### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , DC 20460
OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM
Date: February 12, 2014 

### Subject: Response to Public Comments on the Preliminary Work Plan (PWP) for Aluminum Phosphide, Magnesium Phosphide , and Phosphine

PC Code: 066500 DP Barcode: 0416879 Decision No.: 

### L/P60R7 Registration No

. : N/A Petition No

. : N/A Regulatory Action: N/A Risk Assessment Type: N/A Case No.: N /A TXRNo.:N/A CASNo.: N/A MRID No.: N /A 40 CFR: N /A


### From: Marquea D. King,

# Toxicologi~~

Through:

To: Scott Miller, ORE**~** /J

--- Thurston Morton, Chemist 

# £ Ri sk Assessment Branch IV Health Effects Division (7509P)
Jeff Dawson, Senior Scientist Eli ssa Reaves, Branch Chief Ri sk Assessment Branch IV Health Effects Division (7509P)
Dana Friedman, Chemical Review Manager Ri s k Management and Implementation Branch II Pe s ticide Re-Evaluation Division (7508P)

In resp onse to the publishing ofthe preliminary " Registration Review Human-Health Assessment Scoping Document" (DP 410399 ; Docket# EPA-HQ-OPP-2013-0081), Cytec Industrie s Incorporated, the Physicians Committee for Responsible Medicine, and the Phosphine Producers Association provided comments during the public comment period. The purpose of this memorandum is to addre ss comments that are applicable to HED's scoping document.


### 1. Comments from Cytec Industries Incorporated:
Page 1 of6Comment: "The non-guideline study, "Extended one-generation reproduction study via the inhalation route" will cost close to $1,000,000 to conduct. The study is intended to "allow for the integrated evaluation of multiple organ systems (with an emphasis on the nervous, immune and reproductive systems) across severa l life stages EPA recently decided that an immunotoxicity study would not be necessary for phosphine, and both acute and subchronic neurotoxicity studies have already been conducted and accepted. In 1998, the rat reproductive toxicity study was waived because it was a requirement for food use pesticides, and residues of phosphine are not expected in food or drinking water (whi ch was HED 's finding in the 20 1 3 PWP , as well). The requirement was changed to include non-fo od uses in 2007, however the new regulation states that this study is required, "to support products intended for food uses and to support products intended for nonfood uses if u se of the product is likely to result in significant human exposure over a portion o f the human life span in terms of frequency, magnitude or duration of exposure (emphasis added)." Phosphine residues do not remain in or on food, and cylinderized phosphine gas is dispensed directly into air-tight spaces by tubing with no opportunity for dermal exposure. The only potential exposure to cylinderized phosphine gas is by the inhalation route. The supporting data provided in the monitoring study and a sorption-depuration study (MRID 45898301 and 4906680 l , respectively) discussed in the previous section demonstrate that occupational , worker and bystander exposure to phosphine is minimal. It is clear from the results of these studies that neither the requirement for a rabbit developmental toxicology study and rat reproduction study, nor the proposed alternative extended one-generation reproduction study are needed for risk assessment purposes, because potential exposure is minimal. For these reasons , Cytec respectfully requests that the Agency reconsider including this requirement for an extended one-generation reproduction study."

EPA Response: The HASPOC , based on a weight ofevidence (WOE) approach, determined that an extended one-generation reproduction study in rats was required due tto the lack of currently available hazard and exposure information for phosphine

. However, if the regis trant wishes to submit a formal waiver request with all pertinent worker and bystander exposure information, then the HASPOC would consider this additional information for a weight-ofevidence determination.
Comment : " Dietary Exposure. EPA's previous dietary exposure assessments conducted during the 1999 tolerance reevaluation assumed that 0.006 ppm phosphine was present in all foods (the limit of detection in a residue study) , even though the Agency acknowledged that phosphine gas is highly volatile and will dissipate when cooked or prepared, and no residues are likely to be present in or on food. Non-nursing infants 

### < 1 year were the most highly exposed population, with estimated acute expos ure and risk of 0.004943 mg/kg/day at the 99.9lh percentile of exposure representing 27% ofthe aRID of0.018 mg/kg day , and chronic exposure and risk of0.001004 representing 9% ofthe cRfD. Cytec submitted a study conducted on fresh fruits and vegetables in cold s torage (MRID 485 12301; 48681201) that confirmed that residues are not detected (LOQs in different commodities ranged from 0.0009 to 0.0024 ppm) in treated commodities fo llowing aeration
. EPA has already acknowledged that because of its vola ti lity , no residues of phosphine are likely to remain on food at the consumer level following food

2preparation. Even if a new inhalation study is conducted that results in a lower estima ted acute toxicity endpoint, a dietary risk assessment that assumes the presence of residues when no residues are pres ent is an unnecessary use of time and resources."
EPA Response: HED will take this into consideration and determine if a dietary exposure assessment is required during the Registration Review Risk Assessment.

Comment: "Occupational and Bystander Exposure." Cytec maintains that as a result of these precautions ; the PPA compiled phosphine air monitoring data for metallic phosphides and cylinderized phosphine (MRID 45898301) ; the phosphine sorption-depuration s tudy conducted with the help o f the USDA (MRID 49066801) ; and recent risk mitigation measures that have been added to phosphine product labels as recently as 201 0 ensure that the use of cylinderized phosphine products are not likely to result in significant human exposure
. EPA Response: HED acknowledges the findings ofMRIDs 45898301 and 49066801 and is aware of the recent mitigation measures on recent labels. While the air monitoring study cited above i s informative, it still demonstrates that conditions exist for phosphine exposure, both workers and bystanders. More monitoring information is required to understand the fu ll breadth ofexposure conditions for assessments required during Registration Review.
2. Comments from the Physicians Committee for Responsible Medicine

Comment: "There is considerable scientific evidence showing that maternal stress affects the health and viability of offspring. Inhalation studies can be inherently stressful to pregnant animal s, raising cause for concern as to whether the results from the study would be reflective ofthe actual toxicity ofthe chemical. If the Agency finds that there is no way to avoid this study then we recommend a whole-body exposure method be used versus a nose-only protocol. The extreme confmement associated with this method is troubling on ethical and scient ific grounds. Even in acute exposure situations, the animals experience s ignificant distress

. This distress could affect the integrity ofthe study, Fech ter et al found marked depletions in liver glutathione levels in rats exposed to different types of j et fuel by the nose-only , but not wholebody, exposure scenario. Additionally, restraint was found by Rasco and Hood to exacerbate the developmen tal toxicity of retinoic acid sign ificantly"
EPA Response: HED concurs that there are a number of stressors which in tum could affect the health and viability of offspring. However, inhalation is the·route of concern and nose-only is typically preferred for these inhalation studies. The extended one-generation is study is important in the human health assessment for workers and bystanders for phosphine.

Comment: Non-Guidelin e --Special acute inhalation study ( Phosphine ) " There is enough information available on Phosphine to suggest that for animal welfare reasons this study should not be conducted. Models using nasal epithelial cells, whi le not available commercially, may provide a potential human-relevant model with which to investigate the non- lethal effects of Phosphine

... Multiple nonanimal airway models exist.

.. Because of established techniques for air-liquid interface (ALI) exposure, it is possible to understand the dosimetry of the cells 

### in a way that would mimic very closely the dose that might be seen in actual human exposure

3situations. Airway epithelial cells grown at the ALI retain many of the characterist ics found in vivo, · these models and 3-D tissues such as the examples provided above may be able to provide the mechanistic information or histopathological observations that the Agency is interested in receiving. A comparison of such in vitro results with in vivo results obtained in tests with pho sphine or mechanistically-simi lar airborne chemicals could provide a ''we ight-of

### evidence" estimate of doses at which key nonlethal effects are seen. "
EPA Response: The requirement of a special acute inhala tion study was based on a weight of evidence (WOE) approach. Inhalation is the primary route of exposure and there is a lack of non-lethal hi stopat hology data (respiratory tract). Therefore, the special acute inhalation study would include respiratory tract histology, GSH measurements (i.e., nose) and kinetics/tissue dosimetry (time course) that would directly inform the acute occupational and residential bystander assessments. A lthough the guidelines have not formally adopted in vitro methods , the registrant has the option of submitting to the Agenc y and HASPOC an alternative approach/method that would specifically address all of the acute inhalati on study data requirements.
3. Comments from Phosphine Producers Association (PPA)

Comment: "The PP A feels the requirements for the new data on Inhalation Exposure for App licators (Guidelines 875.1400) and Post-Application Expo sure (Guide line 875.2500) are unneces sary for the fo llowing reasons. (a) Sufficient inhalation data on phosphine is already available for the Agency to assess risks for both application and post

- application (90-day inhalation study in rats: NOAEL of 1.13 mg/kg/day) ; 2 year inhalation study in rats (Newton, 1989 , NOAEL of 3 ppm) is availab le. EPA Response: The PPA cited EPA guideline numbers in their comment which pertain to occupational and residential exposure monitoring data for applicators and those who could be exposed after application. T hese data are still required based on the findings in the MRIDs 4 589830 1 and 49066801. With regard to the comment regarding "sufficient inhalation data", the HASPOC determined in their weight of evidence concl usion that sufficient inhalation data were not available to match the exposure scenarios for assessments required during Registration Review. (b) Phosphine is rapidly degraded in the atmosphere. Due to a half life of 5 ho urs with the mechanism ofdegradation being photoreaction with hydroxyl radicals , the expected reaction products of phosphine in are oxyacids of phosphorus acid and inorganic phosphate which are not volatile. Therefore, inhalation exposure to applicators and post application inhalation exposure are unlikely scenarios

. EPA Response: EPA does not concur with this evaluation ofthe exposure potential associated with phosphine. EPA is aware ofthe half-life of phosphine in air and of the degradation properties; however occupatio nal application and bystander exposure is to be expected and will be assessed during Registration Review. Existing monitoring data indicate tha t there is an exposure potential , as an example, the phosphide treatment manual which provides directions

4for u sers related to protective actions which are required when working in potentially hazardo u s environments (e.g., wear a gas mask at levels up to 15ppm or SCBA when levels exceed 1 5ppm). (c) Phosphine is to be used only by certified applicators and current labels require placarding on structures , containers , and vehicles that have been fumigated. Therefore , once label instructions are followed , training of applicators is applied, and personal protective equipment is worn by applicators, air monitoring i s not relevant.
EPA Response: HED is aware of the placarding , training of applicators, and the personal protective equipment that is worn by applicators. These elements ofthe user manuals provide a standard of use which EPA believes will help reduce and manage , not eliminate exposure potential. In fact , these elements have also been required for other fumigant active ingredients as part of a holistic approach for managing possible exposure s. Given the available data, it appears that there is an exposure potential and it is not clear how these data relate to the current use practices associated with phosphine. (d) Availability ofexposure data: [Phosphine Worker Exposure, Degesch America (2002) , registration Package 51882-015 ] ; NIOSH composite Report, 1987.
EPA Response: HED is aware ofthese data and w ill consider them as appropriate in the upcoming risk assessment process. One of the key aspects of the use of these data will be evaluating them for representativeness compared to current use practices and critically evaluating the research plan used 

### in each study (e.g., reliability of sampling methods, timing and sampler locations).

(e) Detection of concentrations ofphosphine is performed regularly with app lications and appropriate respiratory equipment is used as per the app licator's manual. These level s should be used for risk assessments
EPA Response: HED wi ll evaluate all available data and model occupational app lica tions and residential bystander exposures using PERFUM when it completes its Registration Review Risk Assessment. EPA encourages PPA to summarize and submit such data for consideration by EPA in the registration review process.

(f) Lethality is the only endpoint for over-exposure to phosphine for human exposure incidents. There are no irreversible effects and, therefore , no target organs , including the lungs. EPA Response: HED employs the OPP Incident Da ta System (IDS), the National Pesticide Information Cent er (NPIC ), the California Pesticide illnes s Surveillance Program (PISP) Incident Data, and the American Association of Poison Control Center (AAPCC) to identify both residential and occupational incidents of exposure to pho sphine. Although fatalities are present in these databases, there are other health effects reported and these include: neurological, gastrointestinal, re spiratory , and cardiovascular from individuals who did survive over exposure. Given this , it doe s appear that humans can be exposed at some level and experience non-lethal effects. Also , there is a desire to develop an understanding of the acute inhalation profile in



### 5order to develop risk estimates for both workers and bystanders based on non-lethal effects from the required special acute inhalation study. This will allow for a more informed risk assessment. Regulation based on death as the toxic effect would also require EPA to retain additional safety factors for the severity of the effect.

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