### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM Date: June 17 , 2015 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Fosamine Ammonium. DRAFT Human Health Risk Assessment in Support of Registration Review. PC Codes: I0670 I DP Barcode : 0415249 Decision No.: 483392 Registration Nos.: 42750-241, 42750-247 and 42750-264 (Manufacturing Use Product (MUP)) Petition No.: NA Regulatory Action: Registration Review Ri sk Asses sment Risk Assessment Type: NA Case No.: 2355 TXR No.: NA CAS No .: 25954-13-6 MRID No.: NA 40 CFR: None FROM: Bonnie Cropp-Kohlligian, Risk Assessor '

# ~-**~iy-­**

THROUGH:
TO: Ayaad Assaad, Ph.D., Toxicologist 

# 4--f.J.,J-t,d:. Ivan Nieves, ORE Assessor ...(}**~** Risk Assessment Branch (RAB) IV Health Effects Division (HED) (7509P) 

# p--- Charles W. Smith III, Acting Branch Chie<f:...

___ ---__.) RAB IV, HED (7509P) James Parker /Thomas Moriarty RM 51 Risk Management and Implementation Branch 1 Pesticide Re-Evaluation Divis ion (7508P)

Page I of 16Fos amin e Ammonium Re gi stration Rev i e w DRAFT Human Health Risk Assess ment 0415 249


### Table of Cont ents 1
.0 Executive Summary
.. ..... .... . . . ........ .. ............................. . ........ .... ........ . ..... . .... .. ... . .......... . .. . . .. . 3 2
.0 HED Recommendations
..... . . .. ..... ... ... . ..... ... .... . ..... . ...... .. ......... .. ........ ... ... . ... . . . . . ... ... ....... .. ...... 3 2.1 Data Deficiencies
................ . .. .... .. . .. . .. . .. . .... ... .. .. . . .... .. .. .... .... .. . .... .. .... .. .. .. .. .... ... ............. . ... 3 2.2 Tolerance Considerations
... . ....... . ...... . . . ... . . . ... . . ....... ... . ..... . ....... . .. . .... ... ... . .... .... . ... . .... ... . . . . .. 3 2. 3 Label Recommendations ... .. .... ... ... .. .... .. . . .. .. ..... . ..... ... ... . ..... . .... . ..... .. ... .. . ... .... .. ... . ..... . .... . ... 3 3. 0 Introduction
.. .. . . .. . .. . . . . .... ... . . ... . . . . . .... .. ... . . ... . . . . . . ... . ...... ... ... .. . .... .... .... . . ..... .. ..... . .. . .... . .. ..... . . . ... . .. 3 3
. 1 Chemical Identity
... . .... . . . . . . . . . .. .. .... .. ..... . . . ... .. ..... . . . ... . ..... . .... ... . . . .. ... ........ . .... .... . .................. 4 3. 2 Physical/Chemical Characteristics
.. . ... .. ...... .. ..... . .... . . . ........ . ......... .... . ... . .... .... . .... . ......... ... . 4 3.3 Pe sticide Use Pattern .... . .. .... ... . ..... . . . ... . . . .. .. . . . . .. . . . . . . .. ...... . . .... ... . .... ... ... . ..... .. ......... . ........ ... . . 5 3.4 Anticipated Exposure Pathwa ys . . . ... .. . . .. . . .. .. .. . . .. .. . . .. ...... . ... . .................... . ...... . ... .. ............. 5 4
. 0 Hazard Characteriz ation and Dose-Response Ass essment . ... . . . . . . . .... . . .. . . . . .. . . . ... . . . .. ... . . . . ..... .. 6 4
. 1 Toxicology Analy sis
............................................... . ........ . .... . .... . ..... . ... .. ..... . .............. .. ... . 6 4
.2 Consideration of Toxicity for Children
. . ..... ... ........ . . .. ..... . . . . . ...... . ........ . ........... . . . . ... . ... . .... 7 4
.3 Toxicit y Endpoint and Point of Departure Selections
... ... ... . .......... . .... . ....... . .... ... ...... .. . ... . 7 4
.4 Endocrine Disruption
. . . . .. . .. . .. .. .... .. . . . . . . . . . . ... . ... .. . .. . .. . . ... . . . .. . . . .... . . . . . .. . . . ..... ... . .. . ..... .. ..... ... .... 7 5
.0 Dietar y Expo sure and Ri sk Assessment.. . .. .... .. ..... .. .... ... .. .. ... ... ... . ..... . .... . .... ... ... .. .... . ........ .. .. 8 6
.0 Residential (Non-Oc cupational) Exposure/Risk Characterization ..... .. ... .. . .... ... .. . . .. . .. ... ..... . . 8 6.1 Spray Drift
. ... .. ........ ... ... . ...................... . ... ... ..... . ...... . . . ........ . . . ....... . . . ..... . .. ... ... .. . .. .. . .... . ... .. .. 8 6. 2 Residential Bystander Post-Application Inhalation Exposure
................. .. ........ . ... .. . . .. . ... 8 7.0 Aggregate Exposure/Risk Characteriz ation
..... . .... .. ..... ..... . .. ... .... . .... .. ....... . .. . ..... . ............. .... 8 8
.0 Cumulative Exposure/Risk

### Charact**ri ation**  .... . ... . ... . ....... . ... . .......... .. ... .. .. . ........... . ............ .. 9 9
. 0 Public Health and Pesticide Epidemiology Data
........ . ........... . . . ....... ..... ... .... . ... . ...... . .... . . ...... 9 10
.0 Occupational Exposure/Risk Characterization
................................ . ............ .. ....... .. ....... ... .. . 9 11.0 References
.... . . . ..... .. . ....... . . .. .... . . .. .. . . . . . . ... ... ... . .. . . . .. .. ..... . . . ... . ... .. . . . . . . .. ... ... ... . ..... .. .. . . . . ......... .. .. 10 Appendix A. 

### Toxicolo gy Profile and E xecutive Summaries .. .. ... .. .... . .......... . .... . .... ... .. . . . ........ .. ... 11 A.1 Toxicology Data Requirements
. . ... ................. . ..... . . . ..... .. .. . . ..... . ..... . ....... .. . . .. . . .. .. ... .. ... .. ... 11 A
.2 Tox icit y Profiles: .. ... . .. ... .. .. . ....... .. . ... ... ... ....... . ........... . .. ... ........... . ............. . . . ..... ..... . .. . ...... 12

Page 2 of 16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 

### 1.0 Executive Summary HED has prepared a qualitative human health risk assessment to support Registration Review for the currently registered uses of fosamine ammonium [ethyl hydrogen (aminocarbonyl) phosphonate]
. Given its low toxicity, the HED peer review of the toxicity database did not identify toxicity endpoints for fosamine ammonium. As a result, a quantitative human health risk assessment is not necessary to conclude with reasonable certainty that exposures from the currently registered uses of fosamine ammonium do not pose a significant human health risk. Fosamine ammonium is an herbicide/ plant growth regulator applied as a foliar spray on noncropland to control brush and herbaceous plants. It is used for general weed control in uncultivated non-agricultural areas (e.g. airports, highway , railroad and utility rights-of-way, sewage disposal areas), uncultivated agricultural areas (e.g. , non-crop producing farmyards, fuel storage areas , fencerows) and industrial sites (e
.g. , lumberyards, pipeline and tank farms)
. No data deficiencies were identified for the toxicology , residue chemistry, or occupational/ residential exposure databases. Potential exposure pathways for fosamine ammonium are limited to drinking water and dermal/inhalation worker scenarios. There are no food/feed uses or residential uses/exposures for fosamine ammonium. 

### 2.0 HED Recommendations Exposures from the currently registered uses of fosamine ammonium do not pose a significant human health risk. HED has no objection to the continued registration ofthe current fosamine ammonium pesticide products. 

### 2.1 Data Deficiencies No data deficiencies were identified for the toxicology, residue chemistry, or occupational/ residential exposure databases. 2.2 

### Tolerance Considerations There are no food/feed uses offosamine ammonium and tolerances are not required. In addition, there are currently no established Codex, Canadian or Mexican maximum residue limits (MRLs) for fosamine ammonium. 2.3 

### Label Recommendations None. 

### 3.0 Introduction Fosamine ammonium belongs to the organophosphonate chemical class ofpesticides. Although fosamine ammonium belongs to this subclass of the organophosphates, it is not neurotoxic and does not inhibit cholinesterase. It is an herbicide/plant growth regulator applied as a foliar spray on noncropland to control brush and herbaceous plants. There are no currently registered food/feed uses or residential uses/exposures for fosamine ammonium
.
Page 3of16Fosamine A mmonium Registration Review DRAFT Human Health Risk Assessment D415249 The last human health risk assessment for fosamine ammonium was prepared for the 1994 HED Chapter of the Reregistration Eligibility Document (RED) for Fosamine Ammonium (A. Aikens , 28 June 1994, No DP B arcode). The human health scoping document in support of Registration Review (B
. Daiss , 25 March 20 10 , D372168) required a subchronic inhalation toxicity study, an immunotoxicity study, and a rabbit developmental toxicity study
. These three studies have been submitted and reviewed by the Agency and incorporated into this risk assessment. 

### 3.1 C h emical Identity Tab le 3
. 1. Test Co mpound No me nc la tu re Chemical Structure 

### 0 

## u- l\ H1/ 

# '/ / 

### H

\ .P
.,

N - C/ 

### "o-C-l 2 

### -8H3 I 

# I H 

### 0 Common name Fosamine ammonium IUPAC name ammonium ethy l carbamoy lphosphonate CAS name ethyl hydrogen (aminocarbonyl) phosphonate CAS# 25954

- 13-6 PC Code 10670 1 

### 3 .2 P hys ical/C h emi cal C h aracteris tics Tab le 3
. 2. P hysicoch em ical Prop erties of Fosamine A mmonium
. Parameter Val u e Reference Me l t i

ng point 173-175 °°C (decomposition) Water Solubility Completely miscib l e in water.8 mg/L at 25°C 1995 RED 1 Met hylene chl oride, ether, hexane , < 1 ppm toluene

1 ppm Acetone 2ppm Acetonitri l e Solvent So lubility 17 g./ 100 ml Methano l pH 5
.79 for 1 % solution (w/ v) at 25 °C Density /Specific Gravity 1.24 g/mL at 25 °C Octanol/water partition coefficient Kow = 0
.0012 Vapor Pressure 4 x 10 -6 mm Hg at 25 °C Estimated Octanol/Water Coefficient l og Kow: 4.2 I Reregistration Eligib ility Decision (RED) Fosamine Ammonium (1/95) EPA 738-R-95

-004

Page 4of16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 

### 3.3 Pesticide Use Pattern Fosamine ammonium is an herbicide/plant growth regulator applied as a foliar spray on noncropland to control brush and herbaceous plants
. There are only two currently registered end-use products containing the active ingredient, fosamine ammonium, which are Fosamine 41.5% SC (EPA Reg
. No
. 42750

-241) and DuPont Krenite S (EPA Reg. No. 42750-247)
. Both end-use products are formulated as a 41.5% soluble concentrate (SC) and may be applied by hand-held sprayer and helicopter. The maximum per application and per year use rate is 24 lb a.i./A. It is used for general weed control in uncultivated non-agricultural areas (e
. g. airports, highway, railroad and utility rights-of-way, sewage disposal areas) , uncultivated agricultural areas (e
.g., non-crop producing farmyards, fuel storage areas, fencerows) and industrial sites (e.g ., lumberyards, pipeline and tank farms). It is applied as a pre-plant herbicide to pine plantations to prevent growth ofundesirable seedlings and saplings and suppress growth ofbrush and vines. Direct application to natural or manmade bodies of water (e.g. , lakes, reservoirs, ponds, streams or canals) is not permitted. However, it may be applied in pine plantations and non-crop sites that contain areas of temporary surface water caused by collection of water between plantation beds, in equipment ruts, or in other depressions created by management activities. It is permissible to treat intermittent drainage, intermittently flooded low lying sites, seasonally dry flood plains and transitional areas between upland and lowland sites when no water is present. It is also permissible to treat marshes, swamps and bogs after water has receded, as well as seasonally dry flood deltas. 

### 3.4 Anticipated Exposure Pathways Potential exposure pathways to fosamine ammonium include only drinking water and dermal/inhalation worker scenarios. There are no food/feed or residential uses of fosamine ammonium , so exposure inion food or in residential or non-occupational settings is not expected. 

### 3.5 Consideration of Environmental Justice Potential areas of environmental justice concerns, to the extent possible, will be considered in future human health risk assessments for fosamine ammonium, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http :// epa.gov /compliance /ej /resources/policy/exec _order_ 12898.pdf. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures
. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all registered food uses ofa pesticide. These data are analyzed and categorized by subgroups based on age , season ofthe year, ethnic group, and region
. ofthe country . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use ofpesticide products and associated risks for adult applicators and Page 5of16Fosamine Ammonium Regi stra tion Review DRAFT Human Health Risk Assessment 0415249 for toddlers , youths, and adults entering or playing on treated areas post-application are evaluated
. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups
. 

### 4.0 Hazard Characterization and Dose-Response Assessment The toxicity database for fosamine ammonium was peer reviewed by HED. Study NOELs/LOELs of critical studies potentially impacting toxicity endpoints for risk assessment were updated to NOAELs/LOAELs to reflect current Agency policies
. The recently submitted immunotoxicity, rabbit developmental and rat inhalation studies were also reviewed and incorporated into this assessment. The toxicology database for fosamine ammonium is complete and provides sufficient information to adequately identify hazards for risk assessment purposes. Toxicology studies available for fosamine ammonium include acute 6-pack (60% a.i.) , 90-day subchronic toxicity studies (dog and rat), a one generation rat reproduction study (fertility and reproduction only, no offspring), developmental rat and rabbit studies, an immunotoxicity study , acute delayed neurotoxicity hen study, acute and subchronic neurotoxicity rat studies, a special cholinesterase inhibition study , a 21-day dermal toxicity study, a 28-day inhalation study , mutagenicity studies and a rat metabolism study
. Long-term feeding and cancer studies are not available for fosamine ammonium. However, based on the low toxicity of fosamine ammonium and the lack of toxicity endpoints , these studies would not be expected to impact risk assessment and are not of concern . 

### 4.1 Toxicology Analysis Fosamine ammonium was generally non-toxic up to doses near or above the limit dose in several of the available toxicity studies. Acutely , fosamine ammonium is Toxicity Category IV for oral, dermal, and inhalation
. Fosamine ammonium was slightly irritating to the eye (Toxicity Category III) , but not dermally irritating (Toxicity Category IV) nor a sensitizer. The most notable effect offosamine ammonium toxicity in repeat oral studies is diarrhea in rats occurring at high doses(> 300 mg/kg/day). Diarrhea was seen at
- 300 mg/kg/day in the subchronic neurotoxicity study (SCN) and > 1000 mg/kg/day in the developmental rat and acute neurotoxicity (ACN) studies ; however, bodyweight and food consumption were not impacted and the effect was not considered biologically adverse. There was no evidence of offspring sensitivity or susceptibility to fosamine ammonium. Developmental toxicity was not observed up to and near the limit doses in both the rat and rabbit studies. A fertility and one-generation reproduction study phase ofthe 90-day rat study did not result in changes in fertility or reproduction. Fosamine ammonium showed no neurotoxicity in several neurotoxicity studies up to limit dos es . Cholinesterase inhibition was not observed up to 2 ,000 mg/kg/da y in a special 5-day dosing study in rats. Brain, RBC, and plasma cholinesterase activity was similar to controls. There were also no signs of neurotoxicity in either the ACN or SCN study up to the limit dose (2,000 mg/kg) in both studies. There were also no clinical signs of acute delayed neurotoxicity in hens at a dose of 2000 mg/kg/day
. Page 6of16Fos amine Ammonium Regi stration Review DRAFT Human Health Risk Assessment 0415249 A dermal penetration study is not available for fosamine ammonium
. However, a 21-day dermal toxicity study in rats is available and no effects were observed up to the limit dose. The 28-day inhalation study did not result in systemic toxicity up to 1 mg/L. Minimal to moderate mucous cell hyperplasia was observed in a dose-dependent manner in the nasal cavities of both males and females at all three test substance exposure levels. However, metaplasia or degenerative changes were not observed and were specifically included in the scoring criteria. There were also no changes in respiratory function , no nasal discharge, and no respiratory distress
. Therefore , the hyperplasia observed was considered an adaptive change to irritant exposure and was not considered adverse. A LOAEL was not identified and the NOAEL is 1 mg/L (HDT). Fosamine ammonium showed no evidenc e of immunotoxicity with gavage at the limit dose ( 1000 mg/kg) in mice. Long-term feeding and cancer studies are not available for fosamine ammonium
. However, based on the low toxicity of fosamine ammonium and the lack oftoxicity endpoints for risk assessment, these studies would not be expected to impact risk assessment and are not of concern . 

### 4.2 Consideration of Toxicity for Children Food Quality Protection Act (FQPA) considerations do not apply to fosamine ammonium for the currently registered (non-food) use patterns described in this risk assessment. In addition , no toxicological points of departure were identified for fosamine ammonium and thus , an additional safety factor to protect children is not needed
. 

### 4.3 Toxicity Endpoint and Point of Departure Selections Given the low toxicity throughout the toxicological database , no toxicity endpoints were identified for risk assessment. Therefore, quantitative exposure and risk assessments are not necessary . 

### 4.4 Endocrine Disruption As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute , subchronic and chronic toxicity , including assessments ofcarcinogenicity , neurotoxicity , developmental, reproductive , and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including eff ects on endocrine target organ histopathology, organ weights , estrus cyclicity, sexual maturation, fertility , pregnancy rates , reproductive loss, and sex ratios in offspring
. For ecological hazard assessments , EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part ofits preliminary risk assessment for Registration Review of fosamine ammonium , EPA reviewed the available data and did not identify an endpoint for relevant risk assessment scenarios from the existing hazard database
. However, as required by FFDCA section 408(p ) , fosamine ammonium is subject to the endocrine screening part ofthe Endocrine Disruptor Screening Program (EDSP).

Page 7of16Fosamine Ammonium Registration Review DRAFT Human Health Risk Asses sment 0415249 EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a " naturally occurring estrogen , or other such endocrine effects as the Administrator may designate. " The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen , or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A , or T hormonal systems will proceed to the next stage ofthe EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals
. Between October 2009 and February 2010 , EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for Registration Review and chemicals found in water. Neither ofthese lists should be construed as a list ofknown or likely endocrine disruptors. For further information on the status of the EDSP , the policies and procedures, the lists of chemicals, future lists , the test guidelines and the Tier 1 screening battery , please visit our website. 2 

### 5.0 Dietary Exposure and Risk Assessment Quantitative dietary exposure and risk assessments are not required for fosamine ammonium since no toxicity endpoints have been identified. 

### 6.0 Residential (Non-Occupational) Exposure/Risk Characterization Quantitative residential exposure and risk assessments are not required for fosamine ammonium since no toxicity endpoints have been identified. 

### 6.1 Spray Drift Quantitative spray drift exposure and ri sk assessments are not required for fosamine ammonium since no toxicity endpoints have been identified. 

### 6.2 Residential Bystander Post-Application Inhalation Exposure Quantitative residential bystander post-application exposure and risk assessments are not required for fosamine ammonium since no toxicity endpoints have been identified. 

### 7
. 0 Aggregate Exposure/Risk Characterization As quantitative dietary and residential exposure assessments are not required, a quantitative aggregate assessment is not required either to conclude with reasonable certainty that aggregate exposures to the currently registered uses of fosamine ammonium do not pose a significant
1 See http :// www.rcgulations .gov/#!documentDetail ; D =E PA-H Q-OPPT-2009-0477-0074 for the final second li st of chemicals. 2 2 http ://www .epa.gov /endo / Page 8of16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 human health risk. 

### 8.0 Cumulative Exposure/Risk Characterization Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism oftoxicity, EPA has not made a common mechanism of toxicity finding as to fosamine ammonium and any other substances and fosamine ammonium does not appear to produce a toxic metabolite produced by other substances
. For the purposes of this action, therefore, EPA has assumed that fosamine ammonium does not have a common mechanism of toxicity with other substances. For information regarding EPA ' s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA ' s website at http :// www .epa.gov/pesticides/cumulative /
. 

### 9.0 Public Health and Pesticide Epidemiology Data Both OPP Incident Data System (IDS; 2010-2014) and NIOSH SENSOR-Pesticides (1998- 2011) databases were reviewed for incidents involving fosamine ammonium (S. Recore and E. Evans, 28 January 2015, D415251)
. There were no incidents involving fosamine ammonium reported to IDS from 2010 to January 13, 2015. A query of SENSOR-Pesticides identified one low severity case. Because there continue to be few incidents involving fosamine ammonium reported to either IDS or SENSOR-pesticides there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment. 

### 10.0 Occupational Exposure/Risk Characterization Quantitative occupational handler and post-application exposure and risk assessments are not required for fosamine ammonium since no toxicity endpoints have been identified
.

Page 9of16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 

### 11.0 References Memoranda A. Aikens, 28 June 1994, No DP Barcode , HED Chapter of the Reregistration Eligibility Document (RED) for Fosamine Ammonium. R. Bohaty and D. Judkins , 30 March 2010, D372059 , Registration Review

- Preliminary Problem Formulation for the Ecological Risk and Drinking Water Exposure Assessments for Fosamine Ammonium. B. Daiss, 25 March 2010, D372168 , Fosamine Ammonium: Human Health Risk Scoping Document in Support of Registration Review. S. Recore and E. Evans, 28 January 2015, D415251 , Fosamine Ammonium: Updated Tier I Review of Human Incidents for Preliminary Risk Assessment.
Reregi stration Eligibility Decision (RED) Fosamine Ammonium (1 /95) EPA 738-R-95-004 

### Appendix A. Toxicology Profile and Executive Summaries

cc: B. Cropp-Kohlligian (RABIV) ROI: RABIV (2/23 / 15) B. Cropp-Kohlligian:S I0911 : PY-S : (703)305

-7462:7509P:RABIV

Page 10of1 6Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment D415249 A ppendix A . Toxicology Profile and Executive Summaries A.1 T oxicology Data Requirements
Stud y Tech nical Requ ired Satisfied 870.1100 Acute Oral Toxicity
... .... . ..... ..... .... .. . . . . . . . ........... ............ yes yes 870
. 1200 Acute Dermal Toxicity
....... ................ . . . . . . . . . . . ................ yes yes 870
. 1300 Acute Inhalation Toxicity
.. ............... . . ................ .......... yes yes 870.2400 Primary Eye Irritation
.. ... . ......... .... .......... . . . .. . . . . . ............ yes yes 870.2500 Primary Dermal Irritation ... . . . . ............ . . ........ . ... . ....... . .... yes y es 870 .2 600 Dermal Sensitization
......... ... ......................................... yes yes 870.3100 Oral Subchronic (rodent)
... . . . ....... . .................... . . . ... .. . . . . yes yes 870.3 150 Oral Subchronic (nonrodent)
. . . . ..................................... yes yes 870.3200 28-Day Dermal
... ... . . ........ ....... . . . . . ............................ . . .... yes yes 870
. 3250 90-Day Dermal..
. . .. . . ......................... .......................... . . . no no 870
. 3465 28-Day Inhalation
... . . ... ... ......... ..... . . ............... . .. .. ...... .. . . yes yes 870.3700a Developmental Toxicity (rodent)
. . . . . ............................ . yes yes 870
. 3700b Developmental Toxicity (nonrodent)
.......................... . . yes yes 870.3800 Reproduction
. ........ . .. ... ............. .... . . . . ............................. yes yes 870.4100a Chronic Toxicity (rodent)
.......... . . ....... . ....... ............. ...... no no 870.4 100b Chronic Tox icity (nonrodent)
.......... .. ........................... no no 870
. 4200a Oncogenicity (rat)
... . ... . ... ........ ............. . ............. .... ....... no no 870.4200b Oncogenicity (mouse)
.. .. . . . . . ...... ... . . ..... . ... . . . . . . . . . . . . . . .. . ..... no no 870.5100 Mutagenicity

- Bacterial reverse mutation assay . ................... yes yes 870
. 5300 Mutagenicity

- /n vitro mammalian cell ge n e mutatio n test.. . . ... ye s yes 870
. 5375 Mutagenicity

- /n vitro mammal ian chro mosome aberration t est yes yes 870
. 5395 Mutagenicity

- Mamm a l ian erythrocyte mi c r onucl eus t est. . . . . . . . yes yes 8 7 0
. 6100a Acute Delayed Neurotoxicity (hen)
.... . . . .... .. . . . . . ..... . .. . . . .. no yes 870.6100b 90-Day Neurotoxicity (hen)
.......................................... no 

## - 870
. 6200a Acute Neurotoxicity Screening Battery (rat)
........... . . .. .. yes yes 870
. 6200b 90-Day Neurotoxicity Screening Battery (rat)
.... .. .... . ... yes yes 870
. 6300 Developmental Neurotoxicity
.. . . . ...... .. . .. . . . ........ . .. ... .. . . . . no no 870
.7485 General Metabolism
.. . . .. . . . . . ...... ..... .... . . . . . . ..... . ... . ...... . . . . . . y es yes 870
.7600 Dermal Penetration
. . .... .. . . . . ... ... . . . . . ...... .... .... .... ..... ... .. . ... no no 870
.7800 Immunotoxicity
............... . .................. . ........... . ............ . . yes yes

Page 11of 16Fosamine Ammonium Registration Review DRAFT Human Health Risk Asses s ment 0415249 A.2 Toxicity Profiles:
Table A.2.1 Acute Toxicity Profile - 60% Fosamine Ammonium Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral [Rat] 43846406 LD so > 5000 IV mg/ kg 870.1200 Acute dermal [Rabbit] 43846407 LD so 

### = >5000 IV mg/kg (HOT) ] 870.1300 Acute inhalation [Rat] 43846407 LCso 

### = > 5.84 mg/L IV 870.2400 Acute eye irritation 43846409 Eye irritation III includes corneal opacity, conjunctiva! redness , chemosis, and discharge. Bli stering of conjunctiva also observed 870 .25 00 Acute dermal irritation [Rabbit] 43846410 Mild dermal IV irritation
. Erythema cleared by48 hrs. 870. 2600 Skin sen sitization [guinea pigs] 438 46411 Non-sensitizer NA under conditions of study.

Page 12of 16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment D415249 The toxicity profile table below contains study NOAELs/LOAELs for new studies (i
.e ., immunotoxicity, developmental rabbit and 28

-day inhalation studies) and other studies considered important for determination ofpotential toxicity endpoints for risk assessment (i
.e., 90

- day oral rat and acute neurotoxicity studies). For all other studies the previously determined NOELs/LOELs were not updated to NOAELs/LOAELs. 

### Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Fosamine Ammonium Guideline MRID No. (year)/ No. Study Type Classification /Doses Results 870.3100 90-Day oral 00075736 (1969) NOAEL 

### =250/500 mg/kg/day (HDT) toxicity (rat) Acceptable, non-guideline LOAEL = was not observed. 0 , 200, I000 or 5000 / 10000 ppm in the diet (0, I0 , 50, 250/ 500 mg/kg/day). 870.3150 90-Day oral 4286700 I ( 1993) NOEL= HDT (5000/7500/ 10000 ppm) toxicity (dog) Acceptable, guideline 125 to 250 mg/kg/day N=4/sex/ dose No LOEL established 6 month 0, 200, IOOO or 5000 (!st week)/7500 (2nd & 3rd week)/ 10000 (4th week) ppm (0, 5, 25 and 125 or 187.5 or 250 mg/kg/day)
. 87 0.3200 21 -Day dermal 41998101 1991) NOEL= HDT ( 1500 mg/kg/day) toxicity (Rabbit) Acceptable, guideline Intermittent dermal irritation observed in all 0,50,500, 1500 g roup s in both male and female rabbits. mg/kg/day. 6 hrs/day for 2 1 or 22 days 870.3465 28 -Day inhalation 49196901 (2013) NOAEL = I mg/L (HDT) toxicity (Rat) 0, 0.1 , 0.3 , or I m g/L LOAEL not established (actual exposure concentrations of0, 0.10 , 0 .3 0, or 1
.0 mg/L 870.3700a Prenatal 4232090 I ( 1992) NOEL= 1,000 mg/kg/day developmental Acceptable, guideline LOEL 

### =3 , 000 mg/kg/day , based on clinical (rat) Gavage GDs 7-17 signs oftoxicity (diarrhea 25 observations vs 2 0, 50, 350, I000 or 3000 mid-do se and 0 in controls) and on decreases in mg/kg/day
. body weight gain (GD7-9 , GD! 1-13 , and GDl5

- 17) and food consumption (GD7-13) during the dosing period. Overall bodyweight gain was normal. Rangefinding Study: Developmental NOEL= 3,000 mg/kg/day N=7 (HOT) 0,500, 1000, 3 ,000 , 5000 mg/kg/ day GD7-16 Rangefinding: 2/7 deaths at 5,000 MKD
. Significantly decreased food consumptions and increased clinical signs at 3 ,000 and 5,000 MKD
. No other effects were observed, including reproductive or fetal parameters.
Page 13of 16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 

### Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Fosamine Ammonium Guideline MRID No. (year)/ No. Study Type Classification /Doses Results 870.3700b Prenatal 49149902 (2013) Maternal NOAEL = 700 mg/kg/day developmental Acceptable , guideline LOAEL = was not observed (rabbit) 0, 100, 300, or 700 Developmental NOAEL = 700 mg/kg/day mg/kg/day LOAEL = was not observed Range-finding study 49149901 870.3800 Reproduction and 00075736 (1969) Phase 2 of the study evaluated FlA and Fl b fertility effects Non-guideline Fertility parameters only. (rat) I-generation Based on the fertility parameters evaluated in the study : Reproduction NOAEL 250/500 mg/kg/day Reproduction LOAEL not established
. Offspring parameters not evaluated. 870.4100a Chronic to xicity NA (rat) 870.4100b Chronic toxicity NA (dog) 870.4200 Carcinogenicity NA (rat) 870.4200 Carcinogenicity NA (mouse) 870.5100 Genotoxicity 41891601 (1991) Acceptable Ames bacterial Negative gene mutation assay 870.5300 Genotoxicity 00148267 (1991) Acceptable In vitro Negative mammalian cell gene mutation (HGPRT locu s in CHO) test 870
.5375 Genotoxicity 00147635 (1982) Acceptable In vitro Positive mammalian chromosome aberration assay in CHO cells 870
. 5395 Genotoxicity 00147636 (1982) Acceptable In v ivo Negative chromosome aberration (rat micronucleus) assay Page 14 of 16Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment D415249 

### Table A.2.2 Subchronic, Chronic and Other Toxicity Prorue

- Fosamine Ammonium Guideline MRID No. (year)/ No. Study Type Classification /Doses Results 870 .539 5 Genotoxicity 00147634 (1982) Not tested high enough. Unacceptable In vitro Unscheduled DNA synthesis/rat hvoatocytes 870.5395 Rat Spermatid 4400570 I ( 1996) Unacceptable Micronucleus Special 4294220 I ( 1993) No inhibition ofplasma, erythrocyte (RBC), or Cholinesterase Non-guideline brain ChE inhibition at 2 ,000 mg/kg/day. No Inhibition- rat Supplemental clinical signs or decrease in bodyweights observed. 0 or 2,000 mg/kg/day for NOAEL 2, 000 mg/kg/day 5 days
. Gavage in water LOAEL was not observed. 870.6100 Acute delayed 42934801 ( 1993) No clinical signs and no inhibition ofNTE or neurotoxicity- hen Acceptable/guideline ChE from the brain or spinal cord. 4 Gelatin capsules, 2000 Proliferations oftibial nerve in positive control and treatment but not vehicle control. mg/kg NOAEL 2,000 mg/kg
870.6200a Acute 42946501(1993) NOAEL 2,000 mg/kg neurotoxicity Acceptable, g uideline LOAEL was not observed. screening battery 0 , 500, 1000 or 2000 mg/kg/day 870.6200b Subchronic 42946502 (1993) NOEL < 299 mg/kg/day neurotoxicity Acceptabl e, guideline LOEL = 299 mg/kg/day, based on diarrhea in screening battery 0, 5000, I0,000 or 20,000 ppm in the diet for 96-98 males at all dose level s and in females at 1567 days (299 , 604 or 1193 mg/kg/day. mg/kg/day for males and Males: 6/12 low-, 8/12 mid-, 12/ 12 high- 398,779 or 1567 m g/kg/day for females) Females: 0112 low- , 1112 mid- , 11/1 2 high96-98 days ofdietary No differences in bodyweight or food exposure consumption. No neurotoxic effects at any dose level.
Occasional diarrhea observed in pilot study at similar dose levels.

870
. 6300 Developmental Not Required neurotoxicity

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### Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Fosamine Ammonium Guideline MRID No
. (year)/ No. Study Type Classification /Doses Results 870.7485 Metabolism and 00075740 (1974) Metabolism is rapid with 86% in feces and 11 % pharmacokinetics 00075742 ( 1973) in urine after 48 hrs. Compounds identified in (rat) the feces included 14C radiolabe ll ed fosamine ammonium (86%) and 14C Carbamoylphosphonic Acid (C PA) diammonium salt (14% ). The compounds in the urine were also fosamine ammonium and CPA
. 870.7600 Dermal penetration Not available (species) 870
.7800 lmmunotoxicity 49121701 (2013) NOAEL= I000 m g/kg/day (mouse) Acceptable , guideline LOAEL was not observed
. 28-day gavage 0 , I 00, 500 , and I000 Not immun otoxic in this test mg/kg bw / day

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