UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON. D.C. 20460

OFFICE OF

PREVENTION,

PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

March 25, 2010

SUBJECT: Fosamine Ammonium: Human Health Risk Scoping Document in Support of

Registration Review

PC Code: 106701 DP Barcode: D372168

Decision No.: 424372 Registration No.: NA

Petition No.: None Regulatory Action: Registration Review

Assessment Type: Scoping Document Reregistration Case No.: 2355

TXR No.: None CAS No.: 25954-13-6

MRID No.: None 40 CFR: §180.226

FROM: Becky Daiss, Biologist ::6..:..c C1.~v_j Risk Assessment Branch 4 J

Health Effects Division (7509P)

Office of Pesticide Programs

THROUGH:

Risk

Susan

Assessment

Hummel, Senior

Branch

Scientist

4

,~~

Health Effects Division (7509P)

Office of Pesticide Programs

TO: Russell Wasem

Risk Manager Reviewer

Reregistration Branch I

Pesticide Re-evaluation Division (7508P)

Office of Pesticide Programs

Executive Summary

Attached is Health Effects Division's (HED) human health risk assessment status update

for fosamine ammonium as part ofthe Registration Review process. Fosamine ammonium is an

herbicide. It is formulated as a liquid soluble concentrate. There are no registered food uses for

fosamine. The most recent risk assessment for fosamine ammonium was conducted in June,

1994 in support ofthe Reregistration Eligibility Decision document (RED) which was issued in

January, \995.

Page I of 1\
Page 2 of 11 

The 1994 risk assessment addressed exposures and risks associated with occupational 

exposures to fosamine ammonium. 1) A dietary exposure assessment was not conducted as there 

are no food uses for fosamine ammonium and dietary exposure is not expected. A qualitative 

drinking water exposure assessment determined that drinking water exposures were not of 

concern based on toxicity, fate and transport data for fosamine ammonium and its environmental 

degradates (carbamoylphosphonic acid and carboxylphosphonic acid). A dietary exposure and 

risk assessment is not required based on registered uses. A new drinking water exposure 

assessment is required. 2) A residential exposure assessment was not conducted and is not 

required as there are no residential uses and no anticipated residential exposures. 3) A 

qualitative occupational risk assessment was conducted. A new quantitative occupational 

exposure assessment is needed. 4) An aggregate risk assessment is not required because there 

are no food and no residential uses. 5) A subchronic inhalation toxicity study is required based 

on the registered uses and application methods. 6) A second developmental toxicity study in 

rabbits is required under the revised 40 CFR Part 158 Toxicology Data Requirements for 

nonfood use pesticides. 7) The available rat reproduction study needs to be reviewed and a data 

evaluation record (DER) generated. If the available study is determined to be unacceptable, an 

acceptable study will be required. 8) An immunotoxicity study is required under 40 CFR Part 

158 as a part of the new data requirements for registration of a pesticide (food and non-food 

uses). 
Page 3 of 11 

Introduction 

HED has evaluated the existing human health risk assessments for fosamine ammonium 

to determine whether sufficient data are available and whether a new human health risk 

assessment is needed to support Registration Review. HED has considered the most recent risk 

assessments for fosamine ammonium, updates to its toxicity, exposure and usage databases, and 

current Agency science policies and risk assessment methods. 

Use Profile 

Fosamine ammonium is an herbicide applied to non-agricultural rights-of way, industrial 

sites, fencerows, and pine plantations. It is uses for general weed control in uncultivated nonagricultural 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. Tolerances are not currently established for fosamine 

ammonium since there are no registered food or feed uses. Fosamine ammonium functions as a 

plant growth regulator. It apparently prevents dormant tissues from becoming active and 

growing again but its specific mechanism of action has not been identified. Fosamine 

ammonium is formulated as a water soluble liquid. It is applied by hand-held sprayer and 

helicopter. There are no residential uses and no residential exposures from the registered uses 

are anticipated. 

Chemical Identity 

Fosamine Ammonium Nomenclature 

Chemical Structure 

Common name Fosamine ammonium 

Company experimental name NA 

IUPAC name ammonium ethyl carbamoylphosphonate 

CAS name ethyl hydrogen (aminocarbonyl) phosphonate 

CAS # 25954-13-6 

 

Hazard Identification/Toxicology 

 Acute oral, dermal and inhalation studies were conducted with the 42% ai formulation. 

Based on these studies, fosamine ammonium exhibits low acute toxicity via the oral and 

inhalation routes (Toxicity Categories IV and III respectively and is moderately toxic via the 

dermal route of exposure (Toxicity Category II). Studies with 42% ai formulation indicate that 

fosamine ammonium is not an acute skin irritant, eye irritant or a dermal sensitizer, but it is 

considered a moderate-to-severe eye irritant (Toxicity Category II). Acute toxicity studies on the 
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42% ai formulation are considered adequate and requirements for acute oral, inhalation and 

dermal toxicity studies for fosamine ammonium technical have been waived. 

An acute neurotoxicity study in rats showed clinical signs of toxicity (diarrhea) at the low 

dose and possible neurotoxic effects (slight palpebral closure and irregular respiration) were 

observed at higher doses. Subchonic oral toxicity studies are available in rats and dogs. A 

subchronic study in rats showed evidence of kidney (swollen, vacuolated and degenerate deep 

proximal convoluted tubules) and urinary bladder effects (epithelial hyperplasia) and decreases 

in body weight, body weight gain and food consumption. Increased serum glucose was observed 

at the highest dose tested in one animal in the subchronic oral study in dogs. No other treatment 

related effects were observed in the dog study. Both the subchronic feeding studies in rats and 

dogs are categorized as Non-Guideline/Core Supplementary based on deviations from guideline 

requirements. However, the combined data from the two studies were determined to be 

sufficient to characterize subchronic fosamine toxicity for purposes of risk assessment. An 

acceptable guideline subchronic neurotoxicity study in rats showed clinical signs (diarrhea) at the 

low dose but there was no evidence of neurotoxic effects at any dose level. A 21-day dermal 

toxicity study showed no systemic effects at the highest dose tested (1500 mg/kg/day). A 

prenatal developmental toxicity study in rats showed offspring effects occurring only at or above 

treatment levels which resulted in evidence of parental toxicity. A rat reproduction study was 

available at the time the initial review was conducted in 1994. However, since reproduction 

studies were not required at that time for non food use pesticides, the study was not reviewed and 

documented with a data evaluation record (DER) which summarizes study results and guideline 

acceptability status. No chronic oral toxicity or carcinogenicity studies are available for 

fosamine ammonium. 

Toxicity points of departure (PODs) were not selected for use in risk assessment for any 

exposure route for the 1994 assessment. Acute and chronic dietary exposure endpoints were not 

selected because there are no registered food or feed uses for fosamine ammonium. Toxicity 

endpoints for occupational exposures via dermal and inhalation pathways were not selected for 

the 1994 assessment because the toxicity endpoints from the available toxicity studies did not 

trigger risk concern based on expected exposure (i.e., the No Observed Effect Levels were 

considered sufficiently high). 

 

Data Requirements

Chronic oral toxicity and carcinogenicity studies are not available but are not required for 

fosamine ammonium because there are no current or proposed food uses. A second 

developmental toxicity study in rabbits is required under the revised 40 CFR Part 158 

Toxicology Data Requirements for nonfood use pesticides. A reproduction study in rats is also 

required under the revised Part 158 requirements. The available rat reproduction study needs to 

be reviewed and a DER generated. If the available study is determined to be unacceptable, a 

data call in (DCI) for an acceptable guideline rat reproduction study will be issued to the 

registrant. An acceptable dermal toxicity study is available. A subchronic inhalation toxicity 

study is required based on the registered uses and application methods (i.e., aerial and hand held 

spray). The available acute and subchronic neurotoxicity studies fulfill revised 40 CFR Part 158 

Toxicology Data Requirements under 870.6200. While the results of the available toxicity 
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studies provide no evidence for immunotoxicity, an immunotoxicity study is required as a part of 

new data requirements in the 40 CFR Part 158 for conventional pesticide registration. Because 

the immune system is highly complex, studies not specifically conducted to assess immunotoxic 

endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from 

hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic 

toxicity studies may offer useful information on potential immunotoxic effects, these endpoints 

alone are insufficient to predict immunotoxicity. 

Conclusions

The HED Registration Review problem formulation team has re-evaluated the toxicity 

analysis conducted for the 1994 fosamine ammonium risk assessment based on current Agency 

policies. Based on this evaluation, PODs for inhalation and dermal exposures are required 

according to current standards for hazard identification and endpoint selection. An inhalation 

toxicity study is required based on registered uses and application methods. A developmental 

toxicity study in a second species (rabbit) and an immunotoxicity study are required under 40 

CFR Part 158 (Appendix A). 

 In the absence of required studies, EPA may use a database uncertainty factor of up to 

10X. Once all of the newly required toxicity data have been received and reviewed, the 

Fosamine ammonium Registration Review Team recommends that dermal and inhalation PODs 

and safety factors be established and a new occupational risk assessment conducted. 

Dietary Exposures 

An assessment of dietary exposures is not required because fosamine ammonium has no 

registered food uses. Drinking water degradates of potential concern were identified in the 1994 

assessment. However, a qualitative assessment of potential drinking water exposure conducted 

for the 1995 RED concluded that drinking water risks were not of concern based on toxicity and 

fate and transport data for fosamine ammonium and its environmental degradates 

(carbamoylphosphonic acid and carboxylphosphonic acid). The analysis found that because 

fosamine ammonium degrades rapidly in aerobic and anaerobic environments there is low 

probability that it will be found in either ground or surface water. The environmental degradates 

of fosamine ammonium, carbamoylphosphonic acid and carboxylphosphonic acid were 

determined not to be of toxicological concern. The toxicity finding regarding environmental 

degradates has been reviewed and confirmed by the HED Registration Review Team. 

Conclusions

A dietary exposure assessment is not required for fosamine ammonium because there are 

no registered food uses. However, under the Food Quality Protection Act (FQPA) of 1996, a 

new quantitative drinking water assessment is required for Reregistration Review. 

 

Residential Exposure 

Based on the registered uses there are no residential exposures for fosamine ammonium. 

A residential exposure assessment is not required. 
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Aggregate Exposure 

An aggregate exposure assessment is not required based on registered uses. 

Occupational Exposure 

An occupational exposure assessment was last conducted for fosamine ammonium in 

April, 1994 in support of the RED which was issued in January, 1995. Five worker handler 

exposure scenarios were identified and assessed: (1) open mixing/loading liquid for high 

pressure handwand application, (2) open mixing/loading liquid for fixed-wing aerial application, 

(3) applying with a high pressure handwand, (4) applying with a backpack sprayer, and (5) 

applying aerially. Estimated exposures (mg/kg/day) for occupational handlers were derived for 

dermal and inhalation pathways for each exposure scenario based on application rates and 

standard, scenario specific unit exposures. However, a quantitative assessment of risk to 

handlers was determined to be unnecessary since a qualitative review of results of acceptable 

toxicity studies combined with expected exposure did not trigger risk concerns. Post-application 

exposure and risk was not quantitatively assessed because the potential for post-application 

exposure to fosamine ammonium residues was determined to be low based on use patterns (i.e., 

the herbicide is used in areas where re-entry exposure is expected not to be problematic, such as 

rights-of-ways). 

Conclusions

An updated occupational risk assessment is needed for the Registration Review of 

fosamine ammonium in light of significant changes to standard exposure protocols, assumptions 

and algorithms. A quantitative occupational exposure and risk assessment is required based on 

current standards. Selection of toxicity endpoints for dermal and inhalation worker exposure is 

needed for use in a quantitative worker risk assessment. 

Incident Report 

 No incident cases have been identified for fosamine ammonium at this time. Therefore, 

there does not appear to be a concern 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. 

Cumulative 

EPA does not have, at this time, available data to determine whether fosamine 

ammonium has a common mechanism of toxicity with other substances. EPA has not made a 

common mechanism of toxicity finding for fosamine ammonium and any other substances and, 

fosamine ammonium does not appear to produce a toxic metabolite produced by other substances 

which have tolerances in the U. S. Therefore, EPA has not assumed that fosamine ammonium 

has a common mechanism of toxicity with other substances. 
Page 7 of 11 

Human Studies 

The RED relied in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies were used in developing the 

PHED Surrogate Exposure Guide which was used to estimate exposure to workers. The studies 

have been determined to require a review of their ethical conduct and have received the 

appropriate review. 

Conclusions/Future Actions Needed 

The actions needed in the future Registration Review for fosamine ammonium are listed below. 

Hazard Identification and Endpoint Selection

The existing hazard identification and endpoint selection assessment needs to be reevaluated and 

updated based on current requirements and methodologies for assessing occupational risks from 

use of fosamine ammonium. A developmental toxicity study in rabbits and an immunotoxicity 

study is required in accordance with the revised 40 CFR Part 158 Toxicology Data 

Requirements. The available rat reproduction study needs to be reviewed and a data evaluation 

record (DER) generated. If the available study is determined to be unacceptable, a data call in 

(DCI) for an acceptable guideline rat reproduction study will be issued to the registrant. A 

subchronic inhalation toxicity study is required based on the registered uses and application 

methods (i.e., aerial and hand held spray). 

Dietary Exposure and Risk

A dietary exposure assessment is not required. A new drinking water exposure assessment is 

required. 

 

Residential Exposure and Risk

A residential risk assessment is not required. 

Aggregate Exposure and Risk

An aggregate exposure assessment is not required. 

Occupational Exposure and Risk

A quantitative occupational exposure assessment needs to be conducted to incorporate newly 

identified toxicity endpoints and to reflect current refined exposure assumptions and algorithms. 

Incident Report

An updated incident report is not required at this time. 

Data Requirements

- 28 Day Inhalation Toxicity Study (GLN 870.3465) 

- Developmental Toxicity – Rabbit (GLN 870.3700b) 

- Immunotoxicity study (GLN (870.7800) 
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References 

HED Chapter of the Reregistration Eligibility Document (RED) for Fosamine Ammonium, A. 

Aikens (6/28/94) 

Occupational and Residential Exposure Assessment and Recommendations for the Reregistration 

Eligibility Document for fosamine Ammonium, L Morris (4/12/1994, D199439) 

RFD/Peer Review Report of Fosamine Ammonium, G. Ghali (5/22/94) 

Fosamine Ammonium. Revised Toxicology Chapter, D Canales (3/8/94, D197642) 

Reregistration Elegibility Decision (RED) Fosamine Ammonium (1/95) 
Page 9 of 11 

Appendix A 

Guideline Number: 870.3465 

Study Title: 28-Day Inhalation - Rat 

Rationale for Requiring the Data 

This study is required under the updated data requirements at 40 CFR 158.500 because fosamine 

ammonium is applied as a high volume, high pressure spray so there is a likelihood of significant 

repeated exposure to applicators. As discussed in the footnotes at 40 CFR 158.500, a nonguideline 21- or 28-day study is sufficient in situations, like here, where intermediate-term rather 

than chronic exposure is expected. A 21- or 28-day study would be considerably less costly for 

the registrant to conduct. 

Practical Utility of the Data 

How will the data be used? 

The 28-inhalation toxicity study would allow EPA to properly characterize the hazard and risks 

to occupational workers associated with applying fosamine ammonium as an aerosol. 

How could the data impact the Agency’s future decision-making? 

In the absence of inhalation toxicity data, EPA would have to estimate inhalation risks using oral 

toxicity studies and relying on the assumption that absorption and toxicity of fosamine 

ammonium are the same via the oral and inhalation routes of exposure. Receiving the inhalation 

data would allow the Agency to refine its estimates of inhalation risks, to ensure that those risks 

are not overestimated or underestimated. 

Guideline Number: 870.3700 

Study Title: Pre-natal Developmental Toxicity- Non Rodent Species 

Rationale for Requiring the Data 

The pre-natal developmental toxicity study in a second species (non-rodents) is a new data requirement 

under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for food and nonfood uses. 

The pre-natal developmental toxicity Test Guidelines (OPPTS.870.3700) is designed to provide general 

information concerning the effects of exposure of the pregnant test animals (non-rodent) on the 

developing organism; this may include death, structural abnormalities, or altered growth and an 

assessment of maternal effects.. 

The Agency needs this study in a second species (non-rodents, preferably in rabbits) for food and nonfood use pesticides because the Agency believes that testing in two species (rodents and non-rodents) 

provides a balance assessment, eliminates uncertainty of assessing of risk only in sensitive (or insensitive) 

species, and would adequately characterize potential hazards to pregnant women and their fetuses. 

Practical Utility of the Data 

How will the data be used? 

This study will provide critical scientific information needed to characterize potential hazard to pregnant 

women and their fetuses exposed to the pesticide by the oral route. This study can provide a dose and a 
Page 10 of 11 

Guideline Number: 870.3700 

Study Title: Pre-natal Developmental Toxicity- Non Rodent Species 

toxicological endpoint of concern for quantification of risks for the sensitive population (i.e. pregnant 

females). 

How could the data impact the Agency’s future decision-making? 

If the results of this study indicate the non-rodent species to be more sensitive than the rodents, and 

provides data that indicates that the test material poses either a greater or lesser risk than that currently 

used, the risk assessment would be revised to reflect the magnitude of potential risk derived from the new 

data. Also, the requested data would allow the Agency to determine if the risks were over-estimated or 

under-estimated. If the risks were under-estimated, additional risk mitigation measures could be required. 

If the risks were over-estimated, risk mitigation measures could be reduced. 

Guideline Number: 870.7800 

Study Title: Immunotoxicity

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity 

testing and is designed to evaluate the potential of a repeated chemical exposure to produce 

adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the 

ability of the immune system to respond to a challenge of bacterial or viral infections such as 

tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the 

immune system is highly complex, studies not specifically conducted to assess immunotoxic 

endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from 

hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic 

toxicity studies may offer useful information on potential immunotoxic effects, these endpoints 

alone are insufficient to predict immunotoxicity. 

Practical Utility of the Data 

How will the data be used? 

Immunotoxicity studies provide critical scientific information needed to characterize potential 

hazard to the human population on the immune system from pesticide exposure. Since 

epidemiologic data on the effects of chemical exposures on immune parameters are limited and 

are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies 

are used as the most sensitive endpoint for risk assessment. These animal studies can be used to 

select endpoints and doses for use in risk assessment of all exposure scenarios and are considered 

a primary data source for reliable reference dose calculation. For example, animal studies have 

demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of 

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and 

endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for 

tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 
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Guideline Number: 870.7800 

Study Title: Immunotoxicity

If the immunotoxicity study shows that the test material poses either a greater or a diminished 

risk than that given in the interim decision’s conclusion, the risk assessments for the test material 

may need to be revised to reflect the magnitude of potential risk derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied for 

conducting a risk assessment from the available studies.