review, all registered uses of chlorothalonil will be reviewed. The Agency is aware that GB Biosciences is in the process of removing antimicrobial uses from their technic al formulations. A final review of currently registered labels/end

- use products will be performed during Registration Review. These use patterns may still be included in the final assessment since there are other technical and end

- use registrants with an timicrobial uses of chlorothalonil.

Comment #3 4 from Syngenta Concerning Occupational Handler Assessment: On Page 17 and in Table A6.1 of Attachment 6, EPA states : “ The most recent occupational handler exposure assessment was conducted in December of 2010 (Memo, K. Lowe, 23

- DEC

201O; D371456). Numerous occupational handler scenarios have been assessed in the past; however, the toxicological PODs were revised for the most recent risk assessment and; therefore, only the exposure scenarios and resulting risk estimates from that assessment have been included
in Table A6.1 of the attachments. As mentioned in the residential exposure section, dermal risk was not quantified in the most recent assessment since no hazard was identified via the dermal route for chlorothalonil and the inhalation assessment was conducted using a HEC calculated from a POD from an acute inhalation study. HED determined that inhalation risks were o f concern for both acute exposures (i.e., MOEs were <100) and short

- /intermediate

- term exposure (i.e., MOEs were <1,000).”

Syngenta Comment: On page 17 and in Table A6.1 of Attachment 6, there appear to be some errors in the calculation of the acute MOE values. For example a worker doing mixing/loading of liquids for aerial application or for chemigation, assuming an applica tion rate of 3 lb ai/A and 350 acres/day, would have a baseline inhalation MOE of 53 and with a PF5 respirator the MOE would be 264. Similarly, a worker doing mixing/loading of liquids for groundboom applications, assuming a n application rate of 3 lb ai/A and 80 acres/day, would have a baseline inhalation MOE of 232. Additionally, a worker applying sprays via groundboom, with the same rate and area/day assumption, would have a baseline inhalation MOE of 149. In the footnotes of Table
A6.1 of Attachment 6 , HED values are listed as 0.174 mg/kg/day for acute exposure and 0.052 mg/kg/day for short

- /and intermediate

- term exposures. Syngenta respectfully requests that the algorithm and ventilation assumptions used to calculate these HED values be clarified in the document, as we were unable to reproduce these values based on the information in either the draft EPA/HED 2010 assessment or the EPA 2012 scoping assessment.

HED’s Response: The unit exposure values for occupational handler assessments have been upd ated recently. T he MOEs presented in the 2010 risk assessment are reflective of the available surrogate data at that time. During Registration Review, the most up

- to

- date surrogate values and assumptions will be used to assess all registered uses. In ad dition, the inhalation toxicological endpoint selection and subsequent HEC/HED values may be re

- evaluated based on available information. The Registration Review assessment will include all algorithms and assumptions used in the exposure calculations to p rovide a transparent assessment.