UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON. D .C. 20460

OF FICE OF

PREVE NTION

, PEST ICIDES AND TOXIC SUBSTA NCES

MEMORANDUM

March 25

, 2010

SUBJEC T: 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: Susan Hummel, Senior Scientist

## ,~~ Risk Assessment Branch 4

Health Effects Division (7509P)

Office of Pesticide Programs

TO: R ussell W asem
R isk 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 of the 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 of the 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 dietar y exposure assessment was not conducted as there

are no food uses for fosamine ammonium and diet ary exposure is not exp ected. A qualitative drinking water exposure assessment determined that drinking water e xposures were not of concern based on toxicity, fate and transport data for fosamine ammonium and its environmental degradates (carbamoylphosphonic acid and carb oxylphosphonic acid). A dietary exposure and risk assessment is not required based on regi stered uses. A new drinking water exposure assessment is required. 2) A residential e xposure 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 aggregat e risk assessment is no t required because there are no food and no residential uses. 5) A subchronic inhalation toxicity study is required based on the registered uses and app lication methods. 6) A second de velopmental toxicity study in rabbits is required under the revised 40 CFR Part 158 Toxicology Data Requirements for nonfood use pesticides. 7) The available rat repr oduction study needs to be reviewed and a data evaluation record (DER) generated. If the available study is dete rmined to be unacceptable, an acceptable study will be required. 8) An immunot oxicity study is required under 40 CFR Part 158 as a part of the new data requirements fo r 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 ava ilable and whether a new human health risk assessment is needed to support Registration Revi ew. HED has considered the most recent risk assessments for fosamine ammonium, updates to it s toxicity, exposure and usage databases, and current Agency science policies and risk assessment methods.

Use Profile

Fosamine ammonium is an herbicide applie d 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-cr op producing farmyards, fuel storage areas, fencerows) and industrial sites (e .g., lumberyards, pipeline and ta nk farms). It is applied as a pre-plant herbicide to pine plan tations to prevent growth of unde sirable seedlings and saplings and suppress growth of brush and vines. Tolera nces are not currently established for fosamine ammonium since there are no regist ered food or feed uses. Fosamine ammonium functions as a plant growth regulator. It a pparently 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 li quid. It is applied by hand-held sprayer and helicopter. There are no reside ntial uses and no residential expos ures 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 inhala tion studies were conducted with the 42% ai formulation. Based on these studies, fosamine amm onium exhibits low acute toxicity via the oral and inhalation routes (Toxicity Categories IV a nd III respectively and is moderately toxic via the dermal route of exposure (Toxicity Category II). Studies with 42% ai fo rmulation 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 thePage 4 of 11 42% ai formulation are consider ed adequate and requirements fo r acute oral, inhalation and dermal toxicity studies for fosamine a mmonium technical have been waived.

An acute neurotoxicity study in rats showed clin ical signs of toxicity (diarrhea) at the low dose and possible neurotoxic effect s (slight palpebral closure and irregular respiration) were observed at higher doses. Subchoni c oral toxicity studi es are available in rats and dogs. A subchronic study in rats showed evidence of kidn ey (swollen, vacuolated and degenerate deep proximal convoluted tubules) and urinary bladder effects (epithe lial hyperplasia) and decreases in body weight, body weight gain and food consum ption. Increased serum glucose was observed at the highest dose tested in one animal in the subchronic oral study in dog s. No other treatment related effects were observed in the dog study. Bo th the subchronic feedi ng studies in rats and dogs are categorized as Non-Guideline/Core Su pplementary based on deviations from guideline requirements. However, the combined data fr om the two studies were determined to be

sufficient to characterize subchronic fosamine t oxicity 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 sh owed offspring effects oc curring 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 evaluati on 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 expos ure endpoints were not selected because there are no registered food or feed uses for fosamine ammonium. Toxicity endpoints for occupational exposures via dermal a nd 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 carci nogenicity studies are not availa ble 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 repr oduction 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 availa ble study is determined to be unacceptable, a data call in (DCI) for an accep table 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 neur otoxicity studies fulfill revised 40 CFR Part 158 Toxicology Data Requirements under 870.6200. While the results of the available toxicityPage 5 of 11 studies provide no evidence for imm unotoxicity, an immunotoxicity stud y is required as a part of new data requirements in the 40 CFR Part 158 fo r conventional pesticide registration. Because the immune system is highly complex, studies no t specifically conducted to assess immunotoxic endpoints are inadequate to charact erize a pesticide’s potential im munotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine ch ronic or subchronic toxicity studies may offer useful information on potential immunotoxic e ffects, these endpoints alone are insufficient to pr edict immunotoxicity.

Conclusions

The HED Registration Review problem formula tion team has re-evaluated the toxicity analysis conducted for the 1994 fosamine ammoni um 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 identif ication and endpoint selection. An inhalation toxicity study is required base d 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 uncertain ty 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 ne w occupational risk assessment conducted.

Dietary Exposures

An assessment of dietary exposures is not required because fosamine ammonium has no registered food uses. Drinking wa ter degradates of potential con cern were identified in the 1994 assessment. However, a qualitative assessmen t of potential drinking water exposure conducted for the 1995 RED concluded that drinking water risk s were not of concern based on toxicity and fate and transport data for fosamine a mmonium and its environmental degradates (carbamoylphosphonic acid and carboxylphosphonic acid). The analysis found that because fosamine ammonium degrades rapidly in aer obic 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 concer n. The toxicity finding regarding environmental degradates has been reviewed and confirme d by the HED Registration Review Team.

Conclusions

A dietary exposure assessment is not require d for fosamine ammoni um because there are no registered food uses. However, under the Food Quality Protection Act (FQPA) of 1996, a new quantitative drinking water assessmen t is required for Reregistration Review.

Residential Exposure

Based on the registered uses there are no resi dential exposures for fosamine ammonium. A residential exposure assessm ent is not required.Page 6 of 11 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 is sued in January, 1995. Five worker handler exposure scenarios were identified and asse ssed: (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/da y) for occupational handlers were derived for dermal and inhalation pathways for each expos ure scenario based on application rates and standard, scenario specific unit exposures. However, a quantit ative 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 con cerns. Post-application exposure and risk was not quantitatively assesse d because the potential for post-application exposure to fosamine ammonium residues was dete rmined to be low based on use patterns (i.e., the herbicide is used in areas where re-entry expo sure 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 cha nges 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 fo samine ammonium at this time. Therefore, there does not appear to be a concern that woul d warrant further investig ation. The Agency will

continue to monitor the incident information a nd 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 subs tances. EPA has not made a common mechanism of toxicity finding for fosami ne 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. Therefor e, EPA has not assumed that fosamine ammonium

has a common mechanism of toxici ty with other substances.Page 7 of 11 Human Studies

The RED relied in part on data from studi es 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 Re view for fosamine ammonium are listed below.

Hazard Identification an d Endpoint Selection The existing hazard identification and endpoint se lection assessment needs to be reevaluated and updated based on current requirements and methodol ogies for assessing occupational risks from use of fosamine ammonium. A developmental to xicity study in rabbits and an immunotoxicity study is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. The available ra t 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 st udy is required based on the regi stered 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 assessm ent is not required.

Occupational Exposure and Risk A quantitative occupational exposure assessment needs to be conducted to incorporate newly identified toxicity endpoints a nd to reflect current refined expo sure assumptions and algorithms.

Incident Report An updated incident report is not required at this time.

Data Requirements

- 28 Day Inhalation Toxi city Study (GLN 870.3465) - Developmental Toxicity – Rabbit (GLN 870.3700b) - Immunotoxicity study (GLN (870.7800)Page 8 of 11 References

HED Chapter of the Reregistration Eligibility Document (RED) for Fosamine Ammonium, A. Aikens (6/28/94)

Occupational and Residential Exposure Assessmen t and Recommendations for the Reregistration Eligibility Document for fosamine Ammonium, L Morris (4/12/1994, D199439)

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

Fosamine Ammonium. Revised Toxicol ogy 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 pressu re 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 su fficient 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 applyi ng fosamine ammonium as an aerosol.

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

In the absence of inhalation toxi city data, EPA would have to es timate inhalation risks using oral toxicity studies and relying on the assumption that absorptio n and toxicity of fosamine

ammonium are the same via the oral and inhalati on routes of exposure. Receiving the inhalation data would allow the Agency to refine its estimate s 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 seco nd species (non-rodents) is a new data requirement under 40 CFR Part 158 as a part of the data requireme nts for registration of a pesticide for food and nonfood uses.

The pre-natal developmental toxicity Test Guid elines (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, st ructural abnormalities, or altered growth and an

assessment of maternal effects..

The Agency needs this study in a second species (non-rodents, prefer ably in rabbits) for food and nonfood use pesticides because the Agen cy 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 th e oral route. This study can provide a dose and aPage 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 sp ecies 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, add itional 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 pesticid e (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870 .7800) prescribes functional immunotoxicity testing and is designed to evaluate the potenti al of a repeated chemical exposure to produce adverse effects (i.e., suppression ) on the immune system. Immunos uppression is a deficit in the ability of the immune system to respond to a chal lenge of bacterial or vi ral infections such as tuberculosis (TB), Severe Acqui red Respiratory Syndrome (SARS) , or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to charact erize a pesticide’s potential im munotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine ch ronic or subchronic toxicity studies may offer useful information on potential immunotoxic e ffects, these endpoints

alone are insufficient to predict immunotoxicity.

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provi de critical scientific informati on 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 as sessment. These animal studies can be used to select endpoints and doses for use in risk assessm ent of all exposure scenar ios and are considered a primary data source for reliable reference dos e calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenz o-p-dioxin) among developm ental, reproductive, and endocrinologic toxicities. Additionally, the EPA ha s 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?Page 11 of 11 Guideline Number: 870.7800 Study Title : Immunotoxicity If the immunotoxicity study shows th at the test material poses eith er a greater or a diminished risk than that given in the inte rim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnit ude of potential risk derived from the new data.

If the Agency does not have this data, a 10X da tabase uncertainty factor may be applied for conducting a risk assessment from the available studies.