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: I 0670 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 Risk Assessment 

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 

Risk 

Nieves, 

Assessment 

ORE 

Branch 

Assessor 

(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 Division (7508P) 

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Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 0415249 

Table of Contents 

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 Pesticide Use Pattern ........................................................................................................ 5 

3.4 Anticipated Exposure Pathways ....................................................................................... 5 

4.0 Hazard Characterization and Dose-Response Assessment .................................................. 6 

4.1 Toxicology Analysis ........................................................................................................ 6 

4.2 Consideration of Toxicity for Children ........................................................................... 7 

4.3 Toxicity Endpoint and Point of Departure Selections ...................................................... 7 

4.4 Endocrine Disruption ....................................................................................................... 7 

5.0 Dietary Exposure and Risk Assessment.. ............................................................................. 8 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ....................................... 8 

6.1 Spray Drift ........................................................................................................................ 8 

6.2 Residential Bystander Post-Application Inhalation Exposure ......................................... 8 

7.0 Aggregate Exposure/Risk Characterization ......................................................................... 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. Toxicology Profile and Executive Summaries ....................................................... 11 

A.1 Toxicology Data Requirements ...................................................................................... 11 

A.2 Toxicity Profiles: ............................................................................................................ 12 

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Fosamine 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 of the 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 of fosamine 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 of pesticides. 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. 

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Fosamine Ammonium 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 Barcode). The human health scoping document in support of Registration 

Review (B. Daiss, 25 March 2010, 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 Chemical Identity 

Table 3.1. Test Compound Nomenclature 

Chemical Structure 0 u- l\H1/ '/ / 

H \ .P., 

N- C/ "o-C-l2-8H3 

I I 

H 0 

Common name Fosamine ammonium 

IUPAC name ammonium ethyl carbamoylphosphonate 

CAS name ethyl hydrogen (aminocarbonyl) phosphonate 

CAS# 25954- 13-6 

PC Code 106701 

3.2 Physical/Chemical Characteristics 

Table 3.2. Physicochemical Properties of Fosamine Ammonium. 

Parameter Value Reference 

Melting point 173-175 °°C (decomposition) 

Water Solubility Completely miscible in water.8 mg/L at 25°C 1995 RED1 

Methylene chloride, ether, hexane, 

< 1 ppm toluene 

1 ppm Acetone 

2ppm Acetonitrile 

Solvent Solubility 17 g./100 ml Methanol 

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 log Kow: 4.2 

I Reregistration Eligibility Decision (RED) Fosamine Ammonium (1/95) EPA 738-R-95-004 

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Fosamine 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 of undesirable seedlings and saplings and suppress growth of brush 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 of a pesticide. These data are analyzed and categorized by subgroups 

based on age, season of the 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 of pesticide products and associated risks for adult applicators and 

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Fosamine Ammonium Registration 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 of fosamine 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 of the 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 doses. 

Cholinesterase inhibition was not observed up to 2,000 mg/kg/day 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. 

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Fosamine Ammonium Registration 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 evidence 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 of toxicity 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 of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects 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 of its 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 of the 

Endocrine Disruptor Screening Program (EDSP). 

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Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 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 of the 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 of these 

lists should be construed as a list of known 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 risk 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=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals. 

2 2 http://www.epa.gov/endo/ 

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Fosamine 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 of toxicity, 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. 

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Fosamine 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. 

Reregistration 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 I 0911 :PY-S:(703)305-7462:7509P:RABIV 

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Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment D415249 

Appendix A. Toxicology Profile and Executive Summaries 

A.1 Toxicology Data Requirements 

Study 

Technical 

Required 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 yes 

870.2600 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 Toxicity (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 gene mutation test.. ..... yes yes 

870.5375 Mutagenicity- /n vitro mammalian chromosome aberration test yes yes 

870.5395 Mutagenicity- Mammalian erythrocyte micronucleus test. ....... yes yes 

870.6100a 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 ...................................................... yes yes 

870.7600 Dermal Penetration ....................................................... no no 

870.7800 Immunotoxicity ............................................................. yes yes 

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Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment 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 LDso > 5000 IV 

mg/kg 

870.1200 Acute dermal [Rabbit] 43846407 LDso = >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. 

Blistering of 

conjunctiva also 

observed 

870.2500 Acute dermal irritation [Rabbit] 43846410 Mild dermal IV 

irritation. 

Erythema cleared 

by48 hrs. 

870.2600 Skin sensitization [guinea pigs] 43846411 Non-sensitizer NA 

under conditions 

of study. 

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Fosamine 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 of potential 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, I 000 or 

5000/ 10000 ppm in the 

diet (0, I 0, 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). 

870.3200 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 groups 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) NOA EL = I mg/L (HDT) 

toxicity (Rat) 0, 0.1 , 0.3, or I mg/L LOAEL not established 

(actual exposure 

concentrations of 0, 0.10, 

0.30, 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 of toxicity (diarrhea 25 observations vs 2 

0, 50, 350, I 000 or 3000 mid-dose 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. 

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Fosamine 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 Fl A 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 toxicity 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 locus 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 vivo Negative 

chromosome 

aberration (rat 

micronucleus) 

assay 

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Fosamine 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 

870.5395 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 of plasma, 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 of tibial 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, guideline 

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 Acceptable, guideline LOEL = 299 mg/kg/day, based on diarrhea in 

screening battery 0, 5000, I 0,000 or 20,000 

ppm in the diet for 96-98 males at all dose levels 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 mg/kg/day 

for females) Females: 0112 low-, 1112 mid-, 11/12 high96-98 days of dietary 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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Fosamine Ammonium Registration Review DRAFT Human Health Risk Assessment D415249 

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 radiolabelled fosamine 

ammonium (86%) and 14C 

Carbamoylphosphonic Acid (CPA) 

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= I 000 mg/kg/day 

(mouse) Acceptable, guideline LOAEL was not observed. 

28-day gavage 

0, I 00, 500, and I 000 Not immunotoxic in this test 

mg/kg bw/day 

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