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 £ 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

Jeff Dawson, Senior Scientist 

Elissa Reaves, Branch Chief 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

Dana Friedman, Chemical Review Manager 

Risk Management and Implementation Branch II 

Pesticide Re-Evaluation Division (7508P) 

In response to the publishing ofthe preliminary "Registration Review Human-Health 

Assessment Scoping Document" (DP 410399; Docket# EPA-HQ-OPP-2013-0081), Cytec 

Industries 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 address comments that are applicable to HED's scoping document. 

1. Comments from Cytec Industries Incorporated: 

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Comment: "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 several 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 (which was HED's 

finding in the 2013 PWP, as well). The requirement was changed to include non-food 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 use of the 

product is likely to result in significant human exposure over a portion of 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 of evidence (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 registrant 

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 exposure 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 storage (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 following aeration. EPA has already acknowledged that because of its volatility, 

no residues of phosphine are likely to remain on food at the consumer level following food 

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preparation. Even if a new inhalation study is conducted that results in a lower estimated acute 

toxicity endpoint, a dietary risk assessment that assumes the presence of residues when no 

residues are present 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 study conducted 

with the help of 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 is informative, it still demonstrates that conditions exist for phosphine exposure, both 

workers and bystanders. More monitoring information is required to understand the full breadth 

of exposure 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 

animals, raising cause for concern as to whether the results from the study would be reflective 

of the actual toxicity of the 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 scientific 

grounds. Even in acute exposure situations, the animals experience significant distress. This 

distress could affect the integrity of the study, Fechter et al found marked depletions in liver 

glutathione levels in rats exposed to different types of jet fuel by the nose-only, but not wholebody, exposure scenario. Additionally, restraint was found by Rasco and Hood to exacerbate 

the developmental toxicity of retinoic acid significantly" 

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-Guideline --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, while 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 

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situations. Airway epithelial cells grown at the ALI retain many of the characteristics 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 phosphine or mechanistically-similar airborne chemicals could provide a ''weight-ofevidence" estimate of doses at which key nonlethal effects are seen." 

EPA Response: The requirement of a special acute inhalation 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 histopathology 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. Although the guidelines have not formally adopted in vitro methods, the 

registrant has the option of submitting to the Agency and HASPOC an alternative 

approach/method that would specifically address all of the acute inhalation 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 

Applicators (Guidelines 875.1400) and Post-Application Exposure (Guideline 875.2500) are 

unnecessary for the following 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 available. 

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. These data are still required based on the findings in the MRIDs 

45898301 and 49066801. With regard to the comment regarding "sufficient inhalation data", the 

HASPOC determined in their weight of evidence conclusion 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 hours with the 

mechanism of degradation 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 of the exposure potential associated 

with phosphine. EPA is aware ofthe half-life of phosphine in air and of the degradation 

properties; however occupational application and bystander exposure is to be expected and will 

be assessed during Registration Review. Existing monitoring data indicate that there is an 

exposure potential , as an example, the phosphide treatment manual which provides directions 

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for users related to protective actions which are required when working in potentially hazardous 

environments (e.g., wear a gas mask at levels up to 15ppm or SCBA when levels exceed 15ppm). 

(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 is 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 of the 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 exposures. 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 of exposure data: [Phosphine Worker Exposure, Degesch America (2002), 

registration Package 51882-015]; NIOSH composite Report, 1987. 

EPA Response: HED is aware of these data and will 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 of phosphine is performed regularly with applications and 

appropriate respiratory equipment is used as per the applicator's manual. These levels should 

be used for risk assessments 

EPA Response: HED will evaluate all available data and model occupational applications and 

residential bystander exposures using PERFUM when it completes its Registration Review Risk 

Assessment. EPA encourages PP A 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 Data System (IDS), the National Pesticide 

Information Center (NPIC), the California Pesticide illness Surveillance Program (PISP) 

Incident Data, and the American Association of Poison Control Center (AAPCC) to identify both 

residential and occupational incidents of exposure to phosphine. Although fatalities are present 

in these databases, there are other health effects reported and these include: neurological, 

gastrointestinal, respiratory, and cardiovascular from individuals who did survive over exposure. 

Given this, it does 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 

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order 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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