## TO XICO LOGI CAL PROFI L E FOR AMMONI A

U.S. DEPAR T MENT OF HEALTH AND HUM AN SERVICES Public Health Service Agency for Toxic Substanc es and Disea s e Registry

Septem ber 2004AMMONIA ii



### DISCLAIMER

The use of com p any or pro duct nam e (s) is for identifi cation onl y and d o es not i m ply endorsement by the Agency for Toxic Substanc es and Disea s e Registry

.AMMONIA iii



### UPDATE STATEMENT
A Toxicologi cal Profile for Amm onia, Draft for Publ i c Co mment, was released in Septem ber 2002

. This edition supers edes any previously release d draft or fina l profile. Toxicological profiles are revised and republished as necessary . For inform ation regarding th e update status of previously release d profiles, contact ATSDR at: Agency for Toxic Substanc es and Disea s e Registry Division of T oxicolog y /To x icolog y Info rm ation Branch 1600 Clifton Road NE, Mailstop F-32 Atlanta, Georgia 303 33AMMONIA vi

* Legislative Background The toxicolo g i cal profiles are developed in response to the Superfund Amend m en ts and Reauthorization Act (SARA) of 198 6 (Pu b l i c law 99-499 ) which am en ded the Comprehensive Environm ental Response, Co m p ensation, and Liabili ty Act of 19 8 0 (CERCLA or Superfund)

. This public law directed ATSDR to prepare toxicological profiles for hazard ous s ubstances m o st co mmonly found at facilities on the CERCLA National Prioriti es List and that pose the mo st significant potential threat to hum an health, as determ ined by ATSDR and the EPA. T h e availability of the revis e d priority l i st of 275 hazardous substances was announced in the Federal Register on Novem b er 17, 1 997 (62 FR 6133 2). For prior versions of the list of substances, se e Fe deral Register notices dated April 29, 1996 (61 FR 18744); April 17, 1 987 (52 FR 1286 6); October 20, 1 9 88 (53 FR 41 280); October 26, 198 9 (54 FR 4361 9); October 17, 1990 (55 FR 4206 7); Octo ber 17, 1 991 (56 FR 52 166 ); October 28, 199 2 (57 FR 4880 1); and February 28, 1 994 (59 FR 9486). Section 10 4(i)(3 ) of CERCLA, as amended, directs the Ad m i nistrator of ATSDR to prepare a toxicological profile for each substance on the list.AMMONIA vii



### QUICK REFERENCE FOR HE ALTH CARE PROVIDERS Toxicological Profiles are a unique com p ilation of t oxi cological inform ation on a given hazardous substance. Each profile reflects a co m p rehensive and extensive evaluation, summary , and i n t e rpretation of available toxicologic and epidem iologic inform ati on o na subst ance. Health care providers treating patients potentially exposed to hazardous substances wi ll find th e foll owing inf o rmation helpful for fast answer s to often-asked questions.
Primary Cha p ters/Section s of Interest Chapter 1: Public Health Statem ent : The Public H ealth State m e n t can be a useful tool for educating patients about possible exposure to a hazardous subs tance. It explains a substance’ s relevant toxicolo gic pr operties in a nontechnical, question-and

- answer format, and it incl udes a review of the general health effects observed foll owing expos ure. Chapter 2: Relevance to Public Health : The Relevance to Public Health Sect ion evaluates, interprets, and asses ses t h e significance of toxicity data to hum an health. Chapter 3: Health Effects : Specific health effects of a given ha zardous co m pound are reported b y type of health effect (death, sy st em ic, immunologic, re pro ductive), b yroute of exp o sure, and b ylength of exposure ( acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE : Not a ll health effec t s reported in this sec tion are neces sarily observed in the clinical setting. Please refer to the Public Health State m ent to identify general health effe cts observed following exposure. Pediatrics : Four new sec tions have be en added to e achToxicological Profile to address child health issues: Section 1.6 How Can (C hemical X ) Affect Children? Section 1.7 How Can Families Reduce th e Risk of Exposure to (Chemi cal X )? Section 3.7 Children’s S u sceptibility Section 6.6 Exposures of Children Other Se ctio ns of Interes t: Section 3.8 Biom arkers of Exposure and Effect Section 3.11 Methods for Reducing Toxic Effects
ATSDR Info rmation Center Phone: 1-888- 42-ATSDR or (404) 498-0 110 Fax: (770) 4 88-4 1 78 E-mail: atsdric@cdc.gov Internet : http://www.atsdr.cdc.gov The following additional material can be or dered through the ATSDR Inform ation Center: Case Studies in Environmental M e dicine: Taking a n E x

posure History —The importance of taking an exposure hist or y and how t o conduct on e are desc ribed, and an exam ple of a tho r ough exposure history is provided. Other case studies of interest include Reproduc tive and DevelopmentalAMMONIA viii

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity ; and num erous che m ical- s pecifi c cas e studies

. M

anaging Hazardous M a terials Incidents is a three-v o lum e s e t of reco mmendati ons for on-scene (prehospital) and hospital medical managem e nt of patients exposed during a hazardous materi als incident. Vol u mes I and II are planning guides to assist first responders and hospital em ergency depart m e nt personnel in pl anning f o r incidents th at involve hazar dous m a teri al s. Volum e II I— M

e dical M a n agement Guidelines for Acute Chemical Exposure s—i s a guide for health care professionals treating patients exposed t o hazardous materi als. Fact Sheets (ToxFAQs) provide answers to frequentl yaskedquestions about to xic substances.
Other Agenci es and Organizations The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, injur y , and di sability related to the i n teractions between people and their environment outside the workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway , NE, Atlanta, GA 30341-3 7 24 • Phone: 7 70-48 8-70 00 • FAX: 770-4 88-70 15. The National Institute for Occupational Safety and Health (NIOSH) conducts resear ch on occupational diseases and injuries, responds to request s for assist an ce by i nvestigating problems of health and safety in the workplace, re co mmends standard s to the Occupational Safety and Health Ad m i nistration (OSHA) an d the Mine Sa fety and Health Adm i nistration (MSHA), and trains professionals in occupational safety and health

. Conta c t: NIOSH, 2 00 Independence Avenue, SW, Washing t on, DC 20 20 1 • Phone: 80 0-356- 467 4 o r NIOSH Technical Information Branch, Robert A. Taft Laborator y , Mailstop C-19, 46 76 Col um b ia Parkway, Cincinnati, OH 45226- 1 998

• Phone: 800- 35-NIOSH. The National Institute of E n vironmental Health Sciences (NIEHS) i s the principal federal agency for biom edic al re search on the effects of che m ical, phy sical, and biologic e nvironm e n tal agents on hum an health and well-being. Co ntact: NIEH S, PO Box 12 233, 1 04 T.W. Alex ander Drive, Research Triangle Park, NC 2770 9 • Phone: 91 9-54 1

- 3212.
Referrals The Association of Occupa tional and En vironmental Clinics (AOEC) has developed a network of clinics in the United States to provide expertise in o ccupation a l and enviro nmental issues. Contact: AOEC, 1010 Verm ont Avenue, NW, #5 13, Washingt on, DC 20 00 5 • Phone: 2 02-34 7-49 76

• FAX: 202- 347-4950 • e-mail: AOE C@AOEC.ORG • W e b Page: http://www.aoec.org/. The America n College of Occupational and E n viron m ental M e dicine(ACOEM ) is an associa tion of phy s icians and other healthcare providers sp ecializing in the field of occupational and environm ental medicine. Contact: ACOEM, 55 West Seegers Ro ad, Arlington Heights, IL 6000 5 • Phone: 8 47-8 1 8 -180 0 • FAX: 847-8 18- 9266

.AMMONIA ix



### CONTRIBUTORS

CHEM ICA L MANA GE R(S)/AUT HOR(S): Nickolette Roney , MPH ATSDR, Division of To xicolog y , Atlant a, GA Fernando Llados, Ph.D. Sy racuse Res earch Corporation, North Sy racuse, NY Susan S. Littl e, Ph.D. Sy racuse Res earch Corporation, North Sy racuse, NY David B. Knaebel, Ph.D. Sy racuse Res earch Corporation, North Sy racuse, NY

THE PROFILE HAS UNDERGONE THE F O LL OWI N G A T SDR IN TER NAL R E VI E W S:

1. Health Effect s Review. The Health Effe ct s Review C o mmittee exa m ines the hea lth effects chapter of ea ch profile for consistency and accur acy in interpreting health effect s and classify ing end poi nts. 2. Minimal Risk Level Review. The Mini mal Risk Lev e l Workgrou p considers issues relevant to substance-spe c ific Mini m a l Risk Levels (MRLs) , revie w s the health effects dat a ba se of each profile, and makes reco mmendati ons for derivation of MRLs. 3. Data N eeds R e view. The Rese arch I m p l e m entation Branch revie w s data needs sections to assure consistency across profiles and adherence to instructions in the Guidance.AMMONIA xi



### PEER REVIEW
A peer revie wpanel was asse mbled for a m m onia. T h e panel consisted of the following m e mbers:

1. Dr. Finis Cavender, Private Consultant, Greer, South Carolina; 2. Dr. Jerold Last, Professor, Internal Medi cine, University of California, Davis; 3. Dr. FrederickOeh m e, Prof essor of Toxicology , Medicine/Phy siology , Kansas State Universit y ; and 4. Dr. Martin Alexander, Professor, Depart ment of Soil, Crop, and Atm o spheric Sc iences, Corne ll University , N e w York. These experts collectively have knowledge of ammonia's phy sical and chem ical properties, toxicoki netics, key health end poi nts, mechanis ms of action, hum an and anim al exposure, and quantification of risk to humans. All reviewers were select ed in conform ity with the conditions for peer review specif i ed in Section 104(I)(13) of the Com p reh e nsive Environmental Resp onse, Com p ensation, and Liability Act, as amen ded. Scientists from the Agenc yfor Toxic Substances and Disea se Regi stry (ATSDR) have review ed the peer reviewers' comment s and determ ined which commen t s will be included in th e pr ofile. A listing of the peer reviewer s' co mments not incorporated in the profile , with a brief explanation of the rationale for their exclusion, exi s ts as part of the adm i nistr a tive record for this com pound. A list of databases r e viewed and a list of unpublished documents cited are al so included in the administrative rec o rd. The citation o f the peer review panel should n o t be un d erstood to i m ply its appr oval of the profile' s final content. The responsibility for the conte n t of this prof ile lies with the ATSDR.AMMONIA x iii



### CONTENTS
DISCLAIME R

..................................................................................................................... ......................... ii UPDATE ST ATEMENT

............................................................................................................... .............. iii FOREWORD

....................................................................................................................... ......................... v QUICK REF E RENCE FOR HEALTH CARE PROVIDERS

.................................................................... vii CONTRIBUTORS

................................................................................................................... .................... ix PEER REVIEW

.................................................................................................................... ....................... xi CONTENTS

....................................................................................................................... ........................ xiii LIST OF FIGURES

................................................................................................................ .................. xvii LIST OF TABLES

................................................................................................................. .................... xix 1. PUBLIC HEALTH ST ATEMENT

.................................................................................................... ...... 1 1.1 WHAT IS AMMONIA?

......................................................................................................... ..... 1 1.2 WHAT HAP PENS TO AMMONIA W H EN IT ENT E RS THE ENVIRONME N T?

................. 3 1.3 HOW MIGHT I BE EXPOSED TO AMMONIA?

..................................................................... 3 1.4 HOW CAN AMMONIA ENTER AND LEAVE M Y BODY?

.................................................. 5 1.5 HOW CAN AMMONIA AFFECT MY HEALTH?

................................................................... 6 1.6 HOW CAN AMMONIA AFFECT CHILDREN?

...................................................................... 7 1.7 HOW CAN FAMILIES REDUCE THE RISK OF E X POSURE T O AMMONIA?

.................. 7 1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEE N EXPOSED TO AMMONIA?

.................................................................................................................... ..... 8 1.9 WHAT REC O MMEND A T IONS HAS THE FEDERAL GOVE R N MENT MA DE TO PROTECT HUMAN HE ALTH?

................................................................................................. 9 1.10 WHERE CAN I GET MORE INFORM ATION?

..................................................................... 10 2. RELEVANCE TO PUBLIC HEAL TH

................................................................................................. 13 2.1 BACK GRO UND AND E NVIR ONME N TAL EXPO SURES TO AMMONI A IN THE UNITED ST ATES

.................................................................................................................. ... 13 2.2 SUMMARY OF HEALTH EFFECTS

...................................................................................... 15 2.3 MINIMAL RISK LEVEL S

...................................................................................................... . 18 3. HEALTH EFFECTS

............................................................................................................. ................. 23 3.1 INTRODUCTION

............................................................................................................. ........ 23 3.2 DISCUSSION OF HEAL TH EFFECTS BY ROUT E OF EXPOS U RE

.................................. 23

3.2.1 Inhalation Exposure

.................................................................................................... .......... 25 3.2.1.1 Death

................................................................................................................ ............ 25 3.2.1.2 Sy stem ic Effects

..................................................................................................... ...... 26 3.2.1.3 Imm unological and L y m phoreticular Effects

............................................................... 55 3.2.1.4 Neurological Effects

................................................................................................. .... 55 3.2.1.5 Reproductive Effects

................................................................................................. ... 56 3.2.1.6 Develop m ental Effects

................................................................................................ . 56 3.2.1.7 Cancer

............................................................................................................... ............ 56 3.2.2 Oral Exposure

.......................................................................................................... .............. 57 3.2.2.1 Death

................................................................................................................ ............ 57 3.2.2.2 Sy stem ic Effects

..................................................................................................... ...... 58 3.2.2.3 Imm unological and L y m phoreticular Effects

............................................................... 67 3.2.2.4 Neurological Effects

................................................................................................. .... 68 3.2.2.5 Reproductive Effects

................................................................................................. ... 69AMMONIA xi v

3.2.2.6 Develop m ental Effects

................................................................................................ . 69 3.2.2.7 Cancer

............................................................................................................... ............ 69 3.2.3 Dermal Exposure

........................................................................................................ ........... 70 3.2.3.1 Death

................................................................................................................ ............ 70 3.2.3.2 Sy stem ic Effects

..................................................................................................... ...... 71 3.2.3.3 Imm unological and L y m phoreticular Effects

............................................................... 75 3.2.3.4 Neurological Effects

................................................................................................. .... 75 3.2.3.5 Reproductive Effects

................................................................................................. ... 75 3.2.3.6 Develop m ental Effects

................................................................................................ . 75 3.2.3.7 Cancer

............................................................................................................... ............ 75 3.2.4 Other Routes of Exposure

............................................................................................... ...... 76 3.3 GENOT OXICITY

............................................................................................................. ........ 76 3.4 TOXICOKINETICS

........................................................................................................... ....... 78

3.4.1 Absorption

............................................................................................................. ................ 79 3.4.1.1 Inhalation Exposure

.................................................................................................. .... 79 3.4.1.2 Oral Exposure

........................................................................................................ ....... 79 3.4.1.3 Dermal Exposure

...................................................................................................... .... 80 3.4.2 Distribution

........................................................................................................... ................ 81 3.4.2.1 Inhalation Exposure

.................................................................................................. .... 81 3.4.2.2 Oral Exposure

........................................................................................................ ....... 81 3.4.2.3 Dermal Exposure

...................................................................................................... .... 82 3.4.2.4 Other Routes of Exposure

............................................................................................ 8 2 3.4.3 Metabolism

............................................................................................................. ............... 83 3.4.4 Elim ination and Excretion

.............................................................................................. ....... 83 3.4.4.1 Inhalation Exposure

.................................................................................................. .... 83 3.4.4.2 Oral Exposure

........................................................................................................ ....... 86 3.4.4.3 Dermal Exposure

...................................................................................................... .... 86 3.4.4.4 Other Routes of Exposure

............................................................................................ 8 7 3.4.5 Phy s iologically Based Pharmacokine tic ( P BPK)/Pharm acody nam i c (PD) Models

............. 87 3.5 MECHANIS M S OF ACTI ON

.................................................................................................. 90

3.5.1 Pharm acokinetic Mechanisms

............................................................................................. .. 90 3.5.2 Mechanisms of Toxicity ................................................................................................. ....... 90 3.5.3 Anim al-to-Human Extrapolations

......................................................................................... 91 3.6 TOXICITIES MEDIATED THRO UGH THE NEUROENDOCRINE AXIS

.......................... 92 3.7 CHILDRE N ’S SUSCEPTIBILITY

........................................................................................... 93 3.8 BIOMARKE RS OF EXP O SURE AND EFFECT

.................................................................... 96

3.8.1 Biomarkers Used to Identify or Quantif y Exposure to Amm onia

......................................... 97 3.8.2 Biomarkers Used to Characterize Effects Caused by Amm onia

........................................... 97 3.9 INTERACTIONS WITH OTHER CHEMICALS

.................................................................... 98 3.10 POPULAT I ONS THAT ARE UNUS UALLY SUS C EPTIBLE

............................................ 99 3.11 METHODS FOR REDUCING TOXIC EFFECTS

.............................................................. 100

3.11. 1 Reducing Peak Absorption Following E xposure ............................................................ 100 3.11. 2 Reducing Body Burden

.................................................................................................. . 101 3.11. 3 Interfering with the Mechanism of Action for Toxic Effects

......................................... 101 3.12 ADEQUACY OF THE DATABASE

..................................................................................... 101

3.12. 1 Existing Inf o r

m ation on Health Effects of Amm onia

..................................................... 102 3.12. 2 Identification of Data Need s .......................................................................................... . 102 3.12. 3 Ongoing Studies

....................................................................................................... ....... 110AMMONIA xv

4. CHEMICAL AND P H YSICAL INF O RMATION

.............................................................................. 113 4.1 CHEMICAL IDENTITY

........................................................................................................ . 113 4.2 PHYSICAL AND CH EM ICAL PROP ERTIES

...................................................................... 113 5. PRODUCTION, IMPORT/EXPORT , USE, AND DISPOSAL

.......................................................... 117 5.1 PRODUCTION

............................................................................................................... ........ 117 5.2 IMPORT/EXPORT

............................................................................................................ ..... 121 5.3 USE......................................................................................................................

.................... 122 5.4 DISPOSAL

................................................................................................................. ............. 122 6. POTENTIAL FOR HUMAN EXPOSURE

......................................................................................... 123 6.1 OVERVIE W

................................................................................................................. ........... 123 6.2 RELEASES TO THE ENVIRONMENT

................................................................................ 127

6.2.1 Air

.................................................................................................................... ................... 131 6.2.2 Water

.................................................................................................................. ................. 133 6.2.3 Soil

................................................................................................................... ................... 133 6.3 ENVIRONM ENTAL FAT E

.................................................................................................... 134

6.3.1 Transport and Partitioning

............................................................................................. ...... 134 6.3.2 Transform a tion and Degradation

........................................................................................ 1 36 6.3.2.1 Air

.................................................................................................................. ............. 136 6.3.2.2 Water

................................................................................................................ .......... 137 6.3.2.3 Sedim e nt and Soil

.................................................................................................... ... 138 6.3.2.4 Other Media

.......................................................................................................... ...... 138 6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

............................... 138

6.4.1 Air

.................................................................................................................... ................... 139 6.4.2 Water

.................................................................................................................. ................. 141 6.4.3 Sedim e nt and Soil

...................................................................................................... ......... 143 6.4.4 Other Environmental Media

.............................................................................................. .. 143 6.5 GENERAL P O PULATION AND OCCUPATIONAL EXPOSURE

..................................... 143 6.6 EXPOSURES OF CHILDREN

............................................................................................... 145 6.7 POPULATIONS WITH PO TENTIALLY HIGH EXPOSURES

........................................... 146 6.8 ADEQUACY OF THE DATABASE

...................................................................................... 147

6.8.1 Identification of Data Need s ........................................................................................... .... 147 6.8.2 Ongoing Studies

........................................................................................................ .......... 149 7. ANALYT IC AL METHODS .........................................................................................................

...... 153 7.1 BIOLOGICAL MATERIALS

................................................................................................. 153 7.2 ENVIRONM ENTAL SAMPLES

............................................................................................ 156 7.3 ADEQUACY OF THE DATABASE

...................................................................................... 160

7.3.1 Identification of Data Need s ........................................................................................... .... 160 7.3.2 Ongoing Studies

........................................................................................................ .......... 161 8. REGULATIONS AND ADVISORI ES

............................................................................................... 16 3 9. REFERENCES

................................................................................................................. ................... 171 10. GLOSSARY

.................................................................................................................. .................... 217 APPENDICE S A. ATSDR MINIMAL RISK LEVEL S AND WORKSHEETS

............................................................. A-1AMMONIA xv i

B. USER' S GUIDE

............................................................................................................... ................... B-1 C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

...................................................................... C-1 D. INDEX

...................................................................................................................... .......................... D-1AMMONIA x v ii



### LIST OF FIGURES

3-1. Levels of Significant Exposure to A mmonia and Amm oniu m Co mpounds—Inhalation

............. 41 3-2. Levels of Significant Exposure to A mmonia and Amm oniu m Co mpounds—Oral....................... 63 3-3. Glutam ine Cy cle

........................................................................................................... ................. 84 3-4. The Urea Cy cle Showing th e Com p artmentalization of its Steps Within Liver Cells

................... 85 3-5. Conceptual Representation of a Phy s iologica lly Based Pharmacokinetic (PBPK) Model for a Hy pothetical Chem ical Substance

............................................................................................... .. 89 3-6. Existing Inf o r

m ation on Health Effects of Amm onia

.................................................................. 103 6-1. Frequency of NPL Sites wi th Ammonia Contam ination

............................................................. 124 6-2. Sim p lified Schem a tic for t h e Microbial Processes of the Nitrogen Cy cle

................................... 125AMMONIA xi x



### L I ST OF TABL ES

3-1. Levels of Significant Exposure to A mmonia and Amm oniu m Co mpounds—Inhalation

............. 27 3-2. Levels of Significant Exposure to Ammonia and Amm oniu m Co mpounds—Oral....................... 59 3-3. Levels of Significant Exposure to Ammonia and Amm oniu m Co mpounds—Dermal

.................. 72 3-4. Genotoxicity of Amm onia In Vitro and In V i vo ............................................................................ 77 3-5. Ongoing Studies on the H ealth Effects of Amm onia

................................................................... 111 4-1. Chem ical Identity of Ammonia

.............................................................................................. ..... 114 4-2. Phy s ical and Chem ical Properties of Amm onia

.......................................................................... 115 5-1. Facilities thatProduce, Process, or Use Amm onia

...................................................................... 119 6-1. Releases to the Environm ent from Facili ti es that Produce, Process, or Use Ammonia

............... 129 6-2. Ongoing Stu d ies on Envir onm ental Fate and the Pot e ntial for Human Exposur e to Amm onia

....................................................................................................................... .............. 150 7-1. Analy tical M e thods for Determ in ing Ammonia in Biological Samples

...................................... 154 7-2. Analy tical M e thods for Determ ini ng Ammonia in Environm ental Sam p les

............................... 157 7-3. Ongoing Studies on the D e velopment of Anal y tical Approaches to the Study of Amm onia

...... 162 8-1. Regulations and Guidelines Applicable to Ammonia

.................................................................. 165AMMONIA 1



### 1. PUBL IC HEAL TH STAT EMENT This public health statem ent tells you aboutammonia and the effects of exposure.

The Environm ental Protection Agency (EPA) identif ies the most serious h azardous waste sites in the nation. These sites are then placed on the Nati onal Priorities List (NPL ) and are targeted for long-term fe deral clean-up activ ities. Ammonia has been found in at least 137 of the 1,647 current or form er NPL sites. Although the total num ber of NPL sites evaluated for this substance is not known, the possibility exists that the num ber of sites at which amm o nia is found
m ay increase in the future as m o re sites are ev alu a ted. This inform ation is im portant because these sites may be sources of exposure and exposure to this substance m ay harm you.
When a substance is released either f r om a larg e area, such as an indus trial plant, or from a container, such as a drum or bot tle, it enters the environm ent. Such a release does not always lead to exposure. You can be exposed to a s ubstance only wh en you com e in contact with it. You m ay be exposed by breathing, eating, or dri nking the substance, or by skin contact. If you are exposed to ammonia, m any factors will determ ine whether you will be harm ed. These factors include the dose (how m u ch), the duration (how long) , and how you com e in contact with it. You m us talso consider any other chem i cals you are exposed to and your age, sex, diet, f a m ily traits, lif esty le, an d state of health.

1.1 WHAT IS AMMONIA?
Ammonia is a chem ical that is m a de both by human s and by nature. It is m a de up of one part nitrogen (N) and three parts hydrogen (H 3 

### ). The am ount of a mmonia m a nufactured every year by hum ans is alm o st equal to the amount produc ed by nature every year. However, when ammonia is found at a level that m ay cause con cern, it was likely produced either directly or indirectly by hum ans.AMMONIA 2 1. PUBLIC HEA L TH STA T EMENT 

### Ammonia is a colorless gas with a very sharp od or. Amm o nia in this form is also known as ammonia gas or anhydrous (“without water”) amm onia. Ammonia gas ca n also be com p ressed and becom e s a liqu i d un der pres sure. The odor of a m m onia is fa m iliar to most people because ammonia is used in sm elling salts, house hold cleaners, and window cleaning products. Ammonia easily d i sso lv es in wate r. In this f o rm , it is also known as liquid ammonia, aqueous ammonia, or ammonia solution. In water, m o st of the amm oni a changes to the ionic form of ammonia, known as ammonium ions, wh ich are represented by the formula NH 4 + 

### (an ion is an atom or a group of atoms that has acquired a net el ectric charge by gaining or losing one or m o re electrons). Ammonium ions ar e not gaseous and have no odor. Amm onia and ammonium ions can change back and forth in water. In wells, ri vers, lakes, and wet soils, the amm oni um form is the m o st common. Ammonia can also be com b ined with other substances to form a mmonium
com pounds, including salts such as ammonium c h loride, ammonium sulfate, amm oni um nitrate, and others. Ammonia is very im portant to plant, anim al, and hu m an life. It is found in water, soil, and air, and is a sour ce of m u ch needed nitro g en for plants and anim als. Most of the ammonia in the environm ent com e s from the natural breakdown of m anure and dead plants and anim a l s. Eighty percent of all m anufactured ammonia is used as fertilizer. A third of this is applied directly to soil as pure ammoni a. The rest is used to m a ke other fertilizers that contain ammonium com pounds, usually ammonium salts. Th ese fertilizers are used to provide nitrogen to plants. Ammonia is also used to m anufacture synthe tic fibers, plastics, and explosives. Many cleaning products also contain ammoni a in the form of a m monium ions.

For detailed inform ation on the chem ical propertie s of a m m o nia, see Chapter 4. Details on the production and use of ammonia are in Chapter 5, and m o re inform ation on the environm ental fate of a mmonia and sources of human exposure is in Chapter 6.AMMONIA 3 1. PUBLIC HEA L TH STA T EMENT 

### 1.2 WHAT HAPPE NS TO AMMONIA WH EN IT ENTERS THE ENVI RONMENT ?
Since amm o nia occurs n a turally in th e environm en t, we are regularly expo sed to low levels of ammonia in air, soil, and water. Ammonia exists natura lly in the air at levels between 1 and 5 parts in a billion parts of air (ppb). It is comm only found in ra inwater. The ammonia levels in rivers and b ays are usu a lly less th an 6 parts per m illion (pp m ; 6 ppm = 6,000 ppb). Soil typ i cally contains about 1–5 ppm of a m m onia. The levels of a m m onia vary throughout the day, as well as from season to season. Generally, ammonia leve ls are highest in the summ er and spring. Ammonia is essential for m a mm als and is nece ssary for m a king DNA, R NA, and proteins. It also plays a part in m a intaining a c id -base balance in tissues of m a mm als. Ammonia does not last very long inthe environm ent. Because it is recycled naturally, nature has
m any ways of incorporating and transfor m i ng ammonia. In soil or water, plants and
m i croorganism s rapidly take up ammonia. After fe rtilizer containing ammoni a is applied to soil, the am ount of a m m onia in that soil decreases to low levels in a few days

. In the air, ammonia will last abo u t 1 week.
Ammonia has been found in air, soil, and water sam p les at hazardous waste sites. In the air n e ar hazardous w a ste sites, ammonia can be found as a gas. Ammonia can also be found dissolved in ponds or other bodies of water at a waste site. A mmonia can be found attach ed to soil particles at hazardous waste sites. The average concentration of ammoni a reported at hazardous waste sites ranges from 1 to 1,000 ppm in soil sam p les and up to 16 ppm in water sam p les. See Chapter 6 for m o re detailed inform ation on the environm ental fate of ammonia, a mmonia levels in the environm ent, and exposure to amm o nia.

1.3 HOW MIGHT I BE EXPOSED TO AMMONIA? Ammonia is naturally produced and used by all m a mmals in thei r norm a l m e tabolism. Ammoni a is produced within a person’s body each day. Mostof this ammonia is produced by organs and tissues, but som e is produced by bact eria liv ing in side our inte stines.AMMONIA 4 1. PUBLIC HEA L TH STA T EMENT



### Ammonia is found naturally in th e environm ent. You m ay be exposed to ammonia by breathing air, eating food, or drinking water that contains it, or through skin contact with amm o nia or ammonium com pounds. Exposure to ammonia in the environm ent is m o st likely to occur by breathing in ammonia that has be en releas ed into the air. Ammonia has a very strong odor that is irritating and that you can sm ell whenit is in the air at a level h i gher than 50 ppm. Therefore, you will probably sm ell amm onia before you are exposed to a concentration that may harm you. Levels of ammonia in air that caus e seriou s effects in people are much higher than le vels you would norm a lly be expos ed to at hom e or work. However, low levels of ammonia m a y harm so me people with asthm aand other sensitive individuals.

You can taste ammonia in water at levels of about 35 ppm

. Lower levels than this occur naturally in food and wa ter. Swallowing even sm all a m ounts of liquid ammonia in your household cleaner m i ght cause burns in your m o uth and throat. A few drops of liquid ammonia on the skin or in th e eyes will cause burns and o p en sores if not washed away quickly. Exposure to larger am ounts of liquid amm onia or amm onium ion in the ey es causes severe eye burns and can lead to blindness. Outdoors, y ou m ay be exposed to high levels of ammonia gas in air from leaks and s p ills at production plants and storage faci lities, and from pipelines, tank trucks, railcars, ships, and barges that transport ammonia. Higher levels of ammonia in air m ay occur when fertilizer with ammonia or ammonium com pounds is applied to farm fields. Af ter fertilizer is applied, the concentration of a m m oni a in soil can be m o re than 3,000 ppm; however, these levels decrease rapidly over a few days. Indoors, you m ay be exposed to ammonia while us ing household products that contain ammonia. Som e of these products are amm oni a-cleaning solutions, w i ndow cleaners, floor waxes, and
sm elling salts.AMMONIA 5 1. PUBLIC HEA L TH STA T EMENT 

### Household and industrial cleaning solutions m ay c ontain ammonia, and use of these products at hom e or work m ay lead to exposure to ammonia. Both types of a m m onia cleaning solutions are
m a de by adding amm oni a gas to water to form liquid amm o nia. Household amm onia cleaners typically contain lower levels of ammonia (betw een 5 and 10%) com p ared to industrial cleaning solutions, which can contain higher le vels of ammonia (up to 25%).

Farm ers can be exposed to amm onia when theywork with or apply fertilizers containing ammonia to fields. Farm ers, cattle ranchers, and people who raise other t ypes of livestock and/or poultry can be exposed to ammonia from decaying m anure. Som e m anufa c turing processes also
use amm oni a. Som e older refrigeration un its used ammonia as the refrig erant.

For m o re inform ation on levels of exposure associated with eff ects, see Chapter 3.

1.4 HOW CAN AMMONIA ENTE R AND LE AV E MY BODY? Ammonia can enter your body if you breathe in ammonia gas or if you swallow water or food contain i ng ammonium salts. If you spill a li quid contain i ng ammonia on your skin, a sm all
am ount of a mmonia m i ght enter your body thr oug h your skin; however, more amm oni a will probably enter as you breathe amm o nia gas from the spilled ammonia. After you breathe in ammonia, you breathe most of it out again. The a mmonia that is retained in the body is changed into amm oni um com pounds and carried throughout the body in seconds. If you swallow ammonia in food or water, it will get into your bloodstream and be carried throughout your body in seconds. Most of the ammonia that enters your body from food or water rapidly changes into other substances that will not harm you. The rest of this ammonia leaves your body in urine within a couple of days. For m o re inform ation on how a mmonia can enter and leave your body, see Chapter 3.AMMONIA 6 1. PUBLIC HEA L TH STA T EMENT 

### 1.5 HOW CAN AMMONIA AFFE CT MY HEAL TH?
Scientists u s e m any tests to protect th e public f r o mharmful effects of toxic chem icals and to find ways for treating persons who have been harm ed. One way to learn wheth e r a chem ical will h arm people is to determ ine how the body absorbs, uses, and releases th e ch em ical. For som e chem i cals, an im al testing m ay be necess ary . Ani m al testing m ay also help identify heal th effects such as cancer or bi rth defects. W ithout laboratory anim als, scientists would lose a basic m e thod forgetting inform ation needed to m a ke wise decisions that protect public hea lth. Scientists h ave the r e spo n si bility to treat researchanim als with care an d com p assion. Scient ists m u st com pl ywith strictanim al care guidelines b ecause laws today p r otect the w e lfare of res earch an im als.

Ammonia is a corros i ve substance an d the m a in toxic effects are rest ricted to the sites of direct contact with ammonia (i.e., skin, eyes, respirat ory tract, m outh, and digestive tract). F or exam ple, if you spilled a bottle of concentrated ammonia on the floor, you would sm e ll a strong ammonia odor; you m i ght cough, an d your eyes m i ght water because of irritation. If you were exposed to very high levels of ammonia, you would experience m o re harmful effects. For
exam ple, if you walked into a dense cloud of ammonia or if your skin com e s in contact with concentrated ammonia, your skin, eyes, throat, or lungs m ay be severely burned. These burns
m i ght be serious enough to cause perm anent blindne ss, lung disease, or death. Likew i se, if you accident ally ate or d r ank concentrated ammoni a, you m i ght experien ce burns in your mouth, throat, and stom ach. There is no evidence that ammonia causes cancer. Ammonia has not been classified for carcinogenic effects by EPA, Departm e nt of He alth and Hum an Services (DHHS) (NTP), or th e Internation a l Agency for Resear ch on Cancer (IARC). Ammonia can also have beneficial effects, such as when it is used as a sm elling salt. Certain ammonium salts have long been used in veterinary and hu m an medicine. For m ore inform ation on how a m m oni a can affect your health, see Chapter 3.AMMONIA 7 1. PUBLIC HEA L TH STA T EMENT 

### 1.6 HOW CAN AMMONIA AFFE CT CHILDRE N? This section discusses po tential health effects from exposur es during the period from conception to m a turity at 18 years of age in humans. Children are less likely than adults to be e xposed to concentrated amm oni a because m o st exposures to concentrated ammonia occur in occupa tional settings. Children can still be exposed in the s a m e way as adults to amm onia gas f r om spills o r leaks f r om ammonia tank s or pipelines, especially on farm s whe r e it is used as a fert ilizer. Children can also be exposed to dilute ammonia solutions from househol d cleaners containing ammonia.

The effects of a m m onia on children are likely to be the sam e as for adults. Ammonia is an irritantand the solution and gas can cause burns o f the skin, eyes, m outh, and lungs. If a spill occurs, children m ay be exposed to ammonia for a longer tim e than adults because they m ay not leave the area as quick ly. There is no evidence that exposure to the leve ls of a m m onia found in the environm ent causes birth defects or other developm ental effects. It is not known whether ammonia can be transferred from a pregnant m o ther to a deve loping fetus through the placenta or from a nursing mother to her offspring through breast m ilk. One study in anim als show ed that exposure of mothers to very high levels of ammonia during pregnancy caused their newborn offspring to be
sm aller than norm a l, but this oc curr e d at lev e ls o f amm onia that also affected th e m ot h ers.

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO AMMONIA? If your doctor finds that you have been exposed to significant am ounts of ammonia, ask whether your children m i ght also be exposed. Your doctor m i ght need to ask your state health departm e nt to investigate. You can reduce your risk of exposure to amm oni a by carefully using household products and by avoiding areas where ammonia is used or pr oduced. At hom e , you can reduce your risk ofAMMONIA 8 1. PUBLIC HEA L TH STA T EMENT 

### exposure to ammonia by careful handling of any household products that c ontain ammonia. For
exam ple, som e cleaning products contain amm o ni a; so when you use them, you should be sure that room s a r e adequately ve ntilated during the tim e you ar e using them

. Avoid ammoniacontaining products in glass bottles since breakage could lead to a serious exposure. Y ou should wear proper cloth i ng and eye protection, because ammonia can cause skin burns and d a m a ge eyes if it is splashed on them

. To lower the ri sk of your children bei ng exposed to ammonia, you should tell them to stay out of the room when you are using it. Wh ile use of a m m oniaby a child is not recomm ended, any use by a child should be closely supervised by an adult. You can also reduce your risk of exposure to ammonia by avoiding areas where it is being used. Ammonia is used to fertilize crops, so you can lower your exposure to ammonia by avoiding these areas when it is being applied. You can also lower your exposure to ammonia by avoiding places where it is produ ced. Amm o nia is found in m any anim al wastes, and it m ay be present in high concentrations in the air in livestock buildings. You canlower your exposure to ammonia by avoiding these buildings, es pecially if larg e nu m b ers of anim als are inside. If you are a worker who uses or applies amm onia for farm ing, you can reduce your exposure by using it acco rding to the instru cti ons and wearing proper cloth i ng and pro t ectiv e gear. Be sure to f o llow all in struc tions an d h eed any warning statem ents.

1.8 IS THERE A MEDICAL TEST TO DETERMI N E WHET HER I HAV E BEE N EXPOSED TO AMMONIA?
There are tests that m easure amm oni a/amm onium ion in blood and urine; however, these tests would probably not tell y ou whether you have be en exposed because ammonia is norm a lly found in the body. If you were exposed to harmfu l am ounts of ammonia, you would notice it imm e diately because of the strong, unpleasant, and irritating sm ell, the strong taste, and because of skin, eye, nose, or throat irritation. Expos ure detection levels and m e thods for determ ining ammonia levels in biological m a terial s are discussed in Chapters 3 and 7.AMMONIA 9 1. PUBLIC HEA L TH STA T EMENT
1.9 WHAT RE C O MME NDA TIONS HAS THE FEDE RAL GOVE RNMENT MADE T O PROT ECT HUMAN HE ALTH? 

### The federal governm e nt develops regulations and recomm endations to pr otect public health. Regulations can be enforced by law. The EPA, the Occupatio nal Saf e ty and Health Adm i nistration (OSHA), and the Food and Dr ug Adm i nistration (FDA) are som e federal agencies that develop regulati ons for toxic substances. Recommendations provide valuable guidelines to protect public he alth, but cannot be enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the Nationa l Institute f o r Occupationa l Saf e ty and Health (NIOSH) are two fe deral organizations that deve lop recomm endations for toxic substances. Regulation s and recommendation s can be express e d as “not-to

- exceed ” lev e ls, th at is, levels of a toxic substance in air, w a ter, so il, o r food that do not exceed a critical valu e that is usu a lly based on levels that affect animals; they are then adju sted to levels that will help protect humans. Som e tim es these not-to-exceed levels differ am o ng federal organizations because they used different exposure tim e s (an 8-hour workday or a 24-hour day), different anim al studies, or other factors. Recommendations and regulations are also updated periodically as m o re inform ation becom e s available. F o r the m o st current inform ation, check with the federal agency or organization that provides it. Som e regulations and recomm endations for a mmonia include the following: EPA regulates the amm o nia content in waste wa ter released by several industries. Any discharges or spills of amm onia of 100 pounds or m o re, or of ammonium salts of 1,000 or 5,000 pounds (depending upon the com pound), must be reported to EPA.

Som e restrictions have been plac ed on levels of ammonium s a lts allowable in processed foods. FDA states that the levels of a m m oni a and amm o nium com p ounds norm a lly found in food do not pose a health risk. Maxim u m a llowable le vels in processed foods are as follows: 0.04–3.2% ammonium bicarbonate in baked goods, grain, sn ack foods, and reconsti tuted vegetables; 2.0% ammonium carbonate in baked goods, gelatins, and puddings; 0.001% ammonium chloride inAMMONIA 10 1. PUBLIC HEALTH STATEMENT 

### baked goods and 0.8% in condiments and reli shes; 0.6–0.8% ammonium hydroxide in baked goods, cheeses, gelatins, and puddings; 0.01% mo nobasic ammonium phosphate in baked goods; and 1.1% dibasic ammonium phosphate in bake d goods, 0.003% in nonalcoholic beverages, and 0.012% in condiments and relishes. OSHA has set an 8-hour exposure limit of 25 ppm and a short-term (15-minute) exposure limit of 35 ppm for ammonia in the workplace. NIOSH r ecommends that the level in workroom air be limited to 50 ppm for 5 minutes of exposure. Further information on governmental reco mmendations can be found in Chapter 8.

1.10 WHERE CAN I GE T MORE INFORMATION? If you have any more questions or concerns, plea se contact your community or state health or environmental quality department, or contact ATSDR at the address and phone number below. ATSDR can also tell you the location of occupati onal and environmental health clinics. These clinics specialize in recognizing, evaluating, and tr eating illnesses that resu lt from exposure to hazardous substances. Toxicological profiles are al so available on-line at www.atsdr.cdc.gov and on CD-ROM. You may request a copy of the ATSDR ToxProfiles TM 

### CD-ROM by calling the toll-free information and technical assistance number at 1-888-42ATSDR (1-888-422-8737), by e-mail at atsdric@cdc.gov, or by writing to: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE Mailstop F-32 Atlanta, GA 30333 Fax: 1-770-488-4178AMMONIA 11 1. PUBLIC HEA L TH STA T EMENT 

### Organizations for-profit m ay reque st copies of final Toxicologi cal P r of iles f r om the f o llowing:

National Technical Inform ation Service (NTIS) 5285 Port Royal Road Springfield, VA 22161 Phone: 1-800-553-6847 or 1-703-605-6000 Web site: http://www.ntis.gov/AMMONIA 13



### 2. RELEVANCE TO PUBLIC HEALTH

2.1 BAC KGROUND AND E N VIR O N M E N TAL EX P O SU RES T O A M MONI A IN THE U N ITED STATES
Amm onia is a natural co mpoun d, as well as a m anuf actured co m pound. In nature , m o st ammonia probably comes fro m deco m posing animal excr eta, withthe decay of organic materi als from plants, dea d anim als, and the like also contribut ing si gnificant am o unt s. It is also exhaled b y anim als. Production of fixed nitro g en (NH 3 ) by plants and m i cr oorganism s is esti m at edat 90 to 130 m e tric tons annu ally

. Manufacture of amm onia within the United States was 9.5 m illion metric tons in 2001, which is down from 16.6 m i l lion m e tric to ns in 1999. Co mmerciall y produced ammonia is used prim arily as fertilizer, with plastics, sy nthetic fibers and resins, explosives, and other uses accounting for m o st of the rem a inder.

A m m onia is r e leas ed to the at m o sphere by natura l processe s such as the decay of organic m a tter and ani m al excr eta, or by volcanic eruptions. It can al so be released to the atm o sphere by anthro po genic activities such as fertilizer use; spillage or leakag e from storage or production facilities; or loss fro m waste water e ffluents. The average global a m m onia concentration i nthe atm o sp here ranges from 0.3 to 6 ppb, with c oncentrations someti mes higher in the vicinity of agricultural or industrial areas. For
exam ple, near industrial sources or m an u re heaps in Germ any , amm onia concen trations ranged from 10.3 to 89 ppb. Concentrations m ay be orders of m a g n itude higher near so m e ty pes of livestock areas, such as pigpens, where local at m o spheri c concentrati ons have been reported to be as high as 47 p p m .
Elevated concentrations of a m m onia in water ar e usually due to eff l uent discharges fro m sewage treat ment plants or industri al processes, or runoff fr om f

e rtilized fi elds or livestock areas. Ammonia concentrations can therefor e vary widely in aquatic environm ents, with concentrations being l o wer in bodies of water that are unim p acted by r esidential, industr ial, or farm ing effluents, co m p ared to those that are i m pa cted (where conce n trations can be orders of magnitude hi gher). In uni m p acted waterway s, amm onia con centrations have been re ported to range f r om 8.5 to 43 ppb, whereas in im pacted waterway s, concentrations as high as 16 ppm have been reported.

Soils usuall y obtain additi onal amm onia from natural or synthetic f e rtilizer application, animal excreta, decay ing organic m a tter, o r natural fixation from the at m o sphere. Soils have been reported to have backgroun d concentrations of ammonia ranging from 1 to 5 ppm . Immediately f o llowing ap pl ication ofAMMONIA 14 2. RELEVANCE TO PUB L IC HE ALTH
fertilizer or manure, however, amm onia concentrati ons can rise to 2–3,000 ppm , with levels dropping after 5 day s t o 2–850 ppm . These high amm onia con centrations ar e usually l i m i ted to the upper few centim e ters of topsoil.

In the atm o sp here, a m m oni a can rea c t wi th acidic s ubstances in the air to produce a m m oniu m a e rosols, which can be subject to dr y or wet deposition. T h e b est esti m ate of the half-life of at m o spheric a m m onia is a few day s . In water, amm onia can volatilize to the at m o sphere, be rem oved by m i crobial p r ocesses, or adsorb to sedi m ent and suspended organic m a teri al. In soil, ammo nia can volatilize to the atm o sphere, adsorb to soil particles, undergo m i crob ial transform a tion to nitrate or nitrite ani ons, or be tak e n up b y plants. For the gener a l populatio n, the m o st likely source of e xposure to el evated levels of amm onia is fro m the use of household cleaners c ontaining amm onia or a m m oniu m s a lts

. People who live near farms, who visit farm s during the appli cation of fertilizer, or who live near cattle feedlots, poultr y confi n ement buildi ngs, or other areas where ani m al p opulations are concentrated can also be exposed to ammonia. Local atm o sp heric concentrations inthe se agricultural settings hav e been reported to range fr om 280 to 88,0 00 p pb.

There is also the possibility for ex posure to amm onia via water an d food ingestion. If untreated surface water is inges t ed, the average uptake would be 0. 36 m g /day (assum i ng an amm o n i a concentration in untreated wat e r of 0.18 m g /L and a consum ption rate of 2 L/day ). For m o st sour ces of drinking water, however, adsorption, nitrif ication, and th e convers ion of ammonia to chloram i nes upon chl o ri nation will result in negli g ible levels of amm onia in m o st drinkin g water supplies. Food in g estion can also lead to an exposure to ammonia, primarily due to the use of various ammonium salts as food stabilizers; the esti m ated exposure from th ese food addi tives is 18 mg/day . Populatio ns that live or wo rk near a hazardous waste site that contains amm oni a or amm onium salts could be exposed to above-average levels of ammonia in soil, water, or ai r in sim ilar concentrations as those in agricultural settings. Whil e these exposures m ay occur, the half-lif e of amm onia in nature is probabl y very short. A mmonia has been identified in at l east 137 of 1,647 N a tional PriorityList (NPL) hazardous waste sites.AMMONIA 15 2. RELEVANCE TO PUB L IC HE ALTH
2.2 SUMMARY OF HEALT H EFFECTS
Amm onia is an essential mammali an metabolite for DNA, RNA, and protein sy nthesis and is necessary for maintaining acid-base balance. Amm onia is produced and used endogenous ly in all m a mmalian species. It ha s been esti m a t ed that up to 17 gram s of a mmonia are p r oduced in humans daily

. Of these 17 gram s, ap proxim a tely 4 gram s are produced in th e gutby intestinal bacteria, where it enter s the portal circulation and is metabolized rapidly inthe liver to urea. A mmonia is excreted primarily as urea and urinar y ammonium co m pounds thr oug h the kidne y s . Levels of amm onia in the blood from healthy hum ans range from 0.7 to 2 m g /L.

The m o st i m p o rtant injuri ous effects of exposure to excessive am ou nts of ammonia on hum ans are due to its irritative and corrosive properties. Exposures to ammonia gas cause chemical burns of the respiratory tract, skin, and ey es. Ammonia dissolve s in the water present in skin, m u cous m e m b r anes, and ey es and beco m es a m m oniu m hy droxide, which is a highly ionized weak base that caus e s necrosis of the tissues. Specifically , amm oniu m h ydroxi de causes saponificat ion of cell m e m b r ane lipids resulting in c e ll disruption and death. Additionall y , it extracts water from the cells, and initiates an inflammato ry response, which further damages the surroundi ng tiss u es. Contact with liquid ammonia (not amm oniu m salts) results in cryogenic i n jur y i naddit i on to th e alk a li burns. Air w ay blockage and respiratory insufficiency may be lethal outcom es of exposure to an hy dr ous amm onia vapors or concentrated aerosols. Ingestion of c oncentrated ammoniu m solutions m ay pr oduce severe burns and hem o rrhage of the upper gastrointestinal tract. Survival of the ini tial insu lt m a y be com p romised by i n fections, scarring, and other
co m p lications that m ay de velop day s or weeks following inhalati on or i ngestio n. Effects that have been observed in hu mans exposed to ammonia gas and amm oniu m salt aerosols have also been ob served in ani m als. Hep a tic and renal effects have also b een reported in animals and hum a n s; however, a m m onia does not appe ar to be a pri m ary liver or kidne y t oxicant.

Increas ed sy s t e m ic a m m o n i a/a m m oniu msalts/ion, or hy perammone m i a, is gener a lly not seen following inhalation or derm al exposure, but can r esult from in gestion and fr om certain disease stat es such as cirrhosis of th e liver, acute liver failure, and congenita l deficiencies of any of th e urea cy cle enzy m es. Liver disease can result in decrea sed m e tabolism of a mmonia with resultant increased level s of a m m onia in the bl oodstr eam and in th e brain, whi c h can pr odu ce neurological effects such as seizures and coma, and eventually death. In c h ronic liver failure, arte ria l a m m onia co ncentrations may reach approxim a tely 3.6 m g /L, whereas arterial a m m onia in a c ute liver failure m ay rise as high as 8 m g /L. The most likely and significant effects of exposure to el evated levels of amm onia are discussed below.AMMONIA 16 2. RELEVANCE TO PUB L IC HE ALTH

Respiratory Effects. Amm onia is an upper respiratory irritan t in hum ans. Exposures to levels exceeding 50 ppm re sult in i m m e diat e irr itation to th e nose and throat; however, tolerance appe ars to develop with repeated exposure. Exposur e to an air concentration of 250 ppm is bearable for most persons for 3 0–60 m i nutes. Acute expo sure to highe r levels (500 p p m ) have been shown to in crease respiratory minute vol um e. Accidental exposures to c oncentrated aerosols of amm oniu m salts or hig h concentrations of amm onia gas have resulted in nasophar y ngeal and tracheal burns, airway obstruction and respiratory distress, and bronchiolar and alveolar ede m a. A m m onia vapor readily dissolves in the
m o isture present on the ski n , e y es, orop har ynx and lungs form ing ammoniu m hydroxide whic h dissociates to y i eld hydrox y l ions. C h ro nic occupatio nal exposure to low levels of airborne ammonia (<25 ppm ) had little effect on pulm onaryfunction or odor sensitivity in workers at so m e factories, but studies of farmers exposed to amm onia and other po ll utants in lives tock buil d ings indicated an association between exposure to poll u tants, includi ng amm onia, an d an increase in respiratory sy m p toms (such as bronchial reactivit y / hy perresponsiveness, infl ammation, cough, wheezing, or shortne ss of breath) and/or a decrease in lung function parameter s . Th e contributi on of amm onia t o these respiratory sy m p toms is unclear.
Dermal Effe cts. Skin i s extremely s e nsitive to airborne amm o n i a or amm oni a dissolved in water. The topical da m a ge causedby amm onia is probably due mainly t o i t s reactivity and irritation properties. Its high water solubility allows it to dissolve in m o is ture on these surfaces, react with fatty substances, be absorbed into deeper lay e rs, and inflict e x tensiv e damage. Reports of skin dam a ge in hum ans are num erous, but goo d quant it ative data are lacking. The severity of th e dam a ge is p r oportio nal to the concentration and duratio n of expos ure; f l ushing with water immediately after contact alleviates or prevents effe cts. Dermal exposures to liqui d amm onia or concentrated solutio ns and/ or amm onia gas are frequentl y occupationally related and produce cu taneous burns, blisters, and lesions of vary ing degrees of severity

. Unlike acid burns, which cause a coagulation necr osis, amm onia causes alkali burns, resulting in liquification of the tissue and deeper penetrations. Burns can be severe enoughto require ski ngrafting, and loss of the epiderm a l l ay e r increase s body fluid loss and incidence of infection. While most a m m onia exposures are occupational , househol d p r oducts containing amm o n i a can also cause derm al in jur y . Several cases of y o ung ch il dren (2–3 y ears old) who b it into amm o nia pellets/capsules and sustained oral and esophageal lesions have b een reported in the liter a ture.AMMONIA 17 2. RELEVANCE TO PUB L IC HE ALTH Very lim ited anim al data regarding der m al effect s of exposure to ammonia support the findi n g s in hum ans.
Ocular Effe cts. Reported ocular effects in hum ans follo wing ammonia gas exposure increased in severity with dose and duration. Good quantitative da ta are lacking, but s y m p toms progress as follows: infla m ed ey es, lacri m ation, swelling of the ey elid s, hyp e rem i c conjunctiva, blurre d vision, poss i ble transient blindness, cornea l abrasions, and sustained co rneal da m a ge. A m m onia is slightly irritating to hum an ey es in a brief exposure at conce n trations of 1 00 p p m , and immediately ir ritating to th e ey es and throat at 698 ppm . Exposur e to an air concentration of 250 ppm is bearable for most persons fo r 30– 60 m i nutes.

Lim ited animal data regarding ocular eff ects of exposure to ammonia support the findin g s in hu mans. Neurological Effects. Neurological effects in humans followi ng inhalation or dermal exposure to
amm onia are usually lim ited to bl urred v i sion, m o st likely due to di rect contact, but m o re sev ere exposures, which result in significant elevation of bl o od amm onia levels (hy p erammonem i a), can result in diffuse nonsp ecific encephalopath y , m u scle weakness , decreased deep tendon re flexes, and loss of consciousness. Hy peramm one mia in humans can re sult from c e rt ain disease st ates such as c i rrhosis of the liver, acute liver failure, and congenital deficiencies o f any of the ur ea cy cle enzy m es; hy perammonem i a may lead to e n cephalopathy. Som e have suggested that amm onia may be inv o l v ed in the generation of the sy m p tomatology and progression of Alzhei me r’ s disease as a r esult of pathological a m m o nia metabolism in the brain. Cerebral edema and herniation and in tracranial hy pe rtension have been noted i n ani m al m odel s of hy peramm one mia. The m e chanis m of amm onia-induced encephalopathies h as not been definitivel y el ucidated. It i s thought to i nvolve th e alteration of glutam ate m e tabolism in the brain with resultant increased a c tivation of N-m e th y l -D-asp artate (NMDA) r e ceptors, which causes decr eased protein kinase C-m ediated phosp hor y l at ion of Na + /K+ATPase, incr eased a c tivity of Na + /K+ ATPase, and depletion of ATP. Additi onal evidence of altered energy levels includes changes in so m e T C A cy cleassociat ed com ponents including acetoacetate, and NAD + /NADH ratio, 2-ox ogl utarate, and 3-hy dr ox ybut arate. This reduced ATP level may be involved i namm onia-induced com a and death. A disruptionin neurotransm i ssion has also been suggest ed by alteration of brain tubulin, which i s an essential co mponent of the axonal transport s y stem
.AMMONIA 18 2. RELEVANCE TO PUB L IC HE ALTH
2.3 MINI MAL RI SK LEVEL S
Inhalation M R

Ls

• An MRL of 1.7 ppm has been derived for acute-dur ation inhalation exposure (14 day s or less) to amm onia.
This MRL is based on a lowest-observe d-adverse-eff ect level (LO A EL) of 50 ppm for m ild i rritation to the ey es, nose , and thr o at inhum ans exposed to amm o nia as a gas for 2 h ours (Verberk et al. 1977). I n that study , a group of 1 6 subjects were tested, 8 of th em (experts) knew the effects of amm o n i a from the literature, but had no personal contact, whereas the rema ining 8 subjects (non-experts) were students from a non-science faculty an d were not fam i liar with amm onia or experim e nts in laborator y situations. All
mem b ers of a group were exposed onthe same day t o one of the co ncentrations tested (50, 80, 110, or 140 ppm ). The testing was repeated with a 1-week inte rval. Immediately before and after exposure, vital capacity , forc ed expiratory volum e, and forced insp iratory volum e w e re measured. During exposure, each subject r ecorded subjective feelings every 15 m i nutes as no sensation (0), jus t perceptible (1), distinctly perceptible (2), nuisance (3), offensive (4), or unbearable (5 ). No statistical analy s is was performed and there was no grou p exp o sed to air onl y. Results of the pulm onary functio n tests after exposure were not statistically sig n ificantl y differe nt from pre-exposure values. For the n on- experts, there was a cl ear increa se i nthe num ber of reported s y m p to ms for s m ell, ey e irritation, throat irritation, cough, an d ge neral disco m f ort as the exposure concentra tion increased. The latter was not as clear for the experts. It should also be mentioned that the s ubjective responses appeared m o r e pronounced in the nonexpert group than in th e expert group
. T h e LOAEL w as divided b y an uncertainty factor of 30 (10 to protect sensitive indivi dual s and 3 for th e use of a m i nimal LOAE L). A study of piggerie workers exposed to a mean level of 7.9 ppm amm onia meas ured pulm onary functio n ch ange over a workshift; a
sm all but bor derline signifi cant decrease in pulm onaryfunction was noted (Heederik et al. 1990). This study was not used as a basis for MRL derivation because the workers wer e also exposed to other potential respiratory toxicants (dust and endotoxi ns). Althoughthe Verberk et al. (1977) study has lim it ations (no statistical analy s is, subje c tive e nd poi nts, no co ntro l grou p), it de m onstrates th at concentrations of 50 p p m ammonia produce m i nim a l disco m f ort in healthy m e mbers of the general populati on an d therefore, should be avoi ded. A m o re detailed discussion of addit i onal inform ation supporting the findings of Verberk et al

. (1977) is presented in Appendix A.

No intermediate-duration i nhalati on MRL was derived for amm onia. The onl y available intermediateduration i nhal a tion study inhum ans is th at of Ferguso n et al. (197 7 ). In that stu dy , a grou p of 6 healthyAMMONIA 19 2. RELEVANCE TO PUBLIC HEALTH volunteers, not previously accustomed to workin g in an ammonia environment, were exposed 5 days/week to 25 ppm (2 hours/day), 50 ppm (4 hours/day), or 100 ppm (6 hours/day) of ammonia, or to 50 ppm of ammonia 6 hours/day for 6 weeks. End points monitored included subjective and objective measures of eye and throat irritation as well as pulse rate, respiration rate, pulmonary function (FVC, FEV), assessment of neurological function (reflex, ba lance, and coordination) , and body weight. The exposure protocol consisted of a pre-exposure eval uation by a physician, 3 hours of exposure (this conflicts with exposure data on table 2 of the study and mentioned above), a mid-point physician’s observation, lunch break, 3 additional hours of expos ure, and a third physician’s observation 30 minutes after exposure ceased. The conjunctiva and mucosa of th e nose and throat were examined by a physician before and after each daily exposure and the degree of irritation noted was described as mild, moderate, or marked. Exposure to ammonia had no significant effecton the measures of respiratory function or in the neurological tests conducted. The results of the ev aluations of irritation c onducted by the physician showed no significant differences between the expos ure groups, including the 0 ppm exposure group (preexposure). All subjects experienced some watering of the eyes and a sensation of dryness in the nose and throat, and there was one observation of definite redness in the mucosa of the nose after a 6-hour exposure to 100 ppm during which time, there was an excursion to 200 ppm ammonia. No redness was observed in this subject the following morning. Th roughout the study, the physician observed 6 cases of eye irritation, 20 of nose irritation, and 9 of throat i rritation, and most cases appeared to have occurred the first week of the study during exposure to 50 ppm. It is difficult to determine in this study a no-observedadverse-effect level (NOAEL) or LOAEL for irr itation due to the different exposure durations experienced by the subjects. In general, studies in an imals have used higher exposure concentrations and the overall quality of the studies is less than desirable. For ammonia, a corrosive irritant gas that affects the portal of entry and produces irritation of eyes and respiratory tract, use of human data should be preferred over animal studies.

• An MRL of 0.1 ppm has been derived for chr onic-duration inhalation exposure (365 days or more) to ammonia. This MRL supersedes the previous chronic inhalatio n MRL of 0.3 ppm derived in the 2002 draft for public comment version of this profile. The MRL is based on a NOAEL of 9.2 ppm for sense of smell, prevalence of respiratory symptoms (cough, bronchiti s, wheeze, dyspnea, and others), eye and throat irritation, and lung function parameters (FVC, FEV 1 , FEV 1 /FVC, FEF 50 , and FEF 75 ) in humans exposed for an average of 12.2 years in a soda ash plant (Holness et al. 1989); no LOAEL was determined. The cohort consisted of 52 workers and 35 controls. The subjects were assessed on two workdays: on the first workday of their workweek and on the last workday of their workweek. Spirometry was performed at theAMMONIA 20 2. RELEVANCE TO PUBLIC HEALTH beginning and end of each work shift, so that each wo rker had four tests done. To determine the exposure levels, exposed and control workers were sampled over one work shift; the average sample collection period was 8.4 hours. All of the participants in the study were males. Analysis of the results showed no significant differences in the prevalence of reporte d symptoms, but the exposed workers reported that exposure in the plant aggravated some of their re ported symptoms (cough, wheeze, nasal complaints, eye irritation, and throat discomfort). Odor threshold was not affected by exposure to ammonia and there were no significant differences in baseline lung functions between exposed and control subjects. Analysis of each worker separately showed no significant relationship between the level of ammonia exposure and changes in lung function. Also, when the workers were divided into groups of individuals that were exposed to low (<6.25 ppm), medium (6.25–12.5 ppm), and high (>12.5 ppm) ammonia levels, no significant association was found between reporting of symptoms, decline in baseline function, or increasing decline in function over the work shift an d exposure to ammonia. Furthermore, no association was evident between increasing years of exposure and decreasing lung function. However, the power of the indices of both level and length of exposure is low because only eight workers were in areas with relatively high ammonia exposure. The MRL was calculated by adjusting the mean TWA exposure concentration of 9.2 ppm for continuous exposure (8/24 hours x 5/7 days) and dividing by an uncertainty factor of 10 to protect sensitive individuals. A modifying factor of 3 was added for the lack of reproductive and developmental studies.

Oral MRLs
No oral MRLs were derived for ammonia because of two main reasons. In the first place, the overall quality and/or usefulness of the oral database is limited. The only human acute oral studies available were case reports with no exposure levels (Klein et al. 1985; Klendshoj and Rejent 1966; Lopez et al. 1988). Animal studies were limited to a food intake study (Noda and Chikamori 1976), single-exposure studies with no effect, serious effects, or unsupporte d effects (Benyajati and Goldstein 1975; Koenig and Koenig 1949), a gavage study that lacked study details (Boyd and Seymour 194 6), and a 6-day drinking water study with effects at high levels (B arzel 1975). Rats exposed to 3,102 mg NH 4 + /kg/day in the diet and drinking water for 7 days had statistically si gnificantly reduced body weight gain (64% less) compared to a control group that consumed only 22 mg NH 4 + /kg/day (Boyano-Adánez et al. 1996). Such a high dose of ammonium (as acetate) is equivalent to a 70 kg human ingesting approximately 1.4 lb of ammonium acetate daily. No human studies or repor ts of intermediate-duration oral exposure to ammonia were located. Intermediate-duration animal studies have reported decreases in body weight gain in rats exposed via drinking water (Gupta et al. 1979) or diet (Boyano-Adánez et al. 1996). It should beAMMONIA 21 2. RELEVANCE TO PUBLIC HEALTH mentioned that Gupta et al. (1979) administered ammonium sulfamate to the rats. Ammonium sulfamate is an herbicide whose herbicide properties reside in th e sulfamate portion of the salt and for which there is little toxicity information in the open literature. The EPA (IRIS 2004) has derived an oral RfD for the sulfamate moiety based on the results of Gupta et al. (1979). Following gavage administration of ammonium salts, bone, blood pressure, adrenal gland, and renal effect s have been observed in early studies, generally inadequate by current standards (Bodansky et al. 1932; Fazekas 1939; Seegal 1927). No chronic-duration oral data were located.

An additional reason not to derive oral MRLs for amm onia is because of the role played by the anion of the salt administered. Briefly, in many animal studies, the animals were administered ammonium chloride. Ammonium chloride is commonly used to induce metabolic acidosis in experimental animals. The acidosis is due to the formation of hydrogen ions from the metabolism of ammonium ions to urea. WHO (1986) notes that the ingestion of ammonium chloride in doses around 500–1,000 mg/kg/day for 1– 8 days (longer treatment would worsen the conditio n) has induced metabolic acidosis in mice, guinea pigs, rats, rabbits, and dogs. Me tabolic acidosis can result in a variety of nonspecific changes in neurological, cardiovascular, pulmonary, gastrointes tinal, and musculoskeletal function, as well as in changes in hematological and clinical chemistry parameters. Acidosis following the administration of ammonium chloride is due to the formation of hydr ogen chloride and altho ugh it will occur with any ammonium salt, the degree of acidosis (and associated consequences) will be determined by the ability of the kidneys to excrete the specific anion. DeSousa et al. (1974) showed that administration of hydrochloric acid to dogs induced a significantlygreater decrease in plasma bicarbonate than administration of equivalent quantities of H + as nitric or sulfuric acid. This means that it would be inappropriate to extrapolate findings obtained with ammonium chloride (or any ammonium salt) to equivalent amounts of ammonium, but derived from a different salt. Finally, as discussed by WHO (1986), the amount of excess ammonia (over and above the amount normally produced in the body) that can be safely ingested and assimilated is difficult to define. However, data from human and animals suggest th at that amount may be substantial based on the existence of various efficient ways by which the body can dispose of ammonia.AMMONIA 23



### 3. HEALTH EFFECTS

3.1 INTRODUCTION The prim ary purpose of th i s chapter is to provi de publ ic health officials, phy s icians, toxicol ogi sts, and other interested indivi dual s and grou ps with an ove rall perspective on the t oxico log y of ammonia. It contains descriptions and e v aluations of toxicolo gical studies and epidem iological investigations and provides conc lusions, where possible, onthe relevance of toxicityan d toxico kineti c data to publ ic health. A glossary and list of acrony m s, abbreviations, and s y m bols can be found at th e end of th is profile.

3.2 DISCUSSION OF HEAL TH EFFECT S BY ROUT E OF EX POSURE To help public health professiona ls and others address the needs of persons living or working near hazardous waste sites, the i n form ation in this section is organized first by route of exposure (inhalation, oral, and der m al) and then b y health eff ect (deat h, system ic, imm u nological, ne urological, re productive, developm ent a l, genotoxic, and carcinog enic effect s). These data ar e discussed in term s of three exposure periods: acute (14 day s or l ess), interm ediate ( 15–364 day s ), and chronic (365 day s or m o re). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points inthe f i gures showing n o -observed-adverse-ef fect levels (N OAELs) or lowestobserved-adverse- effect levels (LOAEL s ) reflect the act ual doses ( l evels of exposure) used in the studies. LOAELs hav e been classif i ed into "less serious" or " serious" effect s. "Serious" effects are th ose that evoke failure in a biol ogical sy stem and can lead to morbidity or m o rtality (e.g., acute respirat or y distress or death). "Less s e rious" effects ar e those that are not expected to cause significa nt dy sfunction or death, or those whos e significance to the or gani sm is not entirely clear. ATSDR acknowledges that a considerable am ount of ju dgm ent may be required inestablishing whether an end p o int sho u l d be classifi ed as a NOAEL, "less serious" L OAEL, or "serious " LOAEL, and that in so m e cases, there will be insufficient data to decide whether the effect is indicative of signifi cant dy sfunction. However, the Agency has established guidelines and policies that ar e used to clas sify these end points. ATSDR believes that there is sufficient merit in this appro ach to warrant an attem p t at distinguishi ng b e tween "less serious" and "serious" effects. The distinction be tween "less serious" effe cts and "serious" effects isAMMONIA 24 3. HEALTH E FFE CTS
considered to be im portant because it hel p s the users of the profiles to identif y levels of expos ure at which major health effects start to appear. LOAELs or NO AELs should also help in d e term ining whether or not the effects va ry with dose and/or duration, and pl ace into perspective the po ssible significance of these effects to human health. The significance of the exposure levels shown in th e Levels of Significant Exposure (LSE) tables and figures may d i ffer depending o nthe use r' s perspectiv e. Public health officials and others concerned with appropriate actions to take at hazardous waste s ites may want inf o r

m ation on levels of exposure associat ed wi th m o re subtle effect s in humans or animals (LOAE L s) or exposure levels below which no adverse effe ct s (NOAEL s ) have been observed. Es timate s of levels posing m i ni m a l risk to humans (Minimal Risk Levels or MRLs) m ay be of inte rest to health professionals and citizens alike.

Estim a tes of exposure levels posing m i nim a l risk to humans (Minimal Risk Lev e ls or MRLs) have been made for amm onia. An MRL is defined as an estimat e of daily hum an exposure to a subst ance that is likel y to be without anappr eciable risk of adver se effects (noncarcinogenic) over a specified duration of exposure. M R Ls are deriv e d when reliable and suffici ent data exist to identif y th e target organ(s) of effect or the m o st sensitiv e health effect(s) for a sp ecific duration within a give n route of exposure. MRLs are based on no ncancerous health effects only and do not c onsider carcinogenic effects. MRLs can be derived fo r acute, intermediate, and chronic dur ati on exposures for inhalationand oral rout es. Appropriate methodolog y does not exist to develop M R Ls for dermal exposure. Although m e t hods have be en established to derive th ese level s (Barnes and Dourson 1988; E P A 1990), uncertainties are associatedwith these techniqu es. Furtherm ore, ATSDR acknowledges additional uncertainties inherent in the application of the pro cedures to derive less than lifeti m e MRLs. As an
exam ple, acute inhalation MRLs m ay not be protecti v e for health effects that ar e delay e d in development or are acquired following repeated acute insults, such as hy persensitiv ity reactions, asth m a, or chronic bronchitis. A s these kinds of health effects data beco me available and m e thods to assess levels of significant human exposure im prove , these MRLs will be revised.

A User 's Gui d e has been provided at the end of this profile (see Ap pendix B). This guide should aid in the interpretation of th e tabl es and figures for Levels of Significant E xposure and th e MRLs.AMMONIA 25 3. HEALTH E FFE CTS
3.2.1 Inhalation Exposure 3.2.1.1 Death
There are many reports in th e literature of hum an deaths resulting fr om inhalation of ammonia (Arwood et al. 1985; B u rns et al. 19 85; Close et al. 198 0; Cout urier et al. 19 71; George et al. 200 0; Heifer 1971; Price et al. 1983; So bony a 1977; Walton197 3; Weiser and Mackenroth 1 989; Yang et al. 19 87 ). Most of these reports are of acute accidental exposure to ammonia gas. A review of the early literatur e on amm onia toxicity cites acute exposure to 5,00 0–1 0, 00 0 ppm as being rapidl y fatal in hum ans (Henderson and Haggard 1927; Mulder and Van der Zalm 1967) and exposure t o 2, 5 00–4,5 0 0 ppm as being fatal in about 30 m i nutes (Helmers et al. 1971; Millea et al. 1989). Imm e d i ate deaths resulting from acute exposure to ammonia appear to be caused by airway obstruction while infections and other secondar y co m p lications are lethal factors am ong those who sur v iv e for several day s or we eks. Chem ical burns and ede m a of exposed tissues, including the respiratory tr a c t, ey es, and exposed skin, are often observed after exposure to l e thal levels. Post- m ortem findings i nthe fatal case d escribed by Walton (1973) included extensive edema and burns affecting the m outh, face s, trunk, arms, and upper part of the trunk. The airway at the lary nx was alm o st blocked and th e lungs were greatly distended and congested. Histological exam ination of the lungs sh o w ed acute co ngestion and edem a. The bronchial walls were stripped of their epithelial lining, an d so me smaller bronchi contain e d plugs of d e bris, which included epithelial cells, red blood cells, and dus t cells. No reports of hum an death due to interm ediate or chronic exposure to ammonia were located.

Studies in animals indicate that th e acutely lethal expo sure concentration depends on the expos ure duration. Th e lethal concentration inrats and m i ce increases 5–10 times as the exposure durat ion decreases fro m 16 hours to several m i nu tes (Hilado et al. 1977, 1978; Kapeghian et al. 1982; Morgan 1997; Prok op ' e va et al. 197 3; Weedon et al. 1940)

. Ex posure frequency also ap pears to be an im portant factor in determ ining lethality . Con tinu ous expos ure to 65 3 ppm for 25 day s resulted in nearly 64% lethality in rats, whereas in term ittent exposure (5 day s /week, 8 hour s/day ) t o nearly twice this concentration was toleratedfor 42 day s (Coon et al. 1 970). It appe ars that m a le rats are m o re sensitive than female rats to the lethal effects of ammonia (Appelm an et al. 1 982; St upfel et al. 1971). Anim als exposed to acutely lethal concentrations show severe lesions in the respiratory tract that are si milar to those observed in hum ans. Less sever e l esions of th e liver, heart, and kidne y have been observed following co n tinuous l ong- term exposure to lethal concentrations in rats, guinea pigs, rabbits, and do gs (Coon et al. 1970). However, these may represent sec ondar y com p lications from chronic respiratory tract injur y .AMMONIA 26 3. HEALTH EFFECTS

3.2.1.2 Systemic Effects Respiratory Effects. Ammonia is an upper respiratory irritant in humans. Exposures to levels exceeding 30 ppm result in immediate irritation to the nose and throat (Industrial Bio-Test Laboratories 1973; MacEwen et al. 1970; Sekizawa and Tsubone 1994; Verberk 1977). Four out of six human subjects described moderate irritation of the nose and eyes wh en exposed to 50, but not 30, ppm ammonia gas for 10 minutes (MacEwen et al. 1970). Twenty to 30% of subjects exposed to 72, but not 50, ppm ammonia gas for 5 minutes experienced eye, nasal, and throat irritation (Industrial Bio-Test Laboratories 1973). However, tolerance appears to de velop with repeated exposure (S ekizawa and Tsubone 1994; Verberk 1977). Thus, subjects exposed to 50 ppm ammonia 6 hours/day, 5 days/week for 6 weeks experienced nose and throat irritation only during the first week (Ferguson et al. 1977). Acute exposure to higher levels (500 ppm) has been shown to alter respirator y minute volume (Cole et al. 1977; Silverman et al. 1949). Buff and Koller (1974) suggest that this is due to an effect on "irritant receptors" in the lungs resulting in increased activity of reflex respiratory musc les. This mechanism is also suggested by Cole et al. (1977), who exposed men to 100–331 ppm ammonia gas for 8–11 minutes while they were exercising on a stationary bicycle. Respiratory minute volume w as decreased at concentrations of 150–331 ppm (but not at 100 ppm), and tidal volume was increased at 100 ppm ammonia, but decreased at higher concentrations (Cole et al. 1977). Accidental exposur es to concentrated aerosols of ammonium solutions, high concentrations of ammonia gas, or anhydrous ammonia fumes have resulted in nasopharyngeal and tracheal burns, airway obstruction and respiratory distr ess, and bronchiolar and alveolar edema (Burns et al. 1985; Close et al. 1980; Couturier et al. 1971; de la Hoz et al. 1996; George et al. 2000; Hatton et al. 1979; Heifer 1971; Kass et al. 1972; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Millea et al. 1989; Morgan 1997; O’Kane 1983; Price et al. 1983; Sobonya 1977; Taplin et al. 1976; Walton 1973; Weiser and Mackenroth 1989). Chr onic occupational exposure (about 14 years) to low levels of airborne ammonia (12.5 ppm) had no signif icant effect on pulmonary function or odor sensitivity in a group of workers at a soda ash factory compar ed to a control group from the same factory that was not exposed to ammonia (Holness et al. 1989). An acute-duration inhalation MRL of 1.7 ppm was derived from the Verberk (1977) study, and a chroni c inhalation MRL of 0.1 ppm was derived from the Holness et al. (1989) study; MRLs are presented in Table 3-1 and Figure 3-1 and are discussed in Section 2.3. One human study with somewhat controlled exposure to ammonia showed that pulmonary function was not affected by low levels (25–100 ppm) of ammonia (Ferguson et al. 1977). Transient nose and throatLOAELLess SeriousNOAEL SeriousaSystemKey tofigureReferenceTable 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)ACUTE EXPOSUREDeath132250005000 (rapidly fatal)1 d0.5 hr/dHumanHenderson & Haggard 19272801740117401 (LC50)1 d15 min/dRatProkop'eva et al. 1973310810001000 (LC50)1 d16 hr/dRatWeedon et al. 19404532143021430 (LC50)1 d30 min/dMouseHilado et al. 197755942304230 (LC50)1 d1 hr/dMouseKapeghian et al. 19826781129911299 (LC50)1 d60 min/dMouseProkop'eva et al. 1973710710001000 (LC50)1 d16 hr/dMouseWeedon et al. 1940LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)81150255025 (LC50)1 d1 hr/dRabbitBoyd et al. 19449950255025 (LC50)1 d1 hr/dCatBoyd et al. 1944Systemic10100100 MResp388150150 M (decreased minute volume;increased tidal volume)8-11 minHumanCole et al. 1977115050Resp3897272 (nasal and throat irritation)5 minHumanIndustrial Bio-Test Laboratories, Inc.1973123030Resp3865050 (moderate nasal irritation)10 minHumanMacEwen et al. 1970LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)13Resp155500500 M (nasal and throat irritation;increased minute volume andrespiratory rate)1 d30 min/dHumanSilverman et al. 1949500500 MCardio500500 MHematoOcular500500 M (lacrimation)14Resp1725050 (urge to cough; irritation to noseand throat)b1 d2 hr/dHumanVerberk 1977Ocular5050 (irritation to eyes)15Ocular391100100 (eye irritation)4 wk24 hr/d(Sherman)RatBroderson et al. 1976LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)16Resp89500500 (irritation)1 wk24 hr/d(OFA)RatRichard et al. 1978aRenal500500 (increased kidney weight)Bd Wt500500 (body weight and food intakedecreased 21%)17714714Resp937 dRatSchaerdel et al. 1983714714GastroHemato1515 (slight increase blood pO2)714714Renal714714Dermal714714OtherLOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)18Resp6334403440 M (dyspnea; nasal irritation)42204220 M (congestive intraalveloarhemorrhage, 24% increasedrelative lung weight)1 d1 hr/d(ICR)MouseKapeghian et al. 1982Hepatic34403440 M (degenerative changes;increased relative liver weight)34403440 MBd Wt42204220 M (12% reduction in body weight)19218.6218.6 MResp461085.71085.7 M (temporary dyspnea during firstweek of exposure)1 wk5 d/wk8 hr/d(Beagle)DogCoon et al. 197020218.6218.6 MResp431085.71085.7 M (temporary dyspnea during firstweek of exposure)1 wk5 d/wk8 hr/d(NewZealand)RabbitCoon et al. 1970218.6218.6 MOcular1085.71085.7 M (temporary lacrimation)21Resp9250005000 (acute pulmonary edema)1 d1 hr/dRabbitRichard et al. 1978bCardio25002500 (bradycardia)50005000 (hypertension, acidosis, EKGchange)LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)22Resp38510001000 (dyspnea; rhonchi; rales)1 x10 min(IT)(Mongrel)CatDodd and Gross 1980235050 MResp348100100 M (decreased pulmonary vascularresponse to endotoxinchallenge)6 d(BelgianLandrace)PigGustin et al. 19945050 MCardio100100 M (decreased pulmonary vascularresponse to endotoxinchallenge)100100 MHemato100100 MEndocr2525 MBd Wt5050 M (3% weight loss)241010Resp975050 (frequent coughing)1-2 wk(Duroc)PigStombaugh et al. 19691010Dermal5050 (oral and nasal irritation)1010Bd Wt5050 (reduced weight gain and foodintake)LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)Immuno/ Lymphoret2591500500 M (decreased resistance toinfection)7 d24 hr/dMouseRichard et al. 1978a265050 M349100100 M (decreased pulmonary responseto endotoxin challenge)6 d(BelgianLandrace)PigGustin et al. 1994Neurological27103100100 (sensory irritation)1 d6 hr/dRatTepper et al. 198528102100100 (sensory irritation)1 d6 hr/dMouseTepper et al. 1985INTERMEDIATE EXPOSUREDeath2922641.6641.6 (98% lethality)90 dRatCoon et al. 1970LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)Systemic302525Resp1515050 (transient irritation of nose andthroat)6 wk5 d/wk6 hr/dHumanFerguson et al. 1977100100Cardio2525Ocular5050 (transient eye irritation)31Resp40218.6218.6 M (focal pneumonitis)6 wk5 hr/wk8 hr/d(Squirrelmonkey)MonkeyCoon et al. 19701085.71085.7 MCardio1085.71085.7 MHemato1085.71085.7 MHepatic1085.71085.7 MRenal1085.71085.7 MDermal32Resp13250250 (nasal lesions, epithelialhyperplasia)5-10 wk24 hr/d(Sherman)RatBroderson et al. 1976LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)33218.6218.6Resp211085.71085.7 (nonspecific inflammation)6 wk5 d/wk8 hr/dRatCoon et al. 19701085.71085.7Cardio1085.71085.7Hemato1085.71085.7Hepatic1085.71085.7Renal1085.71085.7Ocular34179.1179.1Resp24369.4369.4 (mild nasal discharge in 25% ofanimals)641.6641.6 (interstitial pneumonitis)90 or 114 d(SpragueDawley)RatCoon et al. 1970369.4369.4Cardio641.6641.6 (myocardial fibrosis)369.4369.4Hepatic641.6641.6 (fatty changes of liver platecells)369.4369.4Renal641.6641.6 (renal tubular calcification)LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)35218.6218.6Resp181085.71085.7 (non specific inflammation)6 wk5 d/wk8 hr/dGn PigCoon et al. 19701085.71085.7Cardio1085.71085.7Hemato1085.71085.7Hepatic1085.71085.7Renal1085.71085.7Dermal369090Resp1013 wk24 hr/d(Hartley)Gn PigTargowski et al. 19849090Hemato9090Ocular9090Bd WtLOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)37170170Resp10618 wk5 d/wk6 hr/dGn PigWeatherby 1952170170Cardio170170GastroHemato170170 (increased hemosiderin)Hepatic170170 (congestion)Renal170170 (congestion)LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)385757Resp27114 dRabbitCoon et al. 19705757Cardio5757Hemato5757Hepatic5757Renal5757Dermal39Resp52100100 (excessive nasal secretion,coughing, trachealinflammation)4 wks(NS)PigDrummond et al. 1980Ocular5050 (excessive lacrimation)5050Bd Wt100100 (18.6% reduction in final bodyweight)Immuno/ Lymphoret40452525 (increased severity of infectionby mycoplasma)4 wk24 hr/d(Sherman andFischer)RatBroderson et al. 1976LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)4187500500 M (reduced resistance to infection)3 wk24 hr/dRatRichard et al. 1978a421009090 (significantly reduceddelayed-type response totuberculin)3 wk24 hr/d(Hartley)Gn PigTargowski et al. 198450504370100100 (decreased serum concentrationof gamma globulin)31-45 d24 hr/d(NS)PigNeumann et al. 1987Neurological441085.71085.7 M396 wk5 hr/wk8 hr/d(Squirrelmonkey)MonkeyCoon et al. 1970451085.71085.7176 wk5 d/wk8 hr/dGn PigCoon et al. 1970LOAELLess SeriousNOAEL SeriousaSystemKey tofigureReference(continued)Table 3-1 Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationChemical Form(ppm) (ppm) (ppm)Exposure/Duration/Frequency(Specific Route)Species(Strain)46505051100100 (lethargy)4 wksPigDrummond et al. 1980CHRONIC EXPOSURESystemic479.29.2cResp33812.2 yr5 d/wk8 hr/dHumanHolness et al. 19899.29.2Oculara The number corresponds to entries in Figure 3-1.b Used to derived an acute-duration inhalation MRL of 1.7 ppm; the MRL was derived by dividing the LOAEL of 50 ppm by an uncertainty factor of 30 (10 for variation in sensitivityamong humans and 3 for use of a minimal LOAEL).c Used to derive a chronic-duration inhalation MRL of 0.1 ppm; the MRL was derived by adjusting the NOAEL of 9.2 ppm for continuous exposure (9.2 x 8/24 hours x 5/7 days) anddividing by an uncertainty factor of 30 (10 for the protection of sensitive individuals, and 3 for the lack of reproductive anddevelopmental studies).Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = female; gastro = gastrointestinal; hemato =hematological; hr = hour(s); LOAEL =lowest-observed-adverse-effect level; M = male; metab = metabolic; min = minute; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; Resp =respiratory; wk = week(s)110100100010000100000 Death9c14m5m6m7m2r3r8h Respiratory22c19d19d101011111212131418m18m16r17r20h20h21h23p23p24p24p Cardiovascular1321h21h23p23p Gastrointestinal17r Hematological1317r23p Hepatic18m Renal16r17r Endocrine23pppmFigure 3-1. Levels of Significant Exposure to Ammonia And Ammonium Compounds - InhalationAcute (≤14 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancerSystemic110100100010000100000 Immuno/Lymphor25m26p26p Neurological28m27rppmFigure 3-1. Levels of Significant Exposure to Ammonia And Ammonium Compounds - Inhalation (Continued)Acute (≤14 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancer

Dermal17r24p24p Ocular131415r20h20h Body Weight18m18m16r23p23p24p24p Other17rSystemic10100100010000 Death29r Respiratory35g35g36g37g303031k32r33r33r34r34r34r38h39p Cardiovascular35g37g3031k33r34r34r38h Gastrointestinal37g Hematological35g36g37g31k33r38h Hepatic35g37g31k33r34r34r38hppmFigure 3-1. Levels of Significant Exposure to Ammonia And Ammonium Compounds - Inhalation (Continued)Intermediate (15-364 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancerSystemic1010010001000039p Body Weight36g39p39p Immuno/Lymphor42g42g40r41r43p Neurological45g44k46p46pppmFigure 3-1. Levels of Significant Exposure to Ammonia And Ammonium Compounds - Inhalation (Continued)Intermediate (15-364 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancer

Renal35g37g31k33r34r34r38h Dermal35g31k38h Ocular36g303033rSystemic0.1110 Respiratory47 Ocular47ppmFigure 3-1. Levels of Significant Exposure to Ammonia And Ammonium Compounds- Inhalation (Continued)Chronic (≥365 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancerSystemicAMMONIA 46 3. HEALTH E FFE CTS
irritation was noted the first week of exposure in m a le and female v o lunteers exposed to 50 pp m , but not 25 ppm ammonia 5 day s /w eek, for 6 weeks. No signi ficant differences wer e noted between exposed and control gr oup s for pulm onary f unctio n tests, phy s ical exam inations, or perform an ce of norm a l job d u ties (Ferguson et al. 1977)

.
A num ber of occupational cohort studies that exam ined farm ers who worked in e n closed livestock buildi ngs have been conducted. These studies all included m e asurements of amm onia in the livestock confinement buildi ngs, as well as measurem ents of one or m o re of the following : total dust, r espirable dust, carbon dioxide, total endotoxi ns, r espirable endotoxins, f ung i , bacteria, and m o lds (Choudat et al. 1994; Corm ier et al. 2000; Donham et al. 199 5, 2 000; H eederik et al. 199 0, 1 991 ; Melbostad and Ed uard 2001; Reynol ds et al. 1996 ; Vogelzang et al. 199 7, 2 0 00). Of the p o llutants m easured, amm o nia and dust
were m o st fre quently associated with res p iratory eff ects, m any of wh ich were te m porary and disappeared with cess ation of exposure. Ammonia levels range d from 2.3 to 20.7 ppm and total dust levels from 0.04 t o 5. 64 m g /m 3

. Mostof these studi es reported an association between exposure to pollut ants, including amm onia, in livestock confinement buildings and an increase in respir atory s y m p toms (such as bronchial reactivity /hyperresponsiveness, inflammation, cough, wh eezing, or shortness of breath) and/or a decrease in pulm onary fun c tion (such as forced expirator y v o lum e in the first second [ FEV 1. 0 ], m a x i mu m expirator y flow rates [ M EF 50 and MEF 75 ] , and m a ximal m i d-expirator y flow rate [ M MEF] ) (Choudat et al. 1994; Cor m ier et al. 2000; Donh am et al. 1995, 2 000; Heederik et al. 199 0; Rey nol ds et al. 199 6; Vogelzang et al. 1997 , 20 0 0 ). One study, however, r e ported correlations onl y b e tween total dust, fun g al spore, and endotoxi n m ean exposure levels and task -specific preval ences (Melbo stad and Eduard 2001)

. Another study reported n o significant correlations betw een lung function or chr onic respiratory s y m p tom s and dust or ammonia levels, but sug g ested that endot oxi ns and bacteria levels may p l ay a role (Heederik et al. 1991). Most studies adjusted for confoundin g f actors, such as sm oking and num ber of y ears worked on a farm , in their statistica l analy ses. All of the studies concluded that prevalence of respirat ory sy m p toms of so m e ty pe was higher in th e farmer cohort than in th e respective co ntrol gr oup. I t is not clear fro m th ese studies w h at the contribution of am m onia is to the respiratory changes, but the
cu m u lative data indicate t h at a m m onia may contribute to transient respiratory distress in farm ers working in enclosed livestock facilities.

A cross-secti onal study of male workers at two fertilizer factories in Saudi Arabi ashowed a si gnificant association between exposure to ammonia gas and re spirator y s y m p toms including bronchial asth m a (Ballal et al. 1998). Work ers in factory one were exposed to air ammonia levels of 2.82 –18 3

. 86 p p m (2.0–1 30. 4 mg/m 3 ), and workers in factor y two were exposed to 0

. 03–9 .87 ppm (0.02– 7.0 m g /m 3 ).AMMONIA 47 3. HEALTH E FFE CTS However, co ntinuous exposure levels for workers could not be calculated becau se the num be r of day s worked per week was not provided by the study auth ors. Logistic regression ana l y s is showed that
amm onia con centration was significantly related to cough, phlegm , wheezing (with and without shortn ess of breath), and asthma, whereas sm oking was only a fact or for wheezing and phleg m . Additionally , those workers exposed to amm o nia levels above the Am erican Conference of Governmental Industrial Hy gienists ( A CGIH) threshold lim it value (TLV) of 25.4 ppm (18 m g /m 3 ) had significantl y h i gher relative risks for cough, phleg m , wheezi ng, dy s pnea, and asthma than workers e xposed to levels below the TLV. Incidence of wheezing was also elevated in workers exposed to ammonia levels below the TLV. Cum u lative amm onia concentration (CAC) of >50 m g /m 3 -years al so showed a significantly increased rel a tive risk for all of the above sy m p to m s c o m p ar ed to workers with a CAC of ≤ 50 m g /m 3 -y ears. None of the relative risks for wo rkers in the second factor y (amm onia lev e ls <25.4 p p m ) were significant. Other occupational studies also evaluated the effect s of amm onia exposure and pulm onary function. Firefighters who reported exposure to ammonia while working ha d a rate of decline of FEV 1 of 1.7 tim es that of no nexposed firefigh ters over a period of 6–1 0 y ears (Tepper et al. 1991)

. Children (8–9 y ears old) who attended tw o schools in the vicinity of a fertilizer p l ant had higher incidences of acute respirat or y diseases t h an ch ildren of the sam e age who attended a school 20 kil o m e ters away (Gomzi and Šari ć 1997). Incidenc e was r e lated to levels of measured pollutants (amm onia, hydrogen flu o ri de, nitrogend i oxide, t o tal suspended part iculate m a tter, and sm oke) in the inside and outside air. Forced expiratory vol um es were not statistically different between the three schools. The se results indicate that exposure to lo w levels of amm o nia (0.04 –0. 2 3 ppm ) and other airborne po llutants may no t cause functional respiratory de ficits, but may lower the resist ance t o respiratory pathogens in children. The se effects may be due i n p art or in whol e to toxicants other than amm onia, such as nitrog en dioxi de.

Case r e ports of individuals acutely exposed to anhy dr ous or aqueous a m m onia r e ported respiratory effects including nasal irritation; epiglottic, lar yngeal, phar y ngeal, tracheal, and pulm onary edem a; dyspnea; wheezing; coughing; rhonc hi; pneum onia; and cardio-respiratory ar rest (de la Ho z et al. 1996; George et al. 2000; Kerstein et al. 2001; Latenser and Lucktong2000; Leduc et al. 1992; L ee et al. 1993; Millea et al. 1989; Mor g an 199 7; Pr udhomm e et al. 1998; Weiser and Mack enroth 1 989). de la Hoz et al. (1996) described the initial and residual effects of three a dult males who had been acutely exposed to amm oniaAMMONIA 48 3. HEALTH E FFE CTS gas in separat e incidents. All three m e n com p la ined of burni ng e y es, throat, and skin, co ugh , and wheezing, and all had been treated at hospitals s hortl y after exposure. Follow-up exam inations 2–21⁄2 y ears later showed persistent dy spnea, cough, and wheezing at rest and/or on exertion, wh ich is consistent with restrictive lung disease secondary t o a c ute amm oni a inhalation i n jur y . Another m an exposed to anhy drous a mmonia gas experienced pharyngeal and laryngeal edema , dy spnea, chest tightness, copious bronchial secretions, and wheezi ng (Leduc et al. 1992); 12 y e ar s postexposure, he continued t o have cough, e x ertional dy s pnea, and r ecurrent bronch i al infections. Sim ilar cases were reported b y K e rstein et al. (2001) an d Latenser and Lucktong ( 200 0 ) ; no foll ow-u p reports were available.

A m o re severe exposure was reported by George et al . (200 0). Anadult m a le was found un conscious next to a b u rst pipe carry i n g liquefied ammonia. He had ocular an d cutaneous b u rns and severe difficulty breathing. O v er the next 27 day s , he suffered m any medical setba c k s, including attacks of brady cardia, a
co m p lete circ ulatory collapse fro m whic h he was resu scitated, and finally , a fatal cardiac arr estfrom severe bleeding. Ano ther sim ilar severe exposur e resulted in th e d eath of the patient 13 day s postexposure due to treatment-resistant broncho pneum onia; histological exam ination showe dm a ssive, hem o rrhagic pulm onary edem a, regions of em phy s ema, and edem a of the epiglottis and glottis (Weiser and Mackenroth 1 989). Reports of apparently rare effect s have b een found. A man exposed occupational l y for 5 m onths to low levels of amm onia gas (8 –15 ppm ) from ammonia-c ontainin g silv er polish dev e loped asthma-like sy m p toms (Lee et al. 1993 ). Separate specific bronchi al prov ocation tests to the silver polish and to 12 p p m ammonia pro duced asthmatic reactions, im p licating the ammonia in the silver polish as the cause

. Another study reported hyposm i a (loss of the sense of sm ell) in a man following acute inhalation exposure (for several hours) to an unkn o w n concentra tion of amm o nia gas; the hyposm i a had not resolved 30 m onths after exposure (Prudhomm e et al. 199 8).

Studies in animals have de m onstr ated si milar dose-ef f ect and duration-effect patterns for the respiratory tract. Acute exposures (1 hour t o 1 week) to low co n centrations of amm onia ( ≤ 1,00 0 ppm ) irritate the upper respirator y tract whereas exposures (3 hour s to 2 weeks) to high concentrations ( ≥ 4,000 ppm ) result in severe damage to the upper and lower respirator y tr act and alveolar capillaries (Coon et al. 1970; Kapeghian et al. 1982; Mayan and Merilan 19 72; Ri ch ard et al. 197 8a, 197 8b; Sc haerdel et al. 1983; Stom baugh et al. 196 9). Pr olonged or re peated exposures to lower levels ( ≥ 150 ppm ) produce inflammation and lesions o f the upper re spiratory tract (Broderson et al. 197 6; Co on et al. 19 70 ).AMMONIA 49 3. HEALTH E FFE CTS Clinical and histological effects have been seen inthe lungs of ani m als following exposure to amm onia gas (Dodd and Gross 1980 ; Gaafar et al. 199 2; Sjö b lo m et al. 1999)

. Cats exposed to 1 , 00 0 pp m amm onia gas for 10 m i nutes and observed for u p to 35 day s sh owed a biphasic course of respiratory patholog y (D odd and Gross 1980). Effects seen at 24 hours p o st-exposure inclu d ed severe dyspnea, anorexia, and dehy dratio n, with rhonchi and coarse rales evident up on auscultatio n. Microscop yof lung sam p les on day 1 showed necrotizing br onchitis in th e large conducting airway s, and necrosis and sloughin g of th e epithelium and acute inflammatory re action in the bronchi. On day 7, th e m u cosal lesions had resolved, but on day 35, var y i ng degrees of bronchi tis and early bronchopneum onia with areas of bul bous e m phy sem awere seen. Gross pathology re vealed varying degrees of congestion, hem o rrhage, edem a, interstitial em phy s e m a , and collapse of the l ungs at all time points. Pul m onary resistance was increased thr oughout th e study (Dodd and Gross 1980). Swiss m i ce exposed to 909 ppm , but not 303 ppm , amm onia gas 6 hours/day , 5 d ay s /week for 4–14 day s ha d histolo g ical lesions in the respiratory epithelium in the nasal cavi ty (Zissu 1995); no lesi ons were observed in the trachea or lungs. Nasal
m

u cosa w as a dversely affected in adult male mi ce exposed to vap o r of 12% amm onia solution for 15 m i nutes/day , 6 day s /week for 4, 5, 6, 7, or 8 weeks (Gaafar et al. 199 2). Histo l ogical chang es progressed from weeks 4–8 from crowd i ng of cells fo rm ing crypts and irregular arrangem e nts to epithelial hy perplasia, patches of squamous m e t a plasi a, loss of cilia, and dy splasia of the nasal epithelium

. One ani m al t h at had loss of polarity of th e epithelium, hy perchrom atism , and m i totic figures with an intact base ment m e m b r ane also had a carcinoma in situ in one nostril. At week 8, one m ouse had an invasive adenocarcinoma of the nasal m u cosa. Hist ochem i cal results were also abnorm a l. The levels and cell locations of succinic dehy droge nase, aci d phosphatase, al kaline phosphatase, and nonspecific esterase activities were altered, indicating altered cell metabolism and energy production, cell i n jur y , proliferation, and possibl y chronic inflammation and neoplastic transformation (Gaafar et al. 1992). Anesthetized, mechanically ventilated rabbits exposed to high level s of nebulized ammonia (2 m L of 23–2 7% ammonia solutio n; estim ated by the study authors as peak amm onia con centrations of 35,000–39,000 ppm ) for 4 minutes had a decrease in blood oxygen saturation and an increase in airway pressure (a measure of cha nges in airway resistance) (Sjöblom et a l . 1999). Arterial oxy g en tension decrea sed from 23.3 (±3.6) to 11.0 (±3.6) kPa and peak airway pressure increas e dfrom 13 (±2) to 17 (±2)
cmH 2 O. At baseline and 5 and 1 5 m i nutes after amm oni a ad ministration, meas ure m ents w e r e taken via a catheter in the left auricular artery , whic h m onito red pressure and sam p led for arterial blood gases, and via transducers in the venti l ator. Thirty and 150 m i nutes after ammonia exposure , rabbits recei ved inhalation the r apy of either 0.5 m g bude sonide (a steroid) or a placebo, and airway pressure, hem odynam i cs, and gas exchange were measured every 30 m i nutes for 6 h ours. Slight, gradu a lAMMONIA 50 3. HEALTH E FFE CTS
im provem e nt of blo od gas param e ters was noted over th e 6-ho ur ob servation period in all rab b i t s, with or without steroi d treatm e nt; however, no p arameters approached normal during th at time period.

Other studies exam ined pigs in norm a l swine produc ti on facilities (Donham 1991) or in envir onm entally regulated enclosures (Diek m an et al. 1993; Gustin et al. 1994; Urb a in et al. 199 4). Donham (1991) investigated the correlation of ho using ai r environm en t (in the finis h ing barn) to swine disea se s and productivi ty over 12 m onths on 2 8 swin e farms. Tota l dust, respirable dust, end o t oxin activity of the dust, and hy dr ogen sulfide levels we re determ ined, an d area dust and m i crobial counts were monitored at 1.2 m e ters ab ove the floor (the hum an breathing zone). Amm onia and car bon di oxide levels were determ ined 1.2 m e ters and 20 cm (swine breathi ng zo ne) above the floor. T h e average ammo nia concentration in the hu m an breathing zo ne for all farm s w as 9.1 ppm ; the mean concentration in the swine breathing zone was 14.5 ppm

. The mean concentrati ons of enviro nm ental cont aminants were calculated for the m o st productive farrowing o p erations and the le ast productiv e ones and com p ared with lower productio n variables (Donham 1991). A mmonia concentrati on was related to num b er of pigs weaned per litter, and tota l and respirable dust concentrations we re related to prolonged age to reach a wei ght of 25 kg. Another co m p ariso ninvolved the stratificatio n of the finishing farm s int o quartiles according to percentage of pigs with spe c ifie d disease conditions and com p ariso nof m ean co ncentrations of various environm ental contam inant s for each farm in eachstrata (Donham 1991). Levels of amm onia ( i n the ani m al breath i ng zone) gre a ter than 25, 29, and 23 ppm wer e asso c i ated with buildings in which pneum onia, pleuritis, and arthritis, respectively , were gr eater than the mean value for the group. Overall, respirable dust (>0.8 m g /m 3 ), amm onia (>23 ppm in the animal breathing zone), and carbon di oxide (>2,000 ppm ) levels were m o st often associated w ith increased disease. Possibl e study shortc om ings noted b ythe s tudy author w e re that pre-existing con d it ions could have been present in th e pigs (before they entered the finishing barns) and that nasal turb inates wer e not routinel y exam ined for abnorm a lities. These data su ggest that amm onia may contribute t o r espiratory and other pathol ogical conditi ons in pi gs raised in crowded, enclosed conditions, but the exact contribution of ammonia is difficult to a ssess. The lungs of youn g pi gs exposed conti nuousl y t o 0, 2 5 , 50 , or 1 00 ppm ammonia gas for 6 day s i nairpollutant exposure cham bers were r e m o ved, ventilated, and perfus e d, and the pulm onary vascular hem odynam i cs and perm eability and th e endotoxi n-i ndu ced vascular response were assessed(Gustin et al. 1994)

. In lungs from pigs exposed to 100 ppm , but not 2 5 or 50 ppm ammonia, the endoto x in-ind uced vascular resp onse seen in lungs from control pi gs was abo lished. The study authors suggested that this is due to a m odification of the balance bet w een vasodilators (such as cy clooxygenase products and platelet activating factor) and vaso constrictors (such as pros tacy clin). Since vasoconstr iction, as induced byAMMONIA 51 3. HEALTH E FFE CTS
endotoxi n, m ay serve as a protective mechanism in the lungs and attenuate edema form ation, the effective abolishment of this effect by amm onia may be detri m ental.
Young p i gs exposed conti nuousl y t o amm onia vapors (0 , 25 , 50 , or 100 ppm ) for 6 day s in air- pollutant exposure cham b e rs had increased num b e rs of neutrophils in nasal lavage flui d in all exposure groups (Urbain et al. 1994) and inc r eased porcine seru m albu min at 100 ppm

. Not all studies have shown adverse respiratory effect s from intermediate exposur e to amm onia vapors. Groups of gil t s (virgin female pigs) were raised fro m the age of 2–4.5 m onths ina convention a l grower unit where th ey were naturally exposed t o my copl asmal and bacterial pathogens th at cause enzootic pneum onia and atrophic rhinitis (Diekman et al . 1993). The pigs were then transferred to environm entally regulated room s, where the y were exposed continu ousl y to low ( m ean 7 ppm ) or m oderate (mean 35 p p m ) leve ls of a m m o nia for 6 weeks. No statistically signific ant differences were seen in the percent of lung tissue containing lesions or in snout grade (Diek m an et al. 1993). N i nety -fi ve percent of all gilts had lung lesions, with a wide range of degree of severity

. Snouts were graded at the level of the second deciduo us prem olar as having n o r m al turbinates (grade of 0) , slight to m o derate degeneration (grade of 1–3 ), or sever e degeneration to com p lete lo ss of turbinat es (grade of 4 or 5). S o m e of the gilts w e re continuously expo sed th rough puberty and breedi ng (a round 205 day s of age) and the lungs and t u r

b inates were exam ined at 30 day s of gest ation. No st atistically significant differences were observed in p e rcent of lung tissue containing lesions o r in snout gra d e (Diek m an et al. 1993).

A num ber of cattle were acutely e xposed to anhydrous amm onia wh en a pipeline running thr o ugh their pasture ruptur ed and leaked 1,80 0 barrels of amm onia in a short peri od of tim e (Morgan 19 97). The
amm onia co m b ined with m o isture and formed a white cloud (amm onia aeroso l), which drift e d south across two ad ditional fields containing c a ttle. In the f i eld where the rupture occurred, four head of cattle were found dead and two others were euthanized beca use of blindness and respir atory distress. Cattle in the adjacent pasture had runny e y es and noses and we re coughing and wheezing. Eight da y s af ter the pipeline rupt ure, the cloud of amm ona aerosol, which had apparent ly settled in a low-l y ing pr otected area, blew back up the valley and exposed the rem a ining cattle again and also exposed a horse in the same pasture. All ani m als had r espiratory distress, elev at e dbody tem p e r atures, and one cow and the horse had swollen tongues and enlarged l y m ph gl ands. All cattle were given antibiotics and som e were treated specifically for respiratory problem s. N o m e asure me nts or estimat ions of amm o nia concentrations were provided and no foll ow-up exam inations were avail a ble to assess long-term effects from the ex posures.AMMONIA 52 3. HEALTH E FFE CTS
All reliable L OAELs and highest NOAE Ls are pres ented in Table 3-1 and Figure 3-1.
Cardiovascular Effects. Acute exposure to hig h l yconcentrated aerosols of amm oniu m com pounds may cause el evated pulse and blood pre ssure, brady c ar dia, and cardiac arrest in hum ans ( G eo rge et al. 2000; Hatton et al. 1979; Montague and Macneil 1980; White 1971). These effects did not occur after acute exposure to 500 ppm amm onia or repeated exposure to 100 p p m amm onia (Ferguson et al. 1977; Silverm an et al. 1949)

. Cardiovascular changes that m ay be analogous t o tho se observed in hum ans have been observed in rabbits exposed to hi gh concentrations of amm o nia (Richard et al. 1978 b). Brady cardia was seen at 2,500 ppm , and hy pertens i on and cardi ac arrhy thm ias leading to c ardiovascular collapse fo llowed acute exposures to concentrations exceeding 5,000 ppm . Pathological correlates for these effects hav e not been dem onstrated

. Atrophy of pericardial fat has b een observed in m i ce exposed to 4, 000 ppm amm onia (Kapeghian et al. 198 2). Myocardial fibrosis has been observed i nrats, guinea pigs, rabbits, dogs, and
m onkey s after prolon ged ( 90 day s ) cont inuous expos ur e to 65 3 p p m (Coon et al. 197 0). The contributi on of these lesions to the m o rbidity and m o rtality of affected ani m als has not been determ ined. Exposure of pigs in vivo t o up t o 1 00 p p m amm onia for 6 day s di d not alter the baseline values of any hem odynam i c or permeability parameters (arterial, pre- or postcapill ary , or veno u s blood fl ow resistance, or total pu lmonar y bl ood f l ow resistance), but di d eliminate the hem ody nam i c response to Escherichia c o liendot oxins in the lungs (Gustin et al. 1994). This may affect the ability of the lungs to resist bact eria l infection. The pulm onary bl ood flow resistanc e m easurem ents were taken in vitro in ventilated and perfused lungs fro m pigs exposed to ammonia in vivo (Gustin et al. 1994)

. Reliable LOAELs andhighest NOAELs for cardiovascular eff ect s ar e prese nted in Table 3-1 and Figure 3-1.
Gastrointes t inal Effects. Exposur e to high l y co ncentrated aerosols of amm oniu m co mpoun ds can produce bur ns of the lips, oral cavity , and pharynx, a l ong with ede m a of these areas (Hatton et al. 1979; Kass et al. 1972; Leduc et al. 1992; Levy et al. 1964; Price et al. 1983; Stroud 1981; Ward et al. 1983; Yang et al. 1987). Gastroi n testinal effects of amm o n i a in anim als have not beenreported. As shown in Table 3-1, pathological changes in the ga strointestin al tract were not observed in guinea pigs e xposed repeatedly to 170 ppm amm onia (Weatherb y 19 52).AMMONIA 53 3. HEALTH E FFE CTS Hematological Effects. C y anosis, elevated white bloo d ce ll count, and pulm onar y artery th rom bosis have been ob served in humans exposed to hi ghl y co ncentrated aerosols of amm oniu m co mpoun ds (Sobony a 19 77; Taplinet al. 1976; Voi s in et al. 197 0; Ward et al. 198 3; White 1971). Standard hematological measurements, including bl o o dhem oglobinand differe nt ial cell counts, have been reported for a few animal speci es. As shown in Table 3-1 and Figure 3-1, acute hem a tological effects of amm onia have n o t been dem o nstrated (Doi g and Willo u ghb y 19 71; Gu stin et al. 19 94). Pi gs exposed to u p to 10 0 p p m ammonia for 6 day s had no statistically significant difference s fro m controls in total leukoc y t es or percent ly m phoc y t es, neutrop h ils, or eosinoph il s (Gustin et al. 199 4). Rep eated exposure to 1 , 100 ppm had no effect on hem a tological param e ters in gui nea pigs , rats, and rabbits (Coon et al. 1970). Weatherby (1952) reported increased co ncen trations of hem o sideri n in the splee nof guinea pigs exposed to 170 ppm ammonia for 18 weeks. Th is suggests the possibility of increased turnover of red bloo d cells; however, this has not be en corroborat ed.
Musculoskeletal Effects. Spas m s of m u scl es of the extre m it ies have resul t ed from an a c ute exposure of a man to anhydrous amm o n i a gas (White 1971), but thi s was probably caused b y an effect of
amm onia on the nervous s y stem
. Hepatic Effects. He morrhagic necrosis of the liver was observ e d in an individual exposed to a lethal concentration of ammonia gas and liqui d for a short period of tim e (<45 m i nutes) (Heifer 1971). No othe r case s of hepatic effect s have been reported in hum ans. Hepatic ef fects ar e usua lly not seen in anim al s exposed to ammonia gas. As shown in Table 3-1, liv er necrosis ha s been observed following acute lethal exposure of mice to 3,440 ppm ammonia for 1 ho ur ( K apeghian et al. 1982)

. Fatty changes of liver plate cells were seen in rats follo wi ng continu ous lon g -term exposure to 642 ppm amm onia for 90 day s , but no such changes were seen in rats, squirrel m onkey s , and guinea pigs e xposed to 1,0 86 p p m ammonia 8 ho urs/day, 5 day s /week for 6 weeks (Coon et al. 1 9 7 0 ).
Renal Effects. No stud ies were located regarding renal e ffects in hum ans after inhalation exposure to
a m m onia. In ani m als, rena l effects do not appear to b e an im portant feature of the toxicity of i nhaled
amm onia. Effects reportedhave not been corroborate d or cannot be interpreted. Mild abnorm a lities in the renal tubules have been described in guinea pi gs e xposed to 170 ppm for 12 weeks, 5 day s /week, 6 ho urs/day; however, renal effects at this relativ ely low level have not been co rroborated ( W eatherby 1952). Exp o s ure to m o re than 6 tim es this concentration for 6 weeks, 5 day s /week, 8 ho urs/d ay d i d n o tAMMONIA 54 3. HEALTH E FFE CTS result in path ological chan ges to the kidn ey (Co on et al. 1970)

. Renal tubular calcification (severity not reported) has been reported in rats continuousl y expos ed to near lethal levels (Coon et al. 19 70 ).
Endocrine Effects. Adrenaline levels in urine, 17-oxy corticos teroids in the urine, and 11- o xycorticosteroid levels in blood were increased in hum ans expo sed to 3.0 ppm ammonia f o r 37 day s (Kalandarov et al. 1984)

. Exposure to 7.2 ppm for 17 day s also incr eased adrenali ne levels in urine and 17- oxy corticosteroids in the urine, and increas ed free, but not tota l, 11-oxy c orticosteroid levels in bloo d (K alandarov et al. 1984)

. Experim e ntal details were lacking i nthis st udy ; additionally , no clinic al or histologi cal data were provided for this or o ther end poi nt s in this study and no su pp orting data are available in the literature. Therefore, the si gnificance of these effect s i s unclear. Exposure of pi gs to up t o 100 ppm
amm onia for 6 day s did no t significantl y alter the plasma cortisol concentration ( G ustin et al. 1994). No statistically significant diff erence was seen in adrena l gland weight of fem a le pigs exposed to about 35 p p m ammonia for 6 we eks or for 6 w eeks plus thro ugh day 30 of gestation com p ared to pig s exposed for sim i lar time frames to about 7 ppm amm onia (Die k m an et al. 1993). No un e xposed contr o ls were included in th at study . The endocrine s y stem does not appear to be a primary target of inhaled amm onia.
Dermal Effe cts. Ammonia gas and aerosols of ammoni u m co m pounds derived from anhydrous
a m m onia ar e derm al irritan t s in hum ans and anim al s. These effe cts are described in the discussion of derm al eff ect s associ ated with de rmal exposure (Section 3.2.3.2).
Ocular Effe cts. Ammonia gas and aerosols of ammoni u m co m pounds derived from anhydrous
a m m onia ar e ocular irritants in hum ans a nd anim als. These effe cts are described in the discussion of ocular effects associat ed with de rm al exposure (Section 3.2.3.2).
Bod yWeig ht Effects. Reduced bo dy weight has been observe d in rats expo sed via inhalation to 500 ppm (Richard et al. 19 78a) and in pi gs exposed to 50 p p m or more amm onia for 6 day s (Gustin et al. 1994; Urbain et al. 1994). Pigs gained l ess wei ght and showed decreased food consum ption when exposed to 1 0 0 ppm amm o nia for 4 or 5 weeks (Dru mm ond et al. 1980; St om baugh et al. 1 9 6 9 ). Fem a le pigs exposed to about 35 ppm for 6 weeks gained l ess weight than those exposed to onl y about 7 ppm (Diek m an et al. 1993)

. Ho wever, females that were continu ousl y e xposed to ab o u t 7 or 35 pp m ammonia from 6 weeks before breeding until day 30 of gestation had no statist i cally signific ant difference in body weight (Diekman et al. 1993); h o wever, no c ontr o ls were included in th is study.AMMONIA 55 3. HEALTH E FFE CTS
3.2.1.3 Immunological and L y mphoreticular Effects
Several case r e ports describe occupational asth m a th at developed due to exposure to aerosols that contained amm oniu m co mpoun ds (Ballal et al. 1998 ; Lee et al. 1993; Weir et al. 1989). Secondary i n f ections often co m p licate th e clinical out co m e of burn s and respirator y lesions related to exposure to h i ghl y co ncentrated aerosols derived from anhy dro u s ammonia (Sobony a19 77; T a plin et al. 1976). However, there is no evidence th at the decr eased immunological resistan ce represents a primary im pairment of the imm u n e sy stem in humans followi ng exposure t o ammonia. Nevertheless, as shown in Table 3-1 and Figure 3-1, studies in ani m als have sh own that acute and long-ter m exposure to ammonia can decrea se the resistanc e to bacterial infection and decrea se i m mune response to infection. A significant increase in m o rtality was obs erved in m i ce exposed to ammonia for 168 hours foll owed by exposure to th e LD 50 of Pasteurella multocida (Rich ard et al. 197 8a). Exposur e of rats to ammonia at ≥ 25 ppm for 4–6 weeks following in ocu l ation with M ycoplasma pu lmonis intranasally signific antly increased the severity of re spiratory signs charact eristi c of m u rine r espiratory my coplas m o sis ( B roderson et al. 1976). Guinea pigs exposed to 90 ppm ammonia for 3 weeks developed a significant decrease in the cell-mediatedimmune resp onse to challenge with a derivative of tu berculin (Targowski et al. 1984). Furtherm ore, the response of blo od and bronchial l y m phoc y t es to mitogens (phy t ohem a gglutinin, concanavalin A, purified pr otein derivati ve of tubercul in) was m ark edly reduced. The hem odynam i c response (increased total pulm onary blood flow resistance) to E. coliendoto x ins in the lungs o f pigs was elim inated by exposure to up to 100 ppm ammonia for 6 day s , which may affect the ability of the lungs t o resist bacterial infection (Gustin et al. 19 94). Also, a r e duction in g a mma globuli nconcentration was reported in pi gs exposed to 100 ppm amm onia for 31–45 day s (Neumann et al. 1987).

3.2.1.4 Neurological Effects
Case r e ports of accident victi m s exposed to hi ghl y concentrated aerosols derived from anhy drous
amm onia describe blurred vision, diffuse nonspecifi c encephalopathy , loss of consciousness, m u scle weakness, and decreased d eep tendon re flexes (Georg e et al. 2000; Hatton et al. 1979; Latenser and Lucktong 20 0 0 ; White 19 7 1 ). Acute exposure to lo wlevels of amm onia (100 ppm ) has been shown to depress free-access wheel running behavior in rodent s (Tepper et al. 1985). No overt sy m p toms of neurological disorders were reported in guinea pigs o r m onkey s th at were exposed to up to 1 , 105 ppm amm onia for 6 weeks (Coon et al. 1970). Exposure of the nasal m u cosa to amm o nia-saturated air elicited vasodilatation and corresponding increased blood fl ow a nd reflex hy pertension in the lower li p of catsAMMONIA 56 3. HEALTH E FFE CTS (Izu m i and Karita 1993). Stim ulation of the nasal mu cosa by chemical irritants has been shown to elicit changes in the respiratory sy stem , such as apnea, lary ngeal spas m , and bronchoconstriction, and in the cardiovascular sy stem , such as brady cardia and variable blood pre ssure changes (Izu m i and Karita 1993). Brain glutam i n e levels have also been shown to increase in rats that inhaled 25 or 300 ppm amm onia vapor for 6 h ours/day for 5 day s , whichis likel y a result of amm o n i a m e tabolism by the astrocy tic glutamate-glutam ine cy cle (Manninen an d Savolainen 1989; Manni nen et al. 198 8).

3.2.1.5 Reproducti ve Effects No studies were located regarding repro ductive effect s in hum ans after inhalation exposure to amm onia. No statisticall ysignificant differences were noted in ov arian or uter ine weights of pigs expose dto about 7 or 3 5 ppm ammonia for 6 weeks (Diekman et al. 1993). Fem a le pigs that were continuo usly exposed to about 35 ppm amm onia fro m 6 weeks before breedin g until day 30 of gestation had no statistically significant dif f erences in age at puberty , num ber of liv e fetuses, or f e tus-to-corpus luteum r a tio com p ared to pigs exp o sed to onl y ab out 7 ppm (Diek m an et al

. 1993). No un e xposed contr o ls were included in th at study

.

3.2.1.6 Developmental Effects
No inform ation was located regarding d e velopmental effects of amm onia in humans following inhalation exposure. No statistically significant diff erence in fe tal length was evident at 30 d ay s of gestation in offspring of p i g dam s that were continuousl y exp o sed to abo u t 7 o r 35 p p m amm onia fro m 6 weeks before breeding until day 30 of gestation (Diek m an et al. 1993)

.

3.2.1.7 Cancer Carcinogenic potential of ammonia by th e inhalation r oute has not b een assessed in hum ans or anim als. One case rep o rt was found of an individual who deve loped epider mal carcino m a of the nasal septu m 6 m onths afte r being badly burned by accidental contact with a refri geration ammonia-oil m i xture (Shimk in et a l . 1954). However, the role of a m m oni ais im possible to ascertain a nd no conclus i on can be drawn from t h is study

. Shi mkin et al. (1954) indicat ed that “no si ngle case can prove a general principle, and it is onl y b y the p ublic ation of addit i onal repor ts of sim i lar cases that enoug h data can beco m e available for critical analy s is.” No other such re ports were locat ed, although othe r cases of inhalationAMMONIA 57 3. HEALTH E FFE CTS exposure to ammonia fro m spills have been followed fo r m o re than 6 m onths after exposure. One of 10 adult m a le m i ce exposed to amm onia gas for 15 m i nutes/day 6 d ay s /week for 8 weeks had mitotic figures with an intact basement m e mbra ne and a carci nom a in situ in one n o stril and one m ouse had an invasive adenocarcino m ao f the nasal mucosa (Gaaf ar

et al. 1992)

. Again, there is no conclusi ve evidence that amm onia play ed a r o le in th e inductio n of the carcinoma. Gaafar et al. (199 2) pr ovided an alternate explanation b y stating that “pro longed expos ure to ammonia m ay interfere with the no rm al protective reflexes of the respiratory nas a l m u cosa re s u lting in the a ccu m u lation of particulate matter initiating or prom oting a neoplastic process.” Howeve r, the plausibility of tum o r formation in only 8 weeks by a weak carcinogen such as particulate matter is debatable.

3.2.2 Oral Expos ure As discussed in Chapter 4, amm onia in aqueous solu ti on exists in e quilibri um wi th ammonium hy droxi de, a weak base, which is partially i onized i nwate r. Deg r ee of ionization is depende nt on pH; at phy s iolo gical pH, amm onium hy dro x ide is 99% i oniz e d, but at pH 9.25, is onl y 50% ionized. Inform ation available for humans exposed to ammoni a by the oral r oute usuall y i nvolved case reports of people who s w allowed household ammoni a (ammonium hy dro x ide ). Studies b y the oral route in anim als generally have used a m m o nium salt s or a m m oni u m h ydroxide. For these rea s ons, oral doses are expressed as m g N H 4 + /kg/ day , givenas the particular amm oniu m com pound.
In many anim al studies, the animals w e re adm i nist ereda m m oniu m c h loride. Amm oniu m chlo ride is
co mm only us ed to induce metabolic aci dosis in expe ri m e ntal ani m als. The acidosis is due to the formation of hy dro g en io n s fro m the m e tabolism of ammoniu m ions to urea. W HO (1986) n o tes that the ingestion of ammoniu m ch loride in doses around 500 –1,000 m g /kg/day for 1–8 day s (longer tr eat ment would worsen the condit i o n ) has induce dm e tabolic aci dosis in m i ce, guinea pigs , rats, rabbits, and do gs. Metabolic aci dosis can res u lt in a variety of nonspecific changes in neurological, cardiovascular, pulm onary , gastrointestina l , and m u scul o skeletal f unction, as well as in changes in hem a tological and clinical chemistry param e t e rs.

3.2.2.1 Death
Hu m an death s due to in gestion of house hold amm onium salts have been reported (Klein et al. 198 5; Klendshoj and Rejent 1966), but no quantitative data for oral expos ure in hum ans were located. AAMMONIA 58 3. HEALTH E FFE CTS
69- y ear-old wo m an who ingested an unknown q u anti ty of lem on ammonia (3% amm oniu m ion) was found sem i-conscious and making gurgl ing respiratory s oun ds (Klein et al. 198 5)

. Radiograph i c results were consistent with aspiration pneum onia, and e ndos copy showed lary ngeal and epiglottic edem a and a friable, ery the m a tous esop h agus with severe corrosive injury

. The woman died several day s later after developing acute respiratory distress sy ndrom e and re nal failure (Klein et al. 1985). A 57-y e ar-old m an was found dead with a glass containing dilute amm onium hy droxide (2.4% ammonium ion) nearby (Klendshoj and Rejent 19 66); auto ps y showed hem o rrhagic esophagus , stomach, and d uode num . As shown in Tab l e 3-2 and Fi g u re 3-2, 3 03 m g amm oni u m/kg as ammonium chloride is a lethal dose in guinea pigs wh en given as single gavage dose (30/4 0 died) (Koenig and Koenig 1949). Death, in this study , resulted from pul m onary edem a. No deaths we re seen in cat s, rabbits, guinea pigs, or rats after a sim ilar dose of amm onium (337 m g ammoniu m /kg given as amm oniu m chlo ride) (Boyd and Se y m our 1946).

3.2.2.2 Sy stemic Effects
No inform ation was located regarding d e rm al or oc ular effects of ammonia or ammoniu m co m pounds in hum ans or an i m als followi ng oral exposure. Respiratory Effects. No inform ati on was locate dregarding respiratory effects of a mmo nia or
amm oniu m com pounds in hum ans following oral exposure. Guinea pigs that received a single gavage dose of ammonium chloride developed serious respir atory effects including increased rat e an d depth of respiration, pulm onary edema, and death by respir ator y failure (Koenig and Koe n ig 1949). Because the blood pH of th e guinea pig s decreased after ad m i nistration of ammonium chloride, adjustments in respiratory rate and depth may have been a com p ens a tory m ech anis m for acidos is. Sim ila rly , ad m i nistration of amm oni um chloride i ndoses of approxim a tely 100 m g of NH 4 + /k g/day (as amm oniu m chloride) or higher for up to a y ear to rabbits resu lted in m e t a bolic acidosis and co m p ensatory changes in respiratory rate and tidal volum e (Seegal 1927). Th e low blood pH results in increased lung ventilation, which increases the elim ination of carbo n dio x ide fro m the blood, and therefore, can be considered a
co m p ensatory response to acidosis rathe r than a direct effect of a m m oniu m ion on the lungs or respiratory sy stem
. Cardiovascular Effects. No information was l o cated regarding cardiovascular effect s of a m m onia
or amm onium co m pounds in hum ans following oral e xposure. No pathol ogical abnorm a lities were noted in the hearts of adult and weanling rats fed doses of up to 79 m g ammoniu m /kg/day as a m m o niumLOAEL Less Serious NOAEL Serious a System Key to figure Reference Table 3-2 Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral

Chemical Form (mg/kg/day) (mg/kg/day) (mg/kg/day) Exposure/ Duration/ Frequency (Specific Route) Species (Strain) ACUTE EXPOSURE Death 1

317 286 286 (death due to pulmonary edema) 1 d Gn Pig Koenig & Koenig 1949 NH4CL Systemic 2 Hemato

113 2325 2325 (elevated serum calcium) 6 d (W) (Sprague- Dawley) Rat Barzel 1975 NH4Cl

3
22 22 F Bd Wt

367 3150.4 3150.4 F (10% reduction in final body

weight) 3 or 7 d (F) (Wistar) Rat Bodega et al. 1993 ammonium acetate

4
22 22 Bd Wt

373 3102.2 3102.2 (final body weight decreased by

15%) 3 or 7 d (F) (Wistar) Rat Boyano-Adanez et al. 1996 ammonium acetate

5 Renal

135 433 433 (renal enlargement due to cell hypertrophy) 7 d Gavage - NS (Sprague- Dawley) Rat Janicki 1970 NH4Cl

6 Resp

122 303 303 (pulmonary edema) 1 d Gavage - NS Gn Pig Koenig & Koenig 1949 NH4CLLOAEL Less Serious NOAEL Serious a System Key to figure Reference (continued) Table 3-2 Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral

Chemical Form (mg/kg/day) (mg/kg/day) (mg/kg/day) Exposure/ Duration/ Frequency (Specific Route) Species (Strain)
Neurological 7
22 22

372 3102.2 3102.2 (decreased binding of

somatostatin to receptors in frontoparietal cortex and hippocampus) 3 or 7 d (F) (Wistar) Rat Boyano-Adanez et al. 1996 ammonium acetate

INTERMEDIATE EXPOSURE Systemic 8 Musc/skel

114 991 991 (reduced calcium less fat-free solid) 330 d (W) Rat Barzel & Jowsey 1969 NH4Cl

Bd Wt 991 991 (reduced body weight)

9
22 22 F Bd Wt

392 3150 3150 F (15% reduction in final body weight after 90 days) 90 d (F) (Wistar) Rat Bodega et al. 1993 ammonium acetate

10
22 22 Bd Wt

375 3102.2 3102.2 (final body weight gain

decreased by 10%) 15 d (F) (Wistar) Rat Boyano-Adanez et al. 1996 ammonium acetate

11
412 412 Renal

118 3 wk

(W) Rat Freedman & Beeson 1961 NH4CLLOAEL Less Serious NOAEL Serious a System Key to figure Reference (continued) Table 3-2 Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral

Chemical Form (mg/kg/day) (mg/kg/day) (mg/kg/day) Exposure/ Duration/ Frequency (Specific Route) Species (Strain)

12
79 79 F Cardio

120 90 d

6 d/wk (W) (albino) Rat Gupta et al. 1979 NH4NH2SO3

79 79 F Gastro

79

79 F Hemato

79

79 F Hepatic

79

79 F Renal

39.5

39.5 F Bd Wt 79 79 F (body weight decreased by 16%)

13 Musc/skel

134 337 337 (bone deformity and softening) 11 wk Gavage - NS Dog Bodansky et al. 1932 NH4Cl Neurological 14
22 22

374 3102.2 3102.2 (decreased binding of

somatostatin to receptors in frontoparietal cortex and hippocampus) 15 d (F) (Wistar) Rat Boyano-Adanez et al. 1996 ammonium acetateLOAEL Less Serious NOAEL Serious a System Key to figure Reference (continued) Table 3-2 Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral

Chemical Form (mg/kg/day) (mg/kg/day) (mg/kg/day) Exposure/ Duration/ Frequency (Specific Route) Species (Strain)
Developmental 15

a The number corresponds to entries in Figure 3-2. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); DW = drinking water; (F)= feed; F = female; Gd = gestation day; G = gavage; gastro = gastrointestinal; hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level;min = minute(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; NS = not specified; wk = week(s)

380 4293 4293 (BW decreased by 16-27%; decreased NMDA receptor function in neurons) Gd 1-ppd 21 (F) (Wistar) Rat Minana et al. 1995 NH3CH3CO210100100010000 Death1g Respiratory6g Hematological2r Renal5r Body Weight3r3r4r4r Neurological7r7rmg/kg/dayFigure 3-2. Levels of Significant Exposure to Ammonia And Ammonium Compounds - OralAcute (≤14 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancerSystemic10100100010000 Cardiovascular12r Gastrointestinal12r Hematological12r Musculoskeletal13d8r Hepatic12r Renal11r12r Body Weight8r9r9r10r10r12r12r Neurological14r14r Developmental15rmg/kg/dayFigure 3-2. Levels of Significant Exposure to Ammonia And Ammonium Compounds - Oral (Continued)Intermediate (15-364 days)c-Catd-Dogr-Ratp-Pigq-Cow-Humansk-Monkeym-Mouseh-Rabbita-Sheepf-Ferretj-Pigeone-Gerbils-Hamsterg-Guinea Pign-Minko-OtherCancer Effect Level-AnimalsLOAEL, More Serious-AnimalsLOAEL, Less Serious-AnimalsNOAEL - AnimalsCancer Effect Level-HumansLOAEL, More Serious-HumansLOAEL, Less Serious-HumansNOAEL - HumansLD50/LC50Minimal Risk Levelfor effectsother thanCancerSystemicAMMONIA 65 3. HEALTH E FFE CTS
sulfam at e for 90 day s in dri nking water (Gupta et al. 1979). T h ese data are presented in Table 3-2 and Figure 3-2.
Gastrointes t inal Effects. Several case s have be en described of y o ung children (2–3 y ears old) who bit into ammonia pellets/capsules (Lopez et al. 1988; Rosenbau m et al. 199 8). T w o of the chil dren drooled and had ulcerative lesions on the tongue and/ or on the buccal m u cosa; one child had superficial ulcerations on the posterio r esophageal wall and the other child ha d edematous, ery them a tous upper and lower lips with areas of des quamation, eschar of th e hard palate, and ede m a and ery thema of the supraglottic structures and upper trachea (Rosenbaum et al. 1998). All of the chil dren experienced one or
m o re of the following s y m p tom s : vo m i ting, dr ooli ng, dy sphagia, c ough , or oral or phar y n g eal burns (Lopez et al. 1988; Rosenb au m et al. 1998). None of the children h a d esophageal or respiratory burns an d all healed within a few days. Esophageal lesions and edem a were reported in fi v e persons who ingested household amm onia (amm o n ium hy dr oxi de), one of whom experien ced acute re s p iratory obstruction (Christesen 1995; Klein et al. 1985)

. These observati ons were not quantified. T h e effects are probabl y due to the alkaline nature of a m m oniu m hy droxid e. Asingle case r e port described a self-ad m inistered
amm onia solution enem a that resulted clinically in an al pain, diffus e abdom inal colic, and ten e sm us (da Fonseca et al. 1998). Sigm oidoscopy showed diffuse er y them a tous friable m u cosa with large ulcerations covered by yellowish exudate that reced ed in a few day s , but chronic inflammat i on and fibros is of the rectu m and si gm oid colon was noted 3 m onths postexposure (da Fonseca et al. 1998). No histopathological abnorm alities of t h e gastrointestin al tract were observed in adult or weanling rats ad m i nistered doses of up to 79 m g a mmonium /kg/day as a mmonium sulfa m ate f o r 90 day s via drinking water (Gupta et al. 1979). Likewise, a 3 % solution of amm oniu m chloride adm i nistered to rats via gastric tube pro duced no gastric m u cosal damage in 1 h our and a 10% solution prod uced onl y a m i nim u m of hem o rrhagic lesions (about 9 mm 2 ) (Takeuchi et al. 19 95). However, sim ilar ad ministration of 1 or 3%
amm oniu m h ydroxi de in r a ts produced severe hem o rrhagic lesions (about 2 6 .6 o r 97.7 mm 2 , respectively ) (Takeuchi et al. 1995)

. Gavage ad m i nistration in rats of 0.3% ammonia (33. 3 m g /kg) pro duced gastric
m

u cosal lesio n s within 5 m i nutes with corres ponding decreases in gastric wall i mmunoreacti v e endothelin-1 (ET-1) and i mmunoreacti v e thy r otr opi n-releasing horm one (TRH) concentrat ions and increase s in gastric juice E T -1 and TRH concentrations (Mori et al. 1998). In situ gastric exposure has also shown ammonia-induced gastric mucosal dam a g e (Murakam i et al. 1995; N a gy et al. 1996). These lesions are ex acerbated by neutrophil pr oducts, especia lly hy pochl o rous acid ( M urakam i et al. 1995) and cy steine prote ases, such a s so m e of the c a thepsins (Na g y et al. 1996). Adm i nistra tion of 0.01% a m m onia in drinking water to rats (approxim a tely 42 m g /kg/day) for 8 weeks resulted in acceleration of cellAMMONIA 66 3. HEALTH E FFE CTS migration leading to m u cosal atrophy in the stomach antrum , incre ased labeling indices, and enlarge m ent of the prolifer ative zone in the antral and body m u cosa (Tsujii et al. 1993). Hematological Effects. No inform a tion was located regarding the hematological effe cts of a m m onia
or amm onium co m pound s in hum ans following oral expos ure. R e peated exposure to amm o nium chloride in anim al s resulted in m e tabolic acidosis with related changes in bone metabolis m and seru m calciu m . For exam ple, rats fed diets containing high levels of ammoniu m ch loride had inc r eased s e ru m calciu m (Barzel 1975). The increased seru m cal cium resulte d from enhanced dem i ner a lization of bone in response to chronic acidosis. This effec t was not fo und to be a specific effe ct of a m m oniu m a nd was reported to oc cur in states of chronic m e t a bolic acidosis produced from r e peated doses of acidify ing agents (e.g., hydrochloric a c id, sulfuric acid). Decrea s e d blood pH was s een in cats fed an aci dify ing diet containing ammoniu m ch loride for sev eral weeks (Kienzle and Wilm s-Eile rs 1994). As shown in Table 3-2 and Figure 3-2, n o effects on blood hem oglobi n or bloo d c e ll counts were observed in adult or weanling rats that received doses of up to 79 m g a mmonium /kg/day adm i nist eredas a mmonium sulfam ate in drinkin g water (Gupta et al. 197 9).
Musculoskeletal Effects. No inform ation was l o cated regarding m u sculos k eletal effe cts of
amm onia or ammoniu m co m pounds in hu mans followi ng oral exp o s ure. Guinea pigs and rats th at received letha l gavage doses of a m m onium chloride developed m u sc le weaknes s , fasciculation, and incoordinatio n (Koenig an d Koenig 1 9 4 9 ). In other an imal studies, repeated ingestion of amm oniu m s a lts resulted in metabolic acidosis, which stim ulated bone dem i neralization. As is sh own in Table 3-2 and Figure 3-2, re peated ingestion of amm o n i um chloride in drinking water resulted i nnet bone resorption in rats and bone deform ities in dogs (Barzel and Jowsey 1 969; Bo dansk yet al. 193 2). This effect can be anticipated with repeated exposure to any acidif y ing a g ent. Hepatic Effects. No inform ation w as located reg arding hepatic effect s of ammonia or a mmoniu m co m pounds i nhum ans following oral exposure. As show n in Tabl e 3-2 and Fi g u re 3-2, n o to xic effects were noted in livers of adul t or weanling rats fed doses of up to 7 9 m g amm oniu m/kg/day as ammoniu m sulfam ate for 90 day s indri nking water (Gupta et al. 1979).
Renal Effects. Renal failure was identified as the cause of death in hu m ans after ingestion of an unkn own amount of ho usehold amm onia (amm oniu mhy dro x id e) ( K lein et al. 1985). It is no t certain if this represent s a pri m ary effect of amm o nium or is secondar y t o m a ssive burns to the gastroint estinal tract.AMMONIA 67 3. HEALTH E FFE CTS

Renal effe cts have been observed in animals followi ng repeated oral doses of ammoniu m ch loride. These effects may b e secondary t o chronic acidosis prod uced from the interaction of ammoniu m ch loride with water (which results in an increas ed H + concentration) rather than from a dire ct ef fect of a m m o nium ion on the ki dne y. Renal enlargem ent, increased bl ood ammonia content, and increased urinary amm onia have been reported in rats exposed to 18 0–43 3 m g / kg/day for 3 –7 day s (Beny a j a ti and Goldstein 197 5; Janicki 1970; Lotspeich 19 65;), b u t are unlikel y t o be indicative of renal patholo g y . T h e high est NOAELs and LOAELs ar e presented in Table 3-2 and Figure 3-2.
Endocrine Effects. No inform ation was located r e gardi ng endocrine effects of ammonia or
amm oniu m com pounds in hum ans following oral exp o sure . Enlarg ed adrenal glands were observed in rabbits that received 124 mg ammoniu m/kg/day as amm oniu m hy dr oxide by gavage in water f o r 17 m onths (Fazikas 1939). These li m ited data suggest th at the endocrine sy stem is not a prim ary target for amm onia or amm onium co m pound s.
Bod yWeig ht Effects. Decre ased b o dy weight or weight gain has been observed in anim a l s following oral exposure to amm oniu m ion (Barzel and Jowsey 1 9 6 9 ; Bodega et al. 1993; Bo yano-Adánez et al. 1996; Gupta et al. 19 79; Noda and Chikam ori 1976). Rats exposed to amm oniu m ion in utero and during lactation (dam s received 4,29 3 m g amm oniu m/kg/day in th e diet from gestational day 1 thr oug h lactation day 21) and then received a normal diet had showed reduced body weight gain (Miñana et al. 1995); bo dy weight gain was reduced b y 2 5 and 1 6 % in m a le an d fem a le offspring, respectively, at 120 day s of age. Rats that were continued on the same amm onia diet as their dams had an even greater reduction in b o dy weight g a in (27 and 2 6 % for males and fem a les, respectively ) (Miñana et al. 199 5). Birth weights were not reported in the Miñana et al. (1995) study

. Gupta et al. (1979) noted increased water intake and reduced food i n ta ke in weanling rats, and decreased body weight in adu lts b u t not weanlings fed 79 m g amm o nium /kg/day in drinking water for 90 day s as ammonium sulfamate. This represents the LOAEL for this effect. A NOAEL of 39.5 m g a m m o nium /kg/day was al so identified in this study (see Table 3-2 and Figure 3-2).

3.2.2.3 Immunological and L y mphoreticular Effects
No inform ation was located regarding i mmunological effects of ammonia or ammoniu m co m pounds in hum ans or an im als after oral exposure.AMMONIA 68 3. HEALTH E FFE CTS
3.2.2.4 Neurological Effects
No inform ation was located regarding n e urological effects of ammonia or amm o nium co m pounds in hum ans after oral exposure. Guinea pigs that received lethal gavage do ses of ammonium chloride (303.5–404.7 m g NH 4 + /kg) developed ne urom uscular effects includ ing fasciculation; incoordination; hype rexcitability to tactile, auditor y , and painful stim u li; and tonic convulsions ( K oenig and Koenig 1949)

.
A num ber of studies have indicated that increased a m m oniu m ion levels in the brain may disrupt energy production and m odify th e availability of some rece ptors that are involved in neur otransm i ssion. Ad m i nistration of 2 0 % amm oniu m acetate in the diet of rats for 20 day s resulted in statisticall ysignificant increase s in brain a m m onium ion (12.8-fold), glut am i n e (37%), and alanine (93%) and in some TCA cy cle-associated com ponents in the brai n includi ng gl uc ose, lactate, and py r uvat e , and decreases in brain cy tosolic NA D + /NAD H rat i o, β -h y dr o x ybutarate, and ATP content (Kosenko et al. 199 3). Rat s with high NH 4 + intake from ad m i nist ration of 20% a m m oniu m a cetate in the diet and 5 m M a m m oniu m a cetate in the water for up to 15 day s had a decreased num be r o f available somatostatin re ceptors in the frontoparietal cortex and hi ppocam pus ( B oy ano-Adánez et al. 1996). Since somatostatin hyperpolarizes neurons in the cerebral cortex, the study authors specu lated that thi s reduction in available rec e ptors may contribute to the alteration of electrophysiologi cal properties of neural tissue cau sed by excess NH 4 + (Boy an o-Adánez et al. 199 6). Bindi ng o f [ H 3 ] M K-801 (an NMDA receptor antagonist) to N M DA receptors was reduced by a pproxim a tely 60% in cereb ellar cell cultures fro m 8-day

- ol d rats exposed to NH 4 + in utero and duri ng la ctation (dams received 4,293 m g amm o nium /kg/day in the diet from gestational day 1 thr oug h la ctation day 8) (Miñana et al. 199 5). Add itionall y , asp artate aminotransferase (AST) inducti on was absen t in treated neurons (occurr ed in neuro n s from control rats), which also indicates i m p a irm e nt of N M DA rec e ptors. Treated neurons were m u ch m o re re sistant to the toxic effects of glutam ate t h an control neurons; since glutamate toxicity is m e dia t ed by NMDA receptors, a ttenuation of glutam ate t oxicity is indi cative of i m paired NMDA receptor function (Miñana et al. 1995). Loss of glial fibrillar yacidic protein (GFAP) has been s hown t o occur in human spontaneous hyperamm onemia (Kim ura and Budka 19 86; Kretzsch m a r et al. 1985; S obel et al. 19 81) and i noth e r hyperammonem i a m odel s , such as portacaval shunt rats (Bodega et al. 1991; Suárez et al. 1992), but was not evident after exposure of r a ts to amm o n i um acetate (20% amm onium acetate in the diet and 5 m M amm onium acetate in the water for up t o 9 0 day s ) (Bodega e t al. 199 3). R a ts fed 19.5% amm oniu m acetate in the diet had increased N H 4 + levels in the brain and altered ass e m bl y and disassem bly of tubulin, an essentialAMMONIA 69 3. HEALTH E FFE CTS

co m ponent of the axonal tr ansport sy ste m in the brain (Miñana et al. 198 9a). The am ount of p o l y m erized tubuli nincreased but the am ount of free tubuli nwas not affected. In vitro experim e nts using brains of rats fed a diet high i nNH 4 +indicated that the cause of the alterati on might be a modification of the tubu lin (and not th e microtubule-associat ed proteins [ M APs] , which m odulate pol y m er ization of the tubuli n ), which may result in a disru p tion i nneur otransm i ssion (Miñana et al. 198 9a). Ad ditional stud i es in rats brain showed that tubulin was significa ntly increasedspecifically in the septum , ventral hippoca m pus, dorsal hipp ocam pus, hypothalam u s, reticular form ation, and fr onta l cortex, but n o t in th e tem poral
am igdala, mammillary nucleus, locus coeruleus, caudate nucleus, or cingulate cortex after 2 months on the high ammonia diet (Mi ñ ana et al. 19 89b).

3.2.2.5 Reproducti ve Effects
No inform ation was located regarding r e productive effects of ammonia or amm o nium co m pounds in hum ans or an i m als followi ng oral exposure.

3.2.2.6 Developmental Effects
No inform ation was located regarding th e developm ental effects of amm onia or amm oniu m com pounds in hum ans. Rats exposed to NH 4 + in utero and duri n g lactation (dams received 4,293 m g a m m oniu m /k g/day in the diet from ge sta tional day 1 through lactation day 21), wh ich then received a
norm a l diet, had a statistically significant reducti on in body weight gain (Miñana et al. 1995); body weight was reduced b y 25 and 1 6 % in m a le and fem a le offspring, res p ectively , at 120 day s of age. Rats that were continued on the sa me a mmonia diet as thei r dams had an even greater decrea se in body weight gain (27 an d 26% for m a les and fem a les, respectivel y) at 120 day s of age (Miñana et al. 1995 ). No inform ation was provided in the study r e garding the health of the dam s , but it i s likely that th e high
amm oniu m d i etary concen tration m a de them hyperamm onemic. Body weights and foo dcons um ption b y the dams througho ut the st udy were not reported.

3.2.2.7 Cancer
No inform ation was located regarding c arcinogeni c effects of ammonia or amm o nium co m pounds in hum ans following oral exp o sure. Expos ure of m i ce to 193 m g ammonium /kg/day as ammonium hy dro x ide in drinkin g water for 2 y ears did n o t pro du ce carcinogenic effects, nor did it affect spontaneousAMMONIA 70 3. HEALTH E FFE CTS developm ent of breast canc e r, which is common to C3 H fe male m i c e (Toth 1972). No evidenc e of a carcinogenic effect was fo und i nm i ce treated by gavage with ammonia dissolve din water alone at a dose of 42 m g NH 4 + /k g/day for 4 weeks or with diethy l p y r o carbonate alone, but 9 of 16 m i ce treated with a
co m b ination of amm onium and p y rocarbonate developed lung tum o rs (Uzvolgy i and Bojan 1980). The
amm onia andpy rocarbonat e m ay have reacted in vivo to form the carcinogen, urethane. In a gr oup of mice treated with urethane, the incidenc e of lung tumors was 9 of 9. Data from studies in vitro cited by Uzvolg y i and Bojan (198 0) dem onstrated the form ati on of urethan e fro m diethyl p y rocarbonate added to beverages co ntaining ammonia. No lun g tum o rs were observed in the offspring of m i ce exposed sim ilarly to NH 4 + and diethy l p y roc arbonate duri ng pregnanc y or duri ng lactation (Uzvol g y i and Bo jan 19 85). I n another study, Tsujii et al. (1992a, 1995) tested th e hypothesis that amm onia produced in the s t omach in hum ans infe c t ed with Helicobacter pylori m ay play a role in the de velopm ent of gastric canc e r . Rats pretreated wit hthe initiator N-m e thy l -N’-nitro-N-n itrosoguanidine ( M NNG) in the drinking water for 24 weeks before receiving 0.01% ammo nia solution in th e drinking water for 24 weeks had a statistic ally significantly greater incide nce of gastric cancer (70% of rats) and nu m b er of tu mors per tum o r-bearing rat (2.1) than rats receiving only MNNG and tap water ( 31% and 1.3 tum o r s /rat) (Tsujii et al. 1992a). Additionally , the size, depth, and m e tast asis of th e MNNG-initiated tum o rs wer e enhanced in the rats treated with ammonia (Tjusii et al. 1995 ). It can be estim ated that the dose of ammonia received b y th e rats was approxim a tely 4 2 m g /kg/day (the dail y intak e fro m food and water for the general po pulation is approxim a tel y0.3 m g /kg/day [ W HO 1986] ). The rele vance of these studies to assess the can cer risk of oral exposure to amm onia is uncertain.

3.2.3 Dermal Exp osure
Derm al exposure to ammonia m ay also result in so m e i nhalation exposure. Therefore, based on the available data , it is not alw ay s clear to what extent eac h route of exposure contributes to the toxicity observed in d e rm al exposure studies.

3.2.3.1 Death
Hu m an and animal deaths involv i ng dermal exposur e to amm onia and ammoni um have been reported (Prokop' eva et al. 197 3; Sl ot 19 38; S o b o ny a 19 77), b u t the extent of exposure i s not kn own, and effects were probably due to inhal a tion exposur e as well. A 25- y ear-old wo m an exposed to ammonia gas fro m a broken pipe had burns on her face, arms, and tors o, and had difficulty breathing and swallowing (SlotAMMONIA 71 3. HEALTH E FFE CTS 1938). She w as treated sym p to matically and with su pportive treatment, but die dabout a m onth after exposure (Slot 1938). Aut ops y show ed edem atous, inflam ed, hem o rrhagic epiglottis, trachea, and lungs. Petechial hem o rrhages were found o nth e heart and the kidne y s w e re congestedwith hem o rrhagic nephritis. A 25- y ear-old man died after a tank of anhy drous ammonia exploded near him while he was farm ing (Sob ony a 19 77). Immediately after exposure he had m ildbilateral c onjunctival edema, burns over about 30% of his body surface, bilateral pul m onary edem a, an d severe respi r atory distress. He developed pn eu m onia and died on th e six tieth day p o s t-exposure. In rats, LC 50 values of 112 , 71. 9, and 48.4 m g ammonia/L were determ ined for exposures of 15, 3 0 , and 6 0 m i nutes, respectively (Pr okop ’eva et al. 1973). These data ar e presented in Table 3-3.

3.2.3.2 Sy stemic Effects
No inform ation was located on hematological, m u sculoske letal, hepatic, endocrine, or bo dy w e ight effects in hum ans or anim als after derm al exposure to ammonia or amm onium

.
Derm al or multiple route e xposure to ammonia or ammoniu m has produced respiratory, cardiovascular, gastrointestinal, renal, dermal, and ocular effect s. Respiratory Effects. Respiratory effects have been reported inhum ans fro m exposure to massive
am ounts of ammonia gas, but n o quant it ative data were located. It is also unclear as to what extent the effects were a result of inha lation and der m alexposure. Tracheitis, bronchitis, edem a, and bronchopneum onia w e re r e ported by Slot (1938). Lung infection and resp iratory distress wer e reported in one case (Sobony a1977). Dy spnea, rales, rhonchi, and blocked air w ay s were found by Levy et al. (1964). The effects probabl y resulted f r om concurrent inhalation and dermal exposure. No inform ation was locat ed regarding respiratory effects of ammonia or a m m onium in ani m als following dermal or ocular exposur e.
Cardiovascular Effects. Elevated pulse, shock, and cardiac f a ilure were reported in humans fro m accidental ex posures to m a ssive am ounts of amm onia g as, but the e x tent of exposure was not quantified (Slot 1938). No inform ati on was locate dregarding c ardiovascular effects of a m m onia or a m m oniu m in ani m als following dermal or ocular exposure.
Gastrointes t inal Effects. Persisten t vom iting was noted by Slot (1938) in human acciden t al m a s s ive exposure cases, but the exte nt of exposur e was not quantified. Oral and phar y ngeal burns and e d em aLOAELTable 3-3 Levels of Significant Exposure to Ammonia And Ammonium Compounds - DermalSpecies(Strain)SystemReferenceNOAEL Less Serious Serious Chemical FormExposure/Duration/Frequency(Specific Route)ACUTE EXPOSUREDeathRat(LC50)71.9mg/Lmg/LProkop'eva et al. 19731881 d30 min/dRat(LC50)48.4mg/Lmg/LProkop'eva et al. 1973831 d60 min/dSystemicHumanOcular50ppmppm(eye irritation)72ppmppmIndustrial Bio-Test Laboratories, Inc. 19733905 minHumanOcular30ppmppm(moderate ocularirritation)50ppmppmMacEwen et al. 197038710 min(Duroc)PigOcular10ppmppm(ocular irritation)50ppmppmStombaugh et al. 19692055 wkmin/dINTERMEDIATE EXPOSURESystemicHumanOcular25ppmppmd = day(s); hr = hour; LOAEL = lowest-observed-adverse-effect level; min = minute(s); NOAEL = no-observed-adverse-effect level;wk = week(s)(transitory eye irritation)50ppmppmFerguson et al. 19771976 wk5 d/wk6 hr/dAMMONIA 73 3. HEALTH E FFE CTS were reportedb y Lev yet al. (196 4) in f o ur hum an m a les accidentally exposed to an unkn own quantity of anhy drous ammonia. Inhalation expos ure m ay have contributed t o these effect s also.
Renal Effects. Renal congestion and hem o rrhagic nephritis we re reported by Slot (1938) in six cases of accidental hum an exposures to highl y concentrated aerosols of ammoniu m derived from an hy drous
amm onia. The exposure level cannot be determ ined from the available data.
Dermal Effe cts. Skin and e y es are extrem ely sensitive to airbor ne amm onia or amm onium in water. The topical da m a ge causedby amm onia is probably due mainly t o i t s alkaline properties. Its high water solubility allows it to dissolve in m o isture on these surfaces, r eact with fatty substances in the corneal lay e r, be abso rbed into deeper lay e rs, an d inflict ex ten s ive dam a ge (Jarudi and Golden 1 973). Reports of skin dam a ge in hum ans are num erous, but goo d quant it ativ e data are lacking. The severity of the da m a ge is proporti ona l to concentration and durat ion of expos ur e; flushing w ith water immediately after contact alleviates or prevents effe cts. Burns, blisters, and lesions of the sk in have been reported (Close et al. 1980; Flur y e t al. 198 3; Sh imkin et al. 1 954; Sl ot 1 9 3 8 ; Taplin et al . 197 6; Walto n 19 73). E x p o sure levels asso cia t ed with dermal effect s are presented in Table 3-3.

Several case r e ports described exposure of indivi duals t o ammonia liquid and/or gas that resulted in cutaneous bur ns (Am s hel etal. 2000; da Fonseca et al

. 1998; George et al. 2000; Kerstein et al. 2001; Latenser and Lucktong 20 0 0 ; Leduc et al. 199 2; Ro senbaum et al. 1998; Weiser and Mackenroth19 89). All exposures were occupat i onall y re lated. Total body surface area burned ranged from 14 to 45% and
m o st had at least s m all are a s of full-thickness burns that required skin grafting. A su mmary of 12 case reports of liquid anhydrous a m m onia in juries reporte d a range of percent body s u rface are aburned of 3–22%, with 25% of the patients having full-thickness burn i n juries (Millea et al. 1989). One case report included a ski nlitm us paper test that showed the pH of the skin to be 10 at the ti me of hospital adm i ssion (Am s hel et al. 200 0). Infe ction of the b u rn woun ds was not unco mmon, with m o st of the p a tients responding to antibiotic tre a tm ent. One person had faci al and neck hy perem i a, ery thematous petechiae on one ear, and ede m atous and peeling lips (Latenser and Lucktong 2000). The individual with 45% total body surface area burned had additional severe injuries, including respiratory an d ocular, and developed circulatory an d hem a tological problems, which led to his death (George et al. 20 00).

Rosenbau m et al. (1998) described two cases of youn g children (2–3 y ears old) who bit into ammonia pellets/capsul es. Both chil dren drooled and had ulcer ative lesions on the tongue and/or on the buccal
m

u cosa. One child had su p e rficial ulcerations on th e p o sterior esophageal wall and the other child hadAMMONIA 74 3. HEALTH E FFE CTS
edem atous, ery thematous upper and low e r lips with areas of desquamation, eschar of the hard palate, and edem a and ery thema of the supraglottic structures and upper trachea. Both children recovered without incident. A single case report described a self-ad m inistered a m m oni u m solution enem a th at resulted in anal pain, diffuse abdominal colic, and tenesm us ( d a Fonseca etal. 1998). Si gm oidoscopy showed diffuse ery them a tous friable m u cosa with large ulcerations c overed b y y e ll owish exudat e . Six day s later, the ulcers had receded, but th e colon was still ery thematous. Three m onths postexpos ure, biopsies showed chronic inflammation and fibrosis of the r ectu m and sigm oid colon, but n o stenos is.

Anim al data regarding der m al and ocular effects of exposure to ammonia support the findi n g s in hum ans. A num ber of cattle were acutely e xposed to anhydrous amm onia fu mes when a pipeline runni ng through their pasture ruptured and l eaked 1,800 b arrels of ammonia in a shor t period of ti me (Morgan 1997). The
amm onia co m b ined with m o isture in th e air and formed a white cloud, whichdr ifted south a c ross two additional fields containing cattle. The noses of the ca ttle in the field with the pipeline turned black and peeled and the horns of cattle in an adjacent field turned black and peeled. Hair coats on all livestock within a 2-m i le radius of th e rupture were singed.
Ocular Effe cts. Reported ocular effects in hum ans fo llowing ammonia or ammoniu m ex posure increase in severity with dose and duration. Good quantitative data are lacking, but s y m p toms progress as follows: inflamed ey es, lacrim ation, swelling of the e y elids (Beare et al. 198 8; Caplin 1 941; Close et al. 1980; Fergus on et al. 19 77 ; Jarudi and Golden 197 3; Legters et al. 198 1; Monta gue and Macneil 198 0; O’Kane 1983 ; Price et al. 1983; Sil v erman et al . 1949 ; Stom baugh 1969; Verberk 19 77; Ward et al. 1983), hyperemic conjunctiva (Caplin 19 41; Hatton et al. 1979; Lev yet al. 196 4; Slot 19 38; S o bony a 1977), transient blindness, blurred vision, and corn eal abrasions (Latenser and Lucktong 2000), and sustained corneal dam a ge (Caplin 1941; Grant 1974: Kass et al. 1972; McGuinness 1969; Str oud 1981; Yang et al. 1987). Amm o nia is slightl yirritating to hu man ey es at concentrations of 100 ppm (Ferguson et al. 1977), and immediately irritating t o the ey es and throat at 698 ppm (Henderson and Hagg ard 1927)

. Exposure to anair concentration of 2 50 p p m is bear able for m o st persons for 30 –6 0 m i nutes (Withers et al. 1986)

. Exposure levels associat ed wi th ocular effects are presen ted in Table 3-3.

Anim al data regarding ocul ar eff ects of exposure to ammoniu m support th e find ings in hu m a ns. Corneal opacity has b een observed in rabbits foll owing br ief e xposures (2 s econds) to a solutio n of 28. 5%
amm oniu m h ydroxide (Grant 1974). V o lum e ad minister ed was not reported. C a ttle in an adjacent fieldAMMONIA 75 3. HEALTH E FFE CTS to a pipeline th at ruptured and released 1,800 barrels of amm onia had runny e y es; two cows in the sam e field with the ruptured pipeline were eut h anized because of blindness and respir atory distress (Morgan 1997).

3.2.3.3 Immunological and L y mphoreticular Effects Secondary i n f ections often co m p licate th e clinical out co m e of burn s and respirator y lesions related to exposures to highl y concentrated aerosols derived fr om anhy dro u s amm onia in which dermal and ocular exposure accom panies inhalation e xpos ure (Sobony a 197 7; Taplinet al. 1976)

. However, there is no evidence that the decreased immunol ogi cal resi stance represents a primary im pairm e nt of the i m m une sy stem in humans. No information was located re garding th e immunolo g ical effects of ammo nia or
amm oniu m in anim als following derm al or ocular exp o sure.
No inform ation was located regarding th e following effects of amm onia or amm oniu m co mpoun ds in hum ans or an im als following derm al or ocular exposur e: 3.2.3.4 Neurological Effects 3.2.3.5 Reproducti ve Effects 3.2.3.6 Developmental Effects

3.2.3.7 Cancer Carcinogenic potential of ammonia has not been establishe d in humans or animals by th e dermal route of exposure. One case report was found of a person w ho developed epi d erm a l carcin oma of the nasal septu m 6 m o nths after being badly burned by accidental contact wi th a refrigeration amm onia- oil m i xture (Shimk in et al. 195 4). It is unclear whether amm onia play ed a role in this tum o r developm ent. No other reports were l o cated, although m any cases of contact w ith amm oni a fro m spills have been fol l owed for
m o re than 6 m onths after exposure.AMMONIA 76 3. HEALTH E FFE CTS
3.2.4 Other Routes of Exposure
There are li mited in vitro d a ta suggesting that amm o n i um ion m a y affect fet a l developm ent (L ane and Gardner 1994 ). Mouse embr y o s (conceived in vivo ) were culturedin m odified m ouse tubal fluid m e diu m (m MTF) or mMTF supplem ented with 300 μm ol/L amm oniu m ion for 48, 69, or 93 hours b e fore being transferred to pseudopregn ant m ouse dams (Lane andGardner 199 4). Exam ination o ngestational day 15 sh owed an apparent relationship between the duration of exposure and th e incidence of exencephaly

. Em bry o s that were culture d with vari ou s concentrations of ammonium ion before being transferred to recipient dams showed increas ed in cidence of exenc e phaly with increas ed a m m oniu m concentration (38–300 μmol/L) and de c r eased percentage of im plantation sites with increased ammoniu m concentration. It is unclear how em bry o s m i ght be exposed to amm onia or amm oniu m in vi vo or if in vivo exposure would affect fetal devel opment and im p l antation in a way sim ilar t o that described in the Lane and Gardner (199 4) study .

3.3 GENOTOXI CITY A single study exam ined the genoto x ic effect of amm onia in humans (Yadav and Kaushik 1 997). Analy s is of blood sam ples from 22 workers exposed to ammonia in a fertilizer factory and 42 control workers not exposed to amm onia showe dincreased fr equency of chrom o so mal aberrations (CAs) and sister chro ma tid exchanges (SCEs), increased m ito tic index (MI), and increased frequency of CAs and SCEs with increasing length of exposure.

Swiss albino mice ad minis t ered a single dose of 12, 25 , or 5 0 m g /kg ammoniu m intraperitoneally had an increased frequenc y of m i cronuclei com p ared to controls (Yadav and Kaushik 1997).

All rem a ining tests of ammonia' s m u tagenicity consist of studies in E. coli , chick fibroblast cells, and Drosophila m e lanogaster ( T able 3-4). Demerec et al . (1951) note dpositive eff ects in a reverse m u tation test in E. coli , but o n l y i ntr eatments using toxic levels of NH 4 + (98% lethality ). Lobasov and Sm irnov (1934) f oun d slight m u tagenic activity in Drosophila f o llowing exposure to amm onia gas, but once again, survival after treatment was <2%

. Auerbach and Robson (19 47) test ed Lobasov and Sm irnov' s results and noted 0.5 % sex-linked lethals. The authors conc luded that alth oughtheir dat adid not sup port the earlier study 's findings, it is possible that a m m onia h as a very slight m u t a genic act ion. In their data presentation, however, they report their findings as ne gative, qualify i ng it as doubtful and probably negative.AMMONIA 77 3. HEALTH E FFE CTS


### Table 3-4. Genotoxicit yof Ammonia In V i tro and In Vivo
Results Species (test sy stem ) End point Form Activation sy stem With activation Without activation Reference In v i tro: Esch eric hi a Rev e r s e NH 3 NT + (at toxic Demerec et al. coli mutation levels) 1951 Chi ck Chr o mo som a l NH 4 Cl + NT + Ro senfel d fibrobla s ts aberratio n s NH 4 OH buffer 1932 Mouse Red u ced cell NH 3 + NH 4 Cl NT + Visek et al. fibrobla s ts division 1972 Mouse Red u ced cell N T + C a pu co 1 9 77 fibrobla s ts division (3T3 ) Mouse DNA repai r NH 4 Cl NT + Cap u c o 197 7 fibrobla s ts inhibition In v i v

o : D r os op h ila Mutageni c NH 3 + NT Loba sov an d m e lanoga ster lethality Smirnov 193 4 D. Sex-linked NH 3 – (dou btful, NT Auerb a ch an d m e lanoga ster r e cess ive lethal prob ably R o bs on 1 9 47 mutations negative) D. Domin ant NH 3 – NT Auerb a ch an d m e lanoga ster lethality R o bs on 1 9 47 Mouse ileal De cre a sed ra te NH 4 Cl NT + Zimber a nd and coloni c of DNA Visek 1 972 a muco sa cell s sy nt he sis

– = negative re sult; + = positive result; (+ ) = w e akl y positiv e result; DNA = deo xyr i bo nuc le ic acid; NH 3 = ammoni a; NH 4 Cl = ammo nia ch lori de; N H 4 OH = ammonium h y d ro x i d e ; N T = not testedAMMONIA 78 3. HEALTH E FFE CTS

In vitro tests of chick fibroblast cells sh owed that buf fered ammonia-ammoniu m chloride solut i ons can induce clum p i ng of chr o mosomes, inhib it spindle for m ation, and r esult in pol yp loidy (Rosenf e ld 193 2). Visek et al. (1972) noted r e duced cell division inm ouse fibroblasts cultured in media to which amm onia and ammonium chloride were added. The effect w as noted in cultures irrespe c ti ve of pH. Decreas ed rate of DNA sy nthesis wa s noted in m ouse m u cosal c e lls in the ileum and colon when seru m N H 4 + levels were significantl y elevated over norm a l level s ; these elevated levels wer e induced by intraperitoneal injection of urease or infusion of amm oniu m chlo ride (Zim ber and Visek 1972a). Iwaoka et al. (1981), responding to con troversy regar d ing m u tagenicity i nfried ham burgers, found that extraction of organic ingre d ients from fried ham bur ger and refrigerated biscuit products with amm oniu m hy droxide or a m m oniu m s u lfate increas ed m u tagenic activities in Salmonella ty phimurium T 98 and TA1538 Am es' microso m al sy stem s, while negative r esults were obtained from ex traction with sodium sulfate. The m ode of actio n is unclear; ammoniu m sal ts m ay in some w ay affect the m u tagen i c activities of some agents, or the y m a y sim p ly be m o re e fficient extractors of m u tagenic com ponents from these foods. Taken togeth er, the data indicate that ammonia and amm oniu m ion m ay have clastogenic and m u tagenic properties.

3.4 TOXICOKINETICS Studies sugge st that amm o nia can be absorbed b y th e inhalation an d oral routes of exposure, but there is less certainty regarding absorption through the skin. Absorption through the e y e has been documented. Most of the i nhaled ammo nia is retained in the upper respiratory tr act and is subsequently eliminated in expired air. Alm o st all of the amm onia produced en d ogenousl yin the intestinal tract is absorbed. Exogenous ammonia is also readil y absorbed in th e i n testinal tract

. Ammonia that reaches th e circulation is widely distributed to all body com p art m ents a lthough substantial first pass m e t a bolism occurs in the liver where it is transform e d into urea and glutam ine. A m m onia or a m m oniu m i on reaching the tissues is taken up b y g l utam ic acid, which participates in tran sam i nation and other reactions. The pri n cipal m eans of excretion of amm onia th at reaches the circulation in mammal s is as urinary urea; m i ni m a l am ounts are excreted in the fece s and in expired air.AMMONIA 79 3. HEALTH E FFE CTS
3.4.1 Absorption 3.4.1.1 Inhalation Exposure Experiments with volunteers show that ammonia, regardless of its tested concentration in air (range, 57– 500 ppm ), is al m o st co m p l e tely retained in the n asal m u cosa (83–92%) during short-term ex posure, i.e., up to 120 seconds (Landah l and Herrm a nn 1 950). Ho wever, longer-term exposure (10–27 m i n u tes) to a concentration of 50 0 ppm resulted in lo wer retenti on (4–30% ), with35 0–4 00 p p m elim inated in expired air by the end of the expos ure period (Si l verm an et al. 1949), sugge sting an adapt i ve capability or saturation of th e absorptive process. Nasal and phar y ng eal irritation, but not tracheal irritation, suggests that amm onia is retained in the upper respirator y tr act. Unchanged l e vels of bloo d-urea-nitrog en (BUN), non-pr otein n itrogen, uri n ary - urea, and ur inary

- amm o nia are evidence of low absorption i n to the bloo d. Exposure to c o mmon occupational lim it s of amm onia inair (25 ppm) with 30% retention (and assu m i ng this quantity i s absorbed int o the blood stream ) would y i eld an increase in blood ammoniu m concentration of 0.0 9 m g /L (calculated by WHO 1986 ). This calculated rise is only 10% above fasting levels, as rep o rted b y Co nn(197 2).

Anim al data provide sup p o rting evi d en ce for high-p e r centage nasal retention, thus protectin g the lower respiratory tr act fro m exposure (Dalhamn [ 1963] and Boyd et al. [ 1944] , rabbit; Egle [ 1973 ] , dog). Continuous exposure of rat s for 24 hours to concentrations up t o 32 ppm resulted in significant increase in blood ammonia levels (Sch aerdel et al. 1983). E xpos ures to 310–1,157 ppm led to significantl y increased blood concentrations of amm onia within 8 hours of exposure initiati on, but bl ood amm onia retu rned to pre-exposure values within 12 h ours of c ontinu ous ex posure and remained so over the rem a ining of th e 24-ho ur expo sure period. This suggests an adaptiv e response m e chanis m may be activated wit hlongerterm exposure (Schaerdel et al. 1983).

3.4.1.2 Oral Expos ure
Case r e ports of hum an ingestion of household ammo nia (a mm onium hy droxide) provide evidence of its absorption by this route, but few provide quantitative data. For exam pl e, in a fatal case of a man who drank an un k nown am ount of a 2.4% sol u tion of ammonium hydro x ide, anal y s is of the conten ts of the sto m ach and blood showed ammoniu m ion concentrations of 1 53 and 3 3 ppm , respectively (Klendshoj and Rejent 19 66). Ina study of v o luntee rs, i ngestion of a single ammoniu m ch loride tablet (approxim a tely 15 m g NH 4 + /kg/day ) led to a sm all transient increase (33% above fasting levels) in arterialAMMONIA 80 3. HEALTH E FFE CTS
blood concentrations of amm oniu m ion in 11 out of 2 0 subjects (Conn 197 2); n o change was noted inthe
rem a ining nine subjects in this group. A m ong 50 ci rrhotic patients, increases of about 150% were noted in arterial blood concentrations of amm o nium ion and return to n o r m al levels was slow (Conn 1972). These data indicate that ingested a m m o nia is readily absorbed from the digesti v e tract and that the liver play s a large role in rem o v i ng it from the blood (Co nn 19 72). Ana l y s is of urine sam p les fro m subjects on high an d low protein diets and given 15 N-amm oniu m chloride, show ed th at 30– 65 % of labeled nitrogen from 15 N-a m m oniu m chlo ride is absorbed and m e t a bolized (Richards et al. 1975). Oral administration of 15 NH 4 Cl t o a group of six s ubjects for six day s resulted in absorpti on of at least 38.7% of the a dm i nister ed radioactivity as determ inedb y the am ount of 15 N that appeared in urinary urea within 24 hours of the last 15 NH 4 Cl i nge stion (Metges et al. 1999)

.
Amm oniu m ion is endo gen ousl y pr oduc ed in the human digestive tract, m u ch of it arising fro m the bacterial degradation of nitr ogenous co m pounds from ingested food. Abo u t 4 , 200 m g /day ar e produced, greater than 70% of which is sy nthesized or liberated within the colon and its fecal contents. The total
am ount absorbed is about 4,150 m g /day, or 99% of the am ount produced (Summerskill and Wolpert 1970); absorp tion after oral loading of N H 4 + is sim i l ar l y com p lete ( F ürst et al. 1969). Evidence fro m Castell and Moore (197 1) and Mossberg and Ross (1 967) sug g ests that absorpti on of NH 4 +increas es a s the pH of the contents of the lumen incre ases, and th atthe a m m onium ion is activ ely transported at the lower pH levels (pH 5 was lowest detect ed absorption). A m m onium ion absorbed from the gastrointestinal tract travel s via the hepatic portal vein directly t o the liver, where in healthy i n dividuals,
m o st of it is converted to urea and glutamine. Hu m a n and anim al data show that little of it re aches the sy stem ic circulation as amm onia or amm oniu m co mpounds, but th at it is a nor mal constituent of plasm a at low levels (Brown et al. 1957; Pitts 1971; Sa lvatore et al. 1963; S u mmerskill and Wol p ert 1970). Analy s is of p l asma drawn from 10 healthy youn g m a le subjects y i elded endo genousl y derived NH 4 + concentrations ranging fro m 30 to 55 μ g NH 3 /100 mL, with a mean of 3 9 μg/1 0 0 m L (Brown et al. 1957)

.

3.4.1.3 Dermal Exp osure Quantitative data on absor p tion fr om ex posure by th e derm al route were not located in the ava ilable literature. Human case rep o rts of derm al exposure de scr ibe local dam a ge (burns, irritations). One report of case histories of five persons exposed to an expl odi ng, bursting an hy dr ous amm onia gas pi pe indicated there was sy stem ic toxicity (vom iting, renal congestio n, delirium ) , but exp o sure was by inhalation as well as dermal route, and it is i m possible to delineate a sy stem ic derm al exposure co ntributi on (Sl o t 19 38).AMMONIA 81 3. HEALTH E FFE CTS WHO (1986) concluded that sy stem ic effects fro m skin and e y e exposure are not quantitativel y im portant. Amm onia is r eadily absorbed into th e eye; it was found to diff use within seconds into cornea, l e ns, drainage sy st em , and retina (Beare et al. 198 8; Jar udi and Golden 1 973). Howev e r, am ounts absorbed were not quantified, and a b sorptionint o sy stem ic cir c ulation was not investigated.

3.4.2 Distributio n 3.4.2.1 Inhalation Exposure No quantitati ve reports of distribution of amm onia from inhalation exposure we re found i nthe available literature. Absorption data from hu m an inhalation exposure suggest that onl y small am ounts of amm onia are absorbed into the s y ste m ic circulatio n (Silverm an et al. 1949; WHO 1986). Initial retention of i nhaled
amm onia in the m u cus of the upper respiratory tractmay be 80% or m o re, but after equilibrium is established (within 30 m i nutes) 70–8 0 % of inspired amm onia is expired in ex h a led air (Silverm an et al. 1949). The l ack of change in blo od nitr ogen co m pounds and uri n ary - amm onia com pounds lends further support t o a li mited absorption int o the s y stem ic circulation (Silver man et al. 1949). To xic effects reported from inhalation exposure sugge st local dam a ge, or change s resulting from necrotic tissue degradation, rather than the presence of e l evated levels of NH 4 + , per se , in tissues other than the respiratory / p h aryngeal tissues. Inform ation o n the dis tributio n of e ndogen ousl y - p roduced amm onia suggests that any NH 4 + absorbed thro ug h inhalation would be distributed to all body com p artments via the blood, where it would be used in protein sy nthesis or as a buffer, a nd that excess levels would be reduced to norm a l by urinar y excretion, or conver t ed by th e li ver to glutam i n e and urea. If present in quantities that overtax these organs, NH 4 + is distributed to other tissues and is known t o be detoxified in the brain (Takagaki et al. 1961; Warren and Schenker 196 4).

3.4.2.2 Oral Expos ure
Hu m an oral exposure data for NH 4 + clearly indicate that it readily e n ters the portal circulation and is delivered to th e liver (Conn 19 72; Fürst et al. 1969) , as has been shown to be th e case for endogenousl y produced NH 4 + (Pitts 1971; Summerskill and Wolpert 1970). In nitr ogen-deficient persons, NH 4 + (as
a m m oniu m a cetate) ad m i nistered orally was absorbed and carried directly to the liver where most of it was converted to urea and excreted in the urine; little change in the negative nitrogen balance was observed (Für st et al. 1969)

. Output of ur ea fro m the liver corresponded to th e am ount of NH 4 + ingested (Fürst et al. 1969).AMMONIA 82 3. HEALTH E FFE CTS

Un-ionized ammonia is fre ely diffusible, whereas the a mm oniu m i on is less so and is relatively confined to the extracellular com p artm ent (Stabenau et al. 1958 ). However, amm oniu m ion is in dy namic equilibrium with dissolved ammonia. Therefore, ammoniu m co m pounds that enter the circulator y s y stem or other body fluids can thus freely penetrate tissu e c e lls as a m m o nia. In hypophy secto m izedrats that were ad minis t ered 15 N-amm oniu m citrate orally b y g avage, labe led protein was found in li ver, kidne y, spleen, heart, and skeletal m u scle 6–72 hours after 15 N-ammonium citrate ad ministration (Vitti et al. 1964). The p e rcentages of ingested label absorbed and then excreted as urea in the urine were not provided (Vitti et al. 1964).

3.4.2.3 Dermal Exp osure No quantitati ve data on dis tribution of ammonia fro m derm al exposure were located in the available literature. Toxic effects fro m derm al exposure sugg est that little or no amm onia gains entr y into the sy stem i c circ ulation by this route.

3.4.2.4 Other Routes of Exposure
Intravenous adm i nistration of NH 4 + (as ammoniu m salts) to people with a nitroge n deficiency ( i n negative nitrogen balance) resulted in an increase in the peripheral blood N H 4 + level and a shift in the nitrogen balance fro m negative to positive; no increase in urin ary urea was seen (Fürst etal. 1969). The nitrogen from NH 4 + , which gains entry into th e ge neral circulation, is distrib ut ed to cells through out th e body and incorporated i n to tissues (Fürst et al. 1969; Vitti et al. 1964). After intraperitoneal injection of
amm oniu m chloride in m i ce, ammonia distribut es to brain tissues within 20 seconds (Warren and Schenker 1964), and in rats, brain c oncentrations increase dra m ati c ally within 5 minutes (Salvatore et al. 1963). Tissues other than blood and bra i n were not an aly zed by these resear chers. Com p arat ive patterns of distributi o n of 15 N-label e d amm onium citrate indicate that the am ount of NH 4 + taken up b ytissues other than the liver is greatest by subcutaneous inj ection, less by intraperitoneal injection, and least following i n tr agastric ad m i nistration. In travenous administration of 15 N-labeled ammoniu m salts leads to rapid distribution of 15 N-labeled metabolites throughout the body , w ith the highest levels of labeled urea appearing in th e kidne y and liver, and le sser amounts in heart, spleen, brain, testes, and carcass. Highest levels of labeled glutam ine were found i nheart and li ver, with lesser am ounts in brain, spleen, carcass, kidne y , an d t estes (Duda and Handler 1 958).AMMONIA 83 3. HEALTH E FFE CTS

3.4.3 Metabolism Quantitative data on hum an m e tabolism of exogenously i n troduced ammonia were not located in the available literature. Amm o nia and ammonium ion are metabolized to urea and gl utam ine m a in ly in th e liver by the process diagrammed in Figures 3-3 and 3- 4 and descr ibed by Fürst et al. (1969) and Pitts (1971). However, it can be rapidl y conv erted to glut am ine in the brain and oth e r tissues as well (Takagaki et al. 1961; Warren and Schenker 196 4). The nitrogen is released from glutam ine within tissue cells and used for pr otein sy nthesis as needed (Duda and Handler 1958; Fürst et al. 196 9; Richards et al. 1975; Vitti et al. 1964). Ingestion of amm oniu m salts leads to alm o st co m p lete conversion of amm oniu m ion int o urea i nthe liver, wh ereas exposure by other routes may lead to its m e tab o lism in body tissues to glutam ine or tissue protein (Fürst et al. 1969; Vitti et a l . 1964). Duda and Handler (195 8) ad m i nistered 0.03 m g /kg b o dy weight of 15 N-amm onium acetate intravenousl y to rats and no ted that 90% was converted to gl utam in e and urea within 3 0 m i nutes, with glutamine being the major early prod uct. L a beled nitrog en was also found in am ino acids, purin es, py rim i din es, and other nitrogeno us com pounds. Morim o to et al. (1988) f o und that th e am ount of 15 N from an intravenous injection of ammoniu m ch loride to rats that was taken up into glutamine-a m ide- N and urea-N reached a peak at 5 m i n u tes and decreased gradual l y from 15 to 60 m i nutes af ter the injection. This finding suggests that urea sy nthesis and glutam i n e sy nthesi s occurred si multaneously w ithin m i nutes after the injection, and glutam ine-amide-N is graduall y transferred to the urea cy cle from 15 to 60 m i nutes following dos ing. L o w amounts (0. 008 % of a 17 m g oral dose) of 15 N-amm oniu m chloride administered repeatedly to rats were converted to 15 N-nitrate in the urine (Saul and Archer 1984).

3.4.4 Elimination and Excretion 3.4.4.1 Inhalation Exposure Studies using low levels of amm onia sh ow that inhal e d a m m onia i s te m porarily dissolved in the m u cus of the upper respirator y tract, and then a hi gh percentage of it is released back into th e expired air. Following exposure to 5 0 0 ppm ammonia for 10– 27 minutes, healthy m a le subjects eliminated 70 –80% of the inspire dammonia by this route ( S ilverm an et al. 1949)

. An aly s is of end o g enous amm o nia levels in the expired air of rats showed concentrations rangin g f r om 10–353 ppb (m ean=7 8 pp b) in nos e-breathing ani m als (B arr o w and Steinhagen 1980).AMMONIA 84 3. HEALTH E FFE CTS 

### Figure 3-3. Glutamine Cycle



### Gluta m i n as e

NH 4 

### +
Gl uta m i n e Sy nth e tas e GLU -N GLU

GLU -N GLU

NH 4 

### + GLU = Gluta m inate; GLU-N = Gluta m in e Source: Brun ner an d Thal er 198 1AMMONIA 85 3. HEALTH E FFE CTS 

### Figure 3-4. The Urea Cycle Sho w ing the C o mpartmentalization of its Step s With in Liver Cells

Incomi ng amine gr oup (v ia

NH 3 – C – NH 3 O Urea Ornithi n e

5 Sp e c if ic ornithine membrane tran spor t sy stem Ornithi n e dehy drogenase )

2ATP + CO 2 + NH 3 + H 2 O

Citrulline

Citrulline 2ADP + P 1 1

Carbamoy l Phospha te 2 P 1

Mat r ix
Mitoch ondrion Inner membrane

Arginine

Arginino succina t e 4

3

Aspara t e AMP + P P 1 ATP Enzy mes cataly zin g ea ch r eaction are : 1) carbamoy l Cy to so l mitoch ondrial glu t a m ate

H 2 O

Fumarat e

- NH 3 phospha te sy nthe ta se (ammonia); 2) or nithi n e Incomi ng amine gr oup (v ia carbamoy l tran sfer ase ; 3) arginino succina t e tran samination from gl utama t e) sy ntheta s e ; 4) arginino succina t e ly ase ; 5) arginase

Source: Leh ninge r 197 5AMMONIA 86 3. HEALTH E FFE CTS The quantitati ve difference between inspired and expir e d amm onia suggests that small am ounts are absorbed across the nasophary n g eal m e m b ranes into the sy stem ic circulation. Absorbed amm onia is excreted by th e kidne y s as urea and urinary amm onium co m pounds (Gay et al. 1969; Pitts 1971; Richards et al. 1975; Summer s kill and Wol p ert 1970), as urea in feces (Rich ards et al. 1975), and as com ponents of sweat (Guy ton 1981; Wands 1981), but quantitative data are lacking. Toxic levels do not deve lop as a result of chronic inhalation exposure because the body has m u ltiple effective mechanism s for detoxif y ing and excreting it.

3.4.4.2 Oral Expos ure
Excretion dat afor hum ans orally exposed to amm onia have been quantified with respect to exc r etion of isotope from 15 N-labeled ammoniu m salts, thus pro v i d ing ani ndic a tion of the t urnover rate of the
co m pound wi thin the body and excretion route of its metabolites. Approxim a tely 72% of a dose of 15 N
was excr eted in the urine of three subjects within 3 day s of ingestio n of amm onium salts in drinking water; 25% (24% urinar y urea and 1% urinar y NH 4 + ) was eli m inated within the first 6 hours after exposure. Ammoniu m salt adm i nistered b y gavage to hum ans led to a corresponding increase in bloo d urea concentration transpor ted out of the liver, leading the authors (F ürst et al. 196 9) to conclu d e that orally ingested ammoniu m salt is quickly and alm o st com p let e ly converted in the liver and eli m inated from the body as urinar y ur ea. Analy s is of urine samples from subjects on high and low prote i n diets showed highe r cu m u lative excretion of 15 N (percent of dose) in the urine of the h i gh pr otein gr oup (approxim a tely 70% ) than that of the lo w protein gr o up (35% ). S m all am ounts of labeled nitr ogen were also excreted as urea in feces (Richards et al. 1975).

These data co rrespond to th at for excretion of endoge nousl y produced amm onia (Davies and Yudkin 1952; Muntwy ler et al. 1956; Summersk ill and Wol p ert 1970; Van Slyke et al. 1943). Amm o nia is also known t o be excreted via sweat (Guy ton198 1; Wands 198 1) and expired air (Barrow and Steinh agen 1980; Larson et al. 1980; R obin et al. 1 9 59; Utell et al. 198 9); q u ant itative data are unavailable for excretion via sweat.

3.4.4.3 Dermal Exp osure Data regardin g excretion of amm onia absorbed fo ll owing derm al ex posure were not located inthe available literature.AMMONIA 87 3. HEALTH E FFE CTS

3.4.4.4 Other Routes of Exposure Data are available on expos ure of hum ans and dogs t o amm oniu m salts by i n trav enous injectio n. Excretion of i s otope after 15 N-a mmonium l actat e injection in thr ee hum an subjects y i elded 5– 7% of isotope excreted as urinary NH 4 + in the fi rst 6 hours p o s texposure, and another 2 % within 3 day s . Approxim a tely 6% of the is otope was excreted as urea in urine i nth e first 6 hours

. An average of approxim a tel y60% of the dose of label was excr eted inurine within 3 day s . These data ar e c onsiderably different from that resulting from oral loading (as de scr ibed in Section 3.4

. 4.2)

. Intravenous loading led to decreased l a beling of urinary urea and grossly incr eased labeling of urinary amm onia; the difference s are attributed by the author s to a "first pass" effe ct from or al loading (Gay et al. 1969). The hepatic transform a tio n of amm oni um ion to urea is so efficient that relatively litt le unco nverted ammonium salt is releas ed to the general circ ulation. Intravenous exposure of seven dogs t o 1 07 m g /kg amm oniu m acetate led to amounts rangi ng from 0.044 to 0.073 m g ammonia excreted in expired air. No measurable am ount of ammonia was present in expired air during the pre-e xposure contr o l period (Ro b in et al. 19 5 9 ).

3.4.5 Ph y s iologi call yBased Pharmacokinetic (PBPK)/Pharm acod y nami c (PD) Mod e ls Phy s iologically based pharmacokinetic ( P BPK) m ode ls use m a the m atic al descri p tions of the uptake and disposition of chem ical substances to quantitatively describe the relationships am ong critical biological processes (Kr i shnan et al. 1994). PBPK m odel s ar e al so called biologically based tissue dosimetry
m odel s . PBPK m odels are increasingly used in risk a sses s m ents, pri m arily to predict the concentration of potentiall y t o xic m o ieti es of a chem ical that will be delivered to any given target tissue following various
co m b inations of route, dos e level, and test speci es ( Cl e well and Andersen 1985). Phy s iol ogic a lly based pharmacody nam i c (PBP D) m odels use mathematical descriptions of the dose-response functi on to quantitatively describe the relationship between targettissue dose and toxic end points.

PBPK/PD models refine our unde rstanding of com p lex quantitativ e dose behaviors by helping to delineate and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of the toxic m o iety , and (2) the target tissue dose and observed responses (Anders e net al. 1987; Andersen and Krishnan 1994). T h ese m odels ar e biologically and m echanistically bas e d and canAMMONIA 88 3. HEALTH E FFE CTS be used to extrapolate the pharm acokinet i c behavior of che m ic al substances fro m high to low dose, from route to ro ute, between species, and between subpop ul ations withi na species. The biolo g ical basis of PBPK m odels results in more m eaningful extrapolati ons than th ose generated with the m o re conventio nal use of uncertainty factors.

The PBPK model for a chemical substan ce is deve loped in four int e rconnected steps: (1) m o d e l representatio n, (2) m odel para m e tri zati on, (3) m odel si m u lation, and (4) m odel validation (K rishnan and Andersen 199 4). In th e early 19 90s, vali dated PBPK m odels were deve loped for a num ber of toxicologically im portant chem ical subst ances, bot h volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBP K m odels for a particular subs tance require estimates of the chem ical substancespecific phy sicoche m ic al para meters, an d species-spe c if ic phy s iolo gical and biol ogical parameters. The
num eri cal est i m ate s of these m odel para meter s are in corporated within a set of differential an d algebraic equations that describe the pharmacokinetic process es . Solving these differential and algebraic equations provides the predictions of tissue dose. Co m puter s then provide process si m u l a t i ons based on these solutions.

The structure and m a the m a tical expressi ons used in PBPK m odels significantly si m p lify the true
co m p lexities of biol ogical sy stems. If the uptake and disposition of the chem ical substance(s) is adequately described, however, this sim p lification is desirable bec au se data are o f ten unavailable for many biological process es. A si m p lified sche m e redu ces the magnitude of cum u lative uncertainty

. The adequacy of the m odel is, t h erefore, of great i m portance, and m odel validation is essential to the use of PBPK m odel s in risk asses s m ent.

PBPK m odel s i m prove the pharmacoki netic extrapolations used in ri sk asse ss me nts that identify the maxi mal (i.e., the safe) levels for hum an exposure to c h em ical subst ances (Ander sen and Krishnan 1994). PBPK m odels provide a scientifically so und m eans to predict the target tissu e dose of chem icals in hum ans who are exposed to enviro nm en tal levels (for ex am ple, levels that m i ght occur at hazardous waste sites) bas e d on the results of studies where doses wer e higher or we re ad m i nister ed in different species. Figure 3-5 shows a concep tualized repre sentation of a PBPK m odel. No data regarding PBPK mode ls for amm onia w e re l o cated.AMMONIA 89 3. HEALTH E FFE CTS 

### Figure 3-5. tation of a Phy s iol ogicall yBased Pharmaco kinetic (P BPK) Model for a

Hypothetical Chemical Substance

Source: ada p t ed from Krishnan et al. 19 94 Note: Thi s is a conceptual representation of a phy siol ogically based pharmacoki netic (PBPK) model for a hypothetical chemical su bst ance. The ch emical sub s ta nce i s sh own to be absorb e d via the skin, by inhalation, o r by ingestio n , metaboli z ed i n the liv er, and excrete d in the urine o r b yexhalation. 

### Lungs

Li v e r

Fat

S l o w l y per f u sed t i s s ues R i c h l y per f u sed t i s s ues

K i dney

Sk i n V E N O U S

B L O O D A R T E R I A L

B L O O D V ma x 

### K m 

### I nges t i on I n hal ed che m i c al E x hal e d che m i c al

GI Tr act

Fec e s

Ur i n e

C h em i c al s i n ai r co n t act i ng ski n 

### Conceptual RepresenAMMONIA 90 3. HEALTH E FFE CTS

3.5 MECHANISMS OF ACT ION 3.5.1 Pharmacokinetic Mechanisms Data regardin g the pharm acokinetic me chanism s of ammonia were not lo cated i nthe available literature.

3.5.2 Mechanisms of Toxicity
Amm onia is an irritant and the prim ary and m o st i mmediate effect of ammonia exposure is b u rns to the skin, e y es, and respiratory tract. The topical da m a ge caused by amm onia is probably due m a inl y to its alkaline properties. Its high water solubility allows it to dissolve in m o isture on the m u cous mem b ranes, skin, and e y e s , form ing a m m oniu m hy droxide, which causes liquef action necrosis of the tissues (Jarudi and Golden 1 973). Specifically , amm o n i um hy dro x id e causes sapo n ification of cell m e mbran e lipids, resulting in c e ll disruption and death. A dditionall y , it extracts wat e r from the cel l s and initiates an inflammatory response, which further damages th e surroundi ng tiss u es (Amshel et al. 2000). Contact with liquid ammonia results in cryogeni c injur y in addition t o the a l kali burns (A mshel et al. 2 000; Wibbenm ey er et al. 1999).

Excess cir c ulating levels of a m m onia (h ypera mm one mia) c an caus e serious neurological effec t s. Hy peramm on em ias can be inherited (i.e. , inbor n erro r s of urea cy cl e enzy m e s) or acquired (i.e., liver toxicity caused by ingested toxins, viral infections , autoimm une dis ease) (F elipo and Butterworth 2002). An extensively studied neur ops y c hiatric disorder kno wn as hepatic encephalopathy develo ps when liver function is im paired and the or gan cannot m e t a bolize amm onia. T h is results in an increased concentration of ammonia in the blo od and brain. The m e chanis m of a m m onia-i nduced encephalopathies has not been definitivel y el ucidated, but is thought to i nvolve th e alteration of glutam ate m e tabolism in the brain and resultant increased a c tivation of NMDA recep tors (Fe lipo et al. 1993; Marcaida e t al. 1992), which causes decreased protein kinase C-mediated phosphor y l ation of Na + /K+ ATPase, increa s e d activity of Na + /K+ ATPase, and depletion of ATP (Kosenko et al. 1994)

. Antagonists of NMDA recep tors, agonists of metabotropic gl utam ate recep tors, agonists of m u scarinic receptors, and inhi bitors of protein kinase C, calc i neurin, or nitric oxide s y nthase prevent glutamate toxicity , indicating that all of these play a role in acute amm onia n e urotoxicity ( F elipo et al. 1 998). Ad diti onal evidence of altered energy levels include changes in so m e T C A cy cle-associated co m ponents including acetoacet ate, and NAD + /NADH ratio, 2-ox ogl utarate, and 3-hy dro x y b u tarate (Kosenk o et al. 199 3). A disruptio nin neurotrans missionAMMONIA 91 3. HEALTH E FFE CTS has also been suggested by alteration of brain tubulin, which is an essential co m p onent of th e axonal transport sy st em (Miñana et al. 198 9a, 1 989b). During certain disease stat es that result in renal tubular injur y , NH 4 + prod uction b y renal pro x i m a l tubules may increase in order to maintain net acid excretion. However, this m ay also contribute to further renal dam a ge by modif y in g the th ird com ponent of com p lement and initi ating the alternative com p lem e nt pathway (Clark et al. 1990). A m m onia can che m i call yinteract with an internal th iolester bond of
co m p lement 3 (C3), resulti ng in anam id e linkage and a subsequent conform a tion a l change of the C3. The altered C 3 then activates the alternat ive co m p le ment pathway , which causes the releas e of chem oattract ants and the assem b ly of the m e m b r ane attack co m p lex of com p lement (Clark et al. 1990)

. A m idated C3 can also bind directly to phagocy t e co m p le m e nt rec e ptors, which causes the relea se of toxic oxy g en species (Clark et al . 1990). It has also been suggested that NH 4 + depresses protein degradation in renal cells an d inhi bits ren a l cell replication, whic h s upports th e findings of ren a l hy pertrophy in renal injury and indicates that N H 4 + m ay inhi bit recovery f r om injury (R abkin et al. 1 993).

Amm oniu m ion m ay also contribute t o adverse effects of Helicobacter pylorion the stomach. H. pylori produces urease, which breaks down urea that is normally present in the stom a c h into amm oni a (Mégraud et al. 1992; T s ujii et al. 1992a). An in v itro study that exa m ined the effect s of ammonia produced by H. pylorion HEp2 cells showed increased cell vacuolation and via b ility of the cells co m p aredto a ureasenegative variant of the same cells (Mégraud et al. 1 992). An in v i vo study suggested that NH 4 + also
causes macroscopic gastric lesions and i n creases the r e lease of endothelin-1 (ET

- 1) and thyrotropin releasing horm one (TRH) from the gast ric m u cosa, p r obabl y via an endothelin A (ET A ) receptor, which exerts ulcero g enic action on the gastric m u cosa (Mori et al. 1998)

. Ammonia may also trig ger the release of cy steine proteases in the stomach that contribute to the development of gastric he m o rrhagic m u cosal lesions (Nagy et al. 1996)

. Neutrophils th at m i grat e to the gastric mucosa in response to the pr esence of H. pylorimay release hypo chlorous acid, which can interact with NH 4 + to produce the powerful cytotoxic oxidizin g agent m onochloram ine (Murakam i et al. 1995).

3.5.3 Animal-to-Human Extrapolations The prim ary effects of amm onia in humans are due to its corrosive and irritative properties. Exposure to
a m m onia gas causes da mag e to the respiratory tract, eyes, and skin when the a m m onia co m b i n es with water to become ammonium hy droxi de, which results in liquefaction necrosis of the tissues, ce ll structural breakdown, and inflammator y dam a ge (Am s hel et al. 2000; Wibbe nmey er et al. 1999). Animal studiesAMMONIA 92 3. HEALTH E FFE CTS
have indicated sim i lar ty pe s of injuries o f the respiratory tract (Coon et al. 197 0; Kapeghian et al. 1982; May an and Merilan 1972 ; Richard et al. 197 8a, 19 7 8b; Schaerdel et al. 1983; S t om baugh et al. 1969) , ey es, and ski n(Morgan 19 97). Oral exposure of hum ans to hig hconcentrations of ammonia and amm oniu m h ydroxi de has been shown to result in buccal, esophageal, and uppe r tracheal bur ns and edema (Christesen 1995; Klein et al. 1985; Rosenbau m et al. 199 8), b ut no reports o f the effects o f amm onia on the stomach or upper gastrointestinal tract in hum ans have been found. One report of an ammonia enema in a human showed diff use ery them a tous, friable m u co sa, and large exudative ulc e rations in th e sig m oid colon and rectum (d a Fonseca et al. 1998). Gavage studies in rats have shown si m ilar le sions of the gastric m u cos awith notable histopathological effects (Mori et al. 1998; T akeuchi et al. 1995; Tsujii e t al. 1993). R a ts, therefore, appear to be an adequate m ode l for th e prim ary effects of a m m onia in humans. How e ver, hum ans are unlikel y to be orally exposed to am ounts of amm onia that would result in th e gastric lesions seen in rats. Elevated levels of endogenousl y pr oduc ed amm onia r esulting from disease st ates apparently may cause or contribute to gastric pathology (Mégraud etal. 1992; Mori et al. 1998; Tsujii et a l . 1992a).

3.6 TOXICITIE S MEDI ATED THROUGH THE NE UR OEN D OCRI NE AXIS Recently , attention has focused on th e potential hazardous effects of certain chemical s on the endocrine sy stem becau se of the ability of these chem icals to m i mic or block endogenous horm ones. Ch em icals with this ty pe of activity ar e m o st co mmonl y referred to as endocrine disruptors

. However, appropriate term inology to describe such effects r e mains controversial. The term inology e ndocrine disruptors , initiall y used by Colborn and Clement (1992), was al so used in 1996 when Congress mandated the Environm ental Protection Agency (EPA ) to develop a screening program for “... certain substa nces [ w hich ] may have an effect prod uced b ya naturally o ccurring estrogen, or o ther such endocrin e effect[s] ...”. To m e et this manda te, EPA convened a panel called the Endocrine Disruptors Screening and Testing Advi sory C o mmittee (EDSTAC), which in1 9 98 com p letedits deliberations and m a de
reco mmendations to EPA c oncerning en docrine disruptors. In 1999, the National Acade my of Sciences releas ed a rep o rt that referred to these sa me ty pes of che m ical s as h o rmonally act i ve agents
. The term inolog y e ndocrine mod u lators has also been used to conve y th e fact that effects caused b y such chem icals may not necessarily be adverse. Many scientis ts agree that chem icals w ith the ability to disrupt
or m odulate the endocrine sy stem are a potential thre atto the health of hu m ans, aquatic anim als, and wildlife. However, others think that en docrine-ac tive che m i cals d o not pose a significant health risk, particularly i nview of the fact that horm one mim i cs exist in the natural environment. Exam ples ofAMMONIA 93 3. HEALTH E FFE CTS
natural hormone m i mics are the isoflavinoid phy t oestr ogens (Adlercreutz 1995; Livingsto n 1 978; May r et al. 1992)

. These chemicals are derived from plants an d are si m ilar i nstructure and action to endogenous estrogen. Although the public health significance and descriptive term inology of substances capable of affecting the endocrine sy s t em remains controversial, scientists agr ee that these chem icals may affect the sy nthesis, secretion, transp ort, bin d in g, action, or el i m ination of n a tural horm o nes in the bo dyresponsible for maintaining h o m e ostasis, reproduc ti on, develo pment, and/or behavior (EPA 1997). Stated differently, such com pounds m ay cause toxicities that are mediatedthrough the neuroendoc rine axis. As a result, these che m i c als m ay play a role in altering, for exam ple, m e tabolic, sexual, immune, and neurobehavioral function. Suc hchem i cals are also thought to be i nvol ved in induci ng breast, testicular, and pr ostate cancers, as well as endo m e triosis (Berger 1994 ; Giwercm an et al. 1 993; Hoel et al. 1992)

. No studies were located regarding t oxici ty m e diated throug h the en docrine axis in hum ans after exposure to ammonia. Two studies exa m ined the effects of induced hy perammonem i a (with infusion of
amm oniu m chloride) in ste e rs on circulating and porta l-drained visceral flux of metabolites and on pancreatic horm ones (Fern andez et al. 1988, 199 0). Plasma glucose increased 12% during i n fusion of
amm oniu m chloride (Fernandez et al. 1988, 1990)

. Plasma insulin decreased up to 46% duri ng amm oniu m chloride inf u sion, and then i n creased up to 122% after infusion was halted (Fernandez et al. 1988); portal- drained visceral release of insulin di d not increase during amm oniu m chloride infusion even with the rise in plasma glucose levels, but increased 109% after cessation of inf u sion (Fernande z et al. 1990). These data indicate that hy peramm onemia in steers may cause reduced hepatic glucose output and glucose- m e di ated pancreati c insulin release.

No in vitro studies were located regardi ng toxicity mediat ed through the endocrine axis by ammonia.

3.7 CHILDREN’ S SUSCEPTIBILITY This section discusses potential health effects fro m exposures duri ng the period from conception to maturity at 18 y ears of age in hum ans, when all bi ol ogical sy stems will have fully developed. Potential effects on offspring resulti ng from exposures of parental germ cells are considered, as well as any indirect effects on the fetus and neo n ate resulting from mate rn al exposure d u ring gestation and lactation. Relevant animal and in vitro m odels are also discusse d.AMMONIA 94 3. HEALTH E FFE CTS
Children are not sm all adu lts. The y differ fro m a dults in their exposures and may differ in their susceptibility to hazardous chem icals. Children’ s uni que phy s iol o gy and behavi or can influence the extent of thei r exposure. E xposures of children ar e di scussed in Section 6.6 Exposures of Children.

Children someti m e s differ from adults in their susceptib ility t o hazardous chem i cals, but whether there is a difference d e pends on the chem ical (Guzelian et al. 1992; NRC 1993). C h ildre n m ay be m o r e or less susceptible than adults to health effect s, and th e relationship m ay change with developmental age (Guzelian et al. 1992; NRC 1993). Vul n erability oft e n depends on developm ental stage. There are critical periods of structural and functio n a l devel opm ent duri ng b o thprenatal and postnatal lif e and a particular structure or funct i on will be most sensitiv e to disrupti on during its criti cal period(s). Damage may not be evident until a later stage of developm en t. There are often differences in pharm acokinetics and m e tabolism between children and ad ults. For exam ple, absorption m ay be di fferent in neo n ates because of the i mmaturity of their g astrointestinal tract and their larg er skin surface ar ea in proportion to body weight ( M orselli et al. 1980; NRC 1993); the ga stroin testinal absorption of lead is greatest in infants and y o ung ch ildren (Ziegler et al. 1978). Distribution of xeno biotic s m ay be diff erent; for exam ple, infants have a larger propor tion of th eir b odies as ex tracellular water and their brai ns and livers are proporti onately larger (Altman and Dittmer 1974; Fom on 1966; F o m on et al. 1982; Owen and Brozek 1966; Widd o w son and Dickerson 196 4). The infant a l so has an immature blood -brain barrier (Adinolfi 1985; Johans on 1 980) an d probabl y an i mmature bloo d- testis barrier (Setchell and Waites 197 5). Many xenobiot ic metabolizing enzy m es have distinctive developm ental patterns. At various stages of growth and develop m ent, levels of particular enzy m es may be higher or l o wer than tho se of adults, and
so m e times unique enzy m e s may exist at particular de velopmental stages (Ko m ori et al. 1990; L eeder and Kearns 1997; NRC 1993; Vieira et al. 1 996). W h eth e r differences in xeno biotic metabolism make the child m o re or less susceptible also depends on whethe r the relevant enzy m es ar e invol ved in a c tivation of the parent com pound to its toxic form or in detox i fica tion. T h ere may also be d i fferences in excretion, particularly i nnewborns who all have a low glom erular filtration rate and have not developed efficient tubular secret ion and resor p tion capacities (Alt man and Dittm er 1 974; NRC 1993; West et al. 1948). Children and adults may di ffer in their capacity to repa ir da m a ge fr om che m ic al insults. Children also have a longer rem a ining lifeti m e in which to express da m a ge fro m chem ical s; this potential is particularly relevant to cancer. Certain characteristics of the developing hum an m ay increase exp o sure or susceptibility , whereas others may decrease susceptibility to the sam e chem ical. For exam ple, alt hough infants breathe m o re air per kilogram of body weight th an adults breathe, this di ffe rence m i ght be so m e what counterbalanced b y theirAMMONIA 95 3. HEALTH E FFE CTS alveoli being less develope d, which results in a di sproportionately s m aller surf ac e area for alv e olar absorption (N RC 1993).

Hu m an and animal data indicate that the primary effects of a mmo nia are irritati on and burns and that the primary targets of amm onia are the respiratory tract, ey es, and ski n (Burns et al. 1985; Close et al. 198 0; Couturier et al. 197 1; de la Hoz et al. 1996; Flur y et al. 198 3; Geor ge et al. 2000 ; Hatton et al. 197 9; Heifer 1971; Holness et al. 1989; Kerstein et al. 200 1; Latenser and Lucktong 2000; Leduc et al. 1992; Millea et al. 1989; M o rgan 1997; Price et al. 198 3; Shi mkin et al. 1954; Slot 19 38 ; Sobo ny a 19 77; Taplin et al. 1976; V e rberk 1977; Weiser and Mackenroth 1 989). T h ere are lim ited data on the to xi city of
amm onia in children and n o inform ation on effects in adults who were exposed as children. Children (8–9 y ears ol d) who attended two school s in the vici ni ty of a fertilizer plant had higher incidences of acute respirat or y diseases t h an children who attended a school 20 kilom e t e rs away (Gomzi 1999; Gom z i and Šari ć 1997). Incidence was relat e d to levels of measured pollutants (a mm on ia, hy drogen fluoride, nitrogen diox ide, total susp ended particulate m a tter, and sm oke) in the inside and outside air ( G o m zi and Šari ć 1997). Forced expirator y v o lum es were not statis tically differ e nt between the three schools (Gomzi and Šari ć 1997). These results indicate that exposure to lo w levels of amm onia ( 0 .04–0.23 ppm) or other airborne poll u tants may n o t cause functional respir atory deficits, but m ay lower the resistanc e to respiratory pathogens in children. There is no indication that chil dren are m o re susceptible to the effects of a m m onia t h an adults. H o wever, children have greater surface ar ea to body weight and lung surface area to body weight ratios, and increase d m i nute volum e to weight ratio, so the y may receive ahigher dose than adults in the sa me situation. Children m ay also tend to be exposed longer than adults because they m ay not be as quick as adults to eva c uate a conta m inated are a .
There are no studies that indicate that metabolis m of a m m onia diff ers betwe e n c h ildren and a dults. Amm onia is eli m inated fr om the body mainly by pr ocessing through th e urea cy cle in the li ver, and urea is then elim in ated in the urine and feces. The urea cy c l e is fully functional in infants at birth; therefore, it is not expected that infants or children are at great er risk of hyperammonem i a. Neurotoxicityresulting from hy perammonem i a involves alteration of levels of some co mponents of th e citric acid cy cle, which leads to depletion of ATP, and starvation of brain cel l s , and depleti on of glutam ate, a precursor to the neurotransm i tter γ -am i nobuty r ate (GABA). It is not e xpected that children are more susceptible than adults to ATP depletion via this mechani s m .
Infants under 6 m onths of age may be more sensitive thanadults to the effects of high levels of nitrates (from nitrification of ammonia in fertilizers) that may be present in groundwater and well water (Pay neAMMONIA 96 3. HEALTH E FFE CTS 1981). Infant s who consume form ula and food m a de with contam i n ated water fr om these sources may develop m e th em oglobinemia, which results in decreased delivery of ox ygen to th e tissues.

3.8 BIOMAR KE RS OF E XP O SU RE A N D EFFECT
Biomarkers are broadl y de fined as indicators signaling ev ents in biologic s y stems or sa m p les. They have been classifi ed as m arkers of exposure, markers of ef fect, and m ark ers of susceptibility (NAS/NRC 1989). Due to a nascent understanding of the us e and interpre tation of b i o m arkers, im pl em entation of biom arkers as tools of exposure in the general popul ation is ver y l i m ited. A bio m arker of ex posure is a xenobiot ic substance or its m e tabolite(s) or the product of an inter action between a xenobi oti c agent and some target
m o lecule(s) o r cell(s) that is m e asured within a com p artm ent of an organism (NAS/NRC 1989). The preferred biomarkers of ex posure are generally th e substance itself or substance-specific metabolites in readily obtainable body fluid(s), or excreta. Ho wever, several fa ctors can confound the use and interpretation of biom arkers of exposure. The bo dy b ur den of a subs tance may be the result of exposures from m o re than one source. The substance being me asured m ay be a m e tabolite of another xe nobiot ic substance (e.g., hi gh uri n ary levels of p h enol can result from exposure to several different aromatic
co m pounds). Depending o nthe pro p erties of the subs tance (e.g., biologic half-lif e) and enviro nmental conditions (e.g., duration and route of exposure), the s ubstance and all of its metabolites may have left the body by th e ti me sam p les can be taken. It may be diff icult to identi fy indi viduals exposed to hazardous substances that are co mmo nl y found i n body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biom arker s of expos ure to ammonia are discussed i nSection 3.8.1.

Biomarkers o f effect ar e de fined as any mea s urable bi ochem i cal, p hy s iologic, or other alteration within an organism that, dependin g o nm a gnitude, can be recognized as an established or p o tential health i m pairment or disease ( N AS/NRC 1989)

. This definit i on encom p asses biochem i cal or cellular signals of tissue dy sfunction (e.g., increas ed liver enzy m e a c tivity or pathologic changes in fem a le geni tal epithelial cells), as well as phy s iologic signs of dy s f unction su ch as increas ed blood pressure or decreas e dlung capacity

. Note that these markers are notoften subs tance specifi c. They also m a y not be directly adverse, but can indicate potential health im pairment (e.g., DNA adducts). Biomarkers of effects caused by amm onia are discuss ed in Section 3.8.2.AMMONIA 97 3. HEALTH E FFE CTS
A biom ark e r of susceptibility is an indic a tor of an inhe rent or acquired lim it ation of an organis m 's ability to respond t o the challenge of exposure t o a specific xenobi otic sub s tance. It can be an intrinsi c genetic or other charact eristic or a preexisting disease that results in an increase in absorb ed dose, a decrease in the biologically e ffective dose, or a target tissue res ponse. If biom arker s of susceptibility exist, the yare discussed in Section 3.10 “Populations That Are Unusually Susceptible”.

3.8.1 Biomarkers Used to Identifyor QuantifyExp osure to Ammonia There are no known specific biom arkers of exposure f o r amm onia. Identification of biom arkers of exposure to ammonia is co nfounded because large amounts of ammonia are produced endogenousl y . Pharm acokinetic studies re veal that after inhalation exposure to lowlevels of amm onia, BUN, non protein nitrogen, urin ary - urea, and urinar y - ammonia levels do not change ( S ilverm an et al. 1949)

. Exposure to
co mm on occupational lim its of amm onia in air (25 ppm ) y i eld increased blood-amm onia lev e ls onl y 10% above fasting levels (WHO 198 6). In on e hum an study, oral in gestion of amm o n i um chloride tablets (approxim a tely 15 m g NH 4 + /kg) y i el ded onl y a transient increase in blood-amm o nia above fasting levels in 11 out of 2 0 subjects tested; no i n crease was observed in the remaining 9 su bj ects (Conn 19 72).

3.8.2 Biomarkers Used to Characterize Effects Cau sed b yAm monia
Effect biomarkers of amm o nia exposure are lim ited to site-of-contact tissue injuri es. Upon inh a lation exposure, distributionof ammonia is usually lim ited to the respirator y tract and i nvolves irritat i on and, at higher concentrations, pu l m onary edema and necros is (Kapeghian et al. 1982; R i chard et al. 1978b; Silverm an et al. 1949)

. Oral exposure to high doses of amm onium chloride has produced pulm onary edem a in ani m als ( K oenig and Koenig 1949). Derm al exposure to ammonia causes skin and ey e irritation and, at higher concentrations, necrosis (Am s hel et al. 2000; da Fonseca et al. 1998; George et al. 2000; Kerstein et al. 200 1; Latenser and Luckto ng 2 000; Led u c et al. 1992 ; Rosenbaum et al. 1998; Weiser and Mackenroth 1 989). T h e severity of inj u r i es by all r out es of exposure are dose-related. Unfortun ately , these effe ct biomarkers ar e not specific for a m m onia a nd can be caused by a variety of caustic substances. The tissues and organs m o st sensitive to amm onia ex pos ure are mainly depende nt on r oute of exposure. After inhalation exposure, which can involve a signi f i cant derm al exposure, the skin and e y es and the respiratory tr act, including the lungs, ar e m o st sens iti ve. Direct derm al exposure produces dose-relat e d effects fro m irritation to necrosis. Ingestion of amm o nium hy dr oxi de has resulted in oral, pharyngeal, andAMMONIA 98 3. HEALTH E FFE CTS esophageal lesions (Christesen 1995; Kle i n et al. 1985)

. The tissue and organ injuries produced by
a m m onia, however, are of lim it ed value as biomarke rs to characteri ze the effe cts caused by amm onia because man yother caustic chem i cals can produce si milar injuries.

3.9 INTERA CTI O NS WIT H OTHE R CH EMIC ALS Exposure to s ubstances that would incre ase the pH of exposed tissues could be expected to enhance the alkalotic effe cts of a m m o n i a, and vice versa. Agen ts acting to elevate the intestinal-tract pH would increase it s local irritant eff ect, and would prom ote its absorption as well (Cast ell and Moore 1971).

Co-ad m inistration of ammonia and diethy l pyrocarbo nate induced lung t u m o rs in Kid:CFLP mice, while neither agent ad m i nistered intragastrically and separatel y was carcinogenic; this effect is believed to be a result of a com pound, urethane (a known carcinogen), pr od uced b ytheir interaction (Uzvolg y i and Bojan 1980, 1985). Sprague-Dawley rats given intrarectal doses of N- methy l -N ’

- nitr o-N-nitrosoguanidine (MNNG) anda m m oniu m a cetate had a h i gher incidence of tum o rs t h an did controls that were ad m i nistered distilled water in place of ammoniu m ac etate (Clinton et al. 1988)

. The role of acetate was not ruled out. Amm onia acted sy nergist i cally with potassiu m ions on py r uvate kinase, a known Ehrlich ascites tu m o r enzy m e (Olavarria et al. 1986).

Some co m pounds play a s ynergistic rol e with amm o nia in pro duci ng hepatic co ma. Sim u ltaneous injection of anammoniu m salt and a fatty acid in Holtman or Sprague-Dawley rats produced c o ma at lower plasma levels than di d injection of either co m pound separately. Inhalatio n of methanethiol or injection with sodium octa noate bl ocked metabolis m of an injected dose of ammonium acet ate and led to elevated bloo d ammonia levels (Zieve et al. 197 4). Data regardin g exposure to m i xtures of atm o spheric cont am inants indicate that, contrar y to wh at m i ght be expected, increased carbon dioxi de concentration (up to 5% in air) does not alter the hy perventilator y rate induced b y hyperamm onemia in dogs ( H errera a nd Kazemi 1980). Amm onia in expired air may neutralize inhaled acid aero s ols (EPA 1979; Larson et al. 1980; Utell et al. 1989)

. Other substances to which people have been exposed have been shown to alter th e toxic effects of
a m m onia. M e thionine sulfoxim i ne, ad ministered by intraperitoneal injection, suppressed the tonic convulsions p r oduced b yin travenous inj ection of amm oniu m chlo ride in m i ce (Hindfelt and Plum 1975; Warren and Schenker 1964 ). Intraperito neal injecti on of alpha-m ethy lglutam i c acid also exerts aAMMONIA 99 3. HEALTH E FFE CTS protective effect against hyperamm onemia in rats (L amar 1970). Nicotinohy dr oxam i c acid and neomy c in ad m i nistered orally reduce blood ammonia levels and in creas e excre tion of urea in treated rats (Harada et al. 1985)

. Ethanol exerted a protective effect on acute amm onia in toxication in mice (O' C onnor et al. 1982), although ethanol w as reported to increase amm onia concen trations in body tissues of treated rats (Mohanachari et al. 1984)

.
Sodium benzoate decreased urea prod uction inammo nia challenged rats (Maswoswe et al. 1986) and hy perammonem i c mice (O' C onnor et al. 198 7). Valp roate, a widely used antiepi leptic drug, h as a hy perammonem i c effect in Wistar rats (Ferrier et al. 1988) an d m a y therefore predispose to ammonia intoxication. Amm onia int e rferes with the metabolis m of pent-4-enoic acid in c u ltured rat he patocy tes and m ay dramatically p o t e ntiate its toxicity (Co ude and Grim b e r 1984).

3.10 POP U LATI ONS T HAT ARE U NUS UALLY S U SCEPTI B L E A susceptible population w ill exhibit a di fferent or e nhanced response to amm oni a than will most persons exposed to the sa me level of a m m onia i nthe envir onment. Reaso ns may include genetic m a keup, age, health and nutritional status, and exposure to othe r toxic substances (e.g., cigarette sm oke). These param e ters result in reduced detoxificati on or excre tio n of amm onia, or com p ro mised function of organs affected b y ammonia. Populations wh o are at gr eater risk due to their unusuall y hig hexpos ure to
amm onia ar e discussed in Section 6.7, Popul ations With Potentiall y High Expos ures.
Persons who suffer fro m s e vere liver or kidne y diseas e m ay be susceptible to amm onia intoxication, as it is chiefly by the actions of these organs that NH 4 + is bi otransformed and excreted (Córdoba et al. 199 8; Gilbert 1988; Jeffers et al. 1988); i ndi vi duals with hereditary urea cy cle disorde r s are also at risk (Schubiger et al. 1991). In these individuals, the levels produced endogenousl y ar e sufficient to produce toxicity . Levels that are likely to be enc ountered in th e environm en t, with the exception of those resulting from high-level accidental exposures, are insignificant, due to the l o w absorption rate, in comparison with levels produced within the body (WHO 1986).

Since a m m o n i a is a respirat ory tract irritant, persons who are hy perreactive to other respiratory irritants, or who are asthmatic, would be expected to be m o re s u sceptible to a m m onia inhalation effect s. The results of an epidem iological study of a group of wor k ers chronically exposed t o airborne amm onia indicate that amm onia inhalation can exacerbate exist i ng s y m p to ms including cough, wheeze, nasal
co m p laints, ey e irritatio n, th roat discom f ort, and ski ni rritation (Ballal et al. 1998)

.AMMONIA 100 3. HEALTH E FFE CTS

3.11 METH OD S FOR R E DU CING T O XI C EFFECTS
This section will describe clinical practi ce and resear ch concerning m e thods for reducing toxi c effect s of exposure to ammonia. However, becau se so me of the treat ments discussed m a y be experimental and unproven, thi s section should not be use das a guide f o r treat m e nt of exposures to ammonia. When specific exposures have occurred, poiso n control cent e rs and m e dical toxicologis t s should be c onsulted for medical advice. The fo llowing texts provide ge neral inform atio n about treatment following exposures alkalies:

Ellenhorn MJ , Barceloux DG. 1997

. Me dical toxicolo g y : Diagnosi s and treatm e nt of hu m an poisoning

. New York, N Y : Elsevier. Haddad LM, ShannonM W , Winchester JF, eds. 19 98. Clinical management of poiso ning and drug overdose. 3 rd ed. Philadel phia, PA: W. B. Sanders Com p any .
3.11.1 Reducing Peak Absorption Follo w i ng Exposure Absorption o f amm onia via derm al exp o sure is not s u ffi cient to b e of concern, but immediate flushing of exposed skin with water or saline will limit derm al damage and reduce derm al absorption of ammonia. It is highl y unli k ely that eno ugh amm onia could be i n g ested to be of danger via absorptionfro m the intestines; however, in indi viduals with l i ve r disease, endogenous production of amm onia may cause toxicity . Em esis should not be induced in case of ingestion of amm onia, but administration of activated charcoal, gastric lavage, or neutralization with weak acids is reco mmended HSDB (2003). Eli m ination of urease-producing enteric bacteria with oral antibio tics decreases the am ount of ammonia abso rbed from the gut (Gilbe rt 1988). Because ammonia is readily sol uble in water at low concentrations, very little m ay reach and be absorbed in th e lungs. I n stead, amm oni a at low concentrations may be absorbed in the
m

u cosa of the upper respiratory tract and swallowed. Movem e nt to an area of fresh air as quickly as possible woul d lim it respiratory damage and absorpti on via the l u n g s.AMMONIA 101 3. HEALTH E FFE CTS
3.11.2 Reducing Bod yBu rden No experim e ntal data regarding m e thods for reducing the amm onia body bur den were located. In healthy people, ammonia is efficie n tly m e tabolized via the urea cy cle, primarily in the liver, and eliminated in the urine and feces (Fürst et al . 1969; Richards et al. 1975).

3.11.3 Interfering w i th the Mechanism of Action for Toxic Effects The prim ary effects of amm onia are rel a ted to its alka linity and its solubility in water, which results in rapid and severe tissue da mage. It is e x tre m ely im p o rtant to get to an area free of ammonia gas and to
rem ove all clothing contam inated with amm onia as qui ckl y as pos sible. Skin and e y es shoul d be irrigated with water for at least 15–20 m i nutes atthe tim e of exposure and periodically f o r 24 hours af ter exposure (Millea et al. 1989). Irrigat i on of th e e y e should conti nue until the pH of the conjunctival sac is less than 8.5 (Grant 19 74). Th is sho u ld be foll owed with prope r medical treatm e nt for respirator y s y m p toms and derm al and ocular burns.

3.12 ADE QUA C Y OF THE DATA BASE Section 104(i )(5) of CERCLA, as amended, directs the Adm i nistrator of ATSDR (in consultatio n with the Ad m i nistrator of EPA and agencies and program s of t h e Public Health Service) to asses s whe ther adequate inform ation on the health e ffec t s of a m m onia is available. Where adequate inform at ion is not available, AT SDR, in conjunction w ith the National Toxicology Program ( N TP) , is required to assure the initiation of a program of resear ch designed to determin e the health effects ( and techniques for developing methods to d e term ine such health effects) of amm onia. The following categories of possible data needs have been identified by a j o int te am of scientists from ATSDR, NTP, and EPA. They are defi ned as substan ce-specific i n form ational needs that if met would reduce the uncertainties of hum an health assessment. This definition shoul d not be interpreted to m e an that all data needs discussed in this secti on m u st be f illed. In the future, the id entified data needs will be evaluated and prioritized, and a substance- specific research agenda will be proposed.AMMONIA 102 3. HEALTH E FFE CTS
3.12.1 Existing Information on Health Effects of Ammonia The existing data on health effects of inhalation, or al, and derm al exposure of humans and animals to
amm onia are su mmarized i nFigure 3- 6. The purpose of this figure is to illustrate the existing i n form ation concerning the health effec t s of a m m onia. Each dot i nthe figure i ndicates that one or m o re studies provide information associ ated with that particular effect. The dot does not necessarily im ply any thing about the q u ality of th e study or stu d ies, nor sho u ldm i ssing information in th is figure be inter p reted as a “data need”. A data need, as defined in ATSDR’ s De cision Guide for Identif y i ng Substance-Specific Data N eeds R e lated to Toxicological Profiles (Age ncy for Toxic Substances and Disea se R e gistry 1989), is substance-specific information necessary to co nduct co m p rehen s ive public he alth assessments. Generally , ATSDR defines a data gap m o re broadl y as any substance-specific i n form ation missing from the scientific literature.

Inform ation r e garding health effects of ammonia in hu mans consists largely of case reports of fatalities or illnesses following m a ssive inhalation and/or derm al e xposures resulting from accidental explosions or leakages. A few controlled studies have been conduct e d on inhalation and oral exposure effects. Health effects of a m m onia in animals have be en investigated in nu m e rou s inhalation st udies, and a f e w oral and derm al exposure studies. Clearly , ammonia is an acutely t oxic chemical in high concentrations. As indicated in Figure 3-6, ava ilable data address these co ncerns, both in hum ans and animals. The data indicate that airway blockage, ede m a, b u rns, and l esions of tissues directly exposed to a m m o nia or NH 4 + are the m o st prom inent amm onia-relatedeffects. Secondar y effects include liver and kidn e y dam a ge, along with de creased resistance to infection.

3.12.2 Identification of Data Needs
Acute-Dura tion Exposure. The available human and anim al data provide strong evide n ce that acute-duration exposure to amm onia can result in sit e -of-contact lesions primarily of the ski n , ey es, and respiratory tr act. In some cases, exposure to ver y high ammonia concentrations has resulted in death (Arwood et al. 198 5; Walto n 19 73). Respirator y tract irritation (Bur ns et al. 1985 ; Close et al. 1980; Couturier et al. 197 1; de la Hoz et al. 1996; Ferguso n et al. 1977; G e orge et al. 2000; Hatton e t al. 197 9; Heifer 1971; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Millea et al. 1989; Morgan 19 97 ; Price et al. 1983; Sekizawa and Tsubon e 1994; S obo ny a 197 7; Ta plin et al. 1 9 7 6 ; Verberk 1977; Weiser and Mackenroth 1989) and im pair ed pulm onary function (Kass et al. 1972; Silve rm an et al. 1949) have b een observed in hum ans acutely exposed to amm onia gas. Animal studies suppo rt theAMMONIA 103 3. HEALTH E FFE CTS 

### Figure 3-6. Existing Information on Health Effects of Ammonia

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Ex i s t i n g St u d i e sAMMONIA 104 3. HEALTH E FFE CTS
identification of the respirator y tract as a sensitive target of toxicity (Coon et al. 1970; Kapeghi an et al. 1982; May an and Merilan 1972; Richard et al. 197 8a , 197 8b; Scha erdel et al. 1983; Stom baugh et al. 1969). Nonre s piratory tract effects ( e .g., cardiovascular effects, renal effects) hav e also been observed following i n halation expos ure. However, these eff ect s were not consistently obs erved or m ay be secondary to the respiratory tract dam a g e . Additi onal studies would be useful to assess the potential toxicity of NH 4 + to rem o te tissues. The available acut e data wer e c onsidered adequate to derive an acuteduration i nhal a tion MRL (Verbeck et al. 197 7). No a c ute-duration oral MRL was derived for NH 4 +

. The acute-duration oral database consists of case r e por ts with no dose inform ation (Klein et al. 1985; Klendshoj an d Rejent 196 6; Lopez et al. 198 8) and s e veral ani m al studies that exa m ined a limited num ber of end points (Noda and Chikam ori 1976), involveda single expos ure resulting i nno effect, serious effects, or unsupported eff ects (Beny a jati and Goldst ei n 197 5; Ko enig and Koe n ig 1 949), an d a repeated exposure study that found e ffects at high dosages (Bar zel 1975). I n addition, m an yanim al studies have been conduct e d with ammonium chloride, a substance widely used experimentally to i nduce metabolic acidosis in ani m als. Metab o lic acidosis is not a c onsequence of the amm oniu m ion, b u t is due to the formation of hy dro g en chl o ride. Metabolic acidosis can affect the lungs, kidne y, nervo u s system , liver, and bone. Ingestion of concentrated ammonia will cau se irritatio n and dam a ge to the m outh, throat, and gastrointestinal tract. Give n the levels of a m m oni a in the environm ent, such exposure scenari o is unlikel y . Additional oral e xposure studi es do not seem warr anted at this time. The available data on the derm al toxicity of amm onia suggest that th e skin is a sensitive target of toxicity . C u taneous bur ns have been reported in hum ans exposed to amm onia liquid and/or airbor ne amm onia (Am s hel et al. 2000; da Fonseca et al. 1998; George et al. 2000; Kerstein et al. 2001; Latenser and Lucktong 2000; Leduc et al. 1992; Rosenb au m et al. 1998; Weiser and Mackenroth198 9). Ocul ar effects (inflam e d ey es, lacrimation, swelling of th e ey elids, tran sient blindnes s , blurred visi on, and cor n eal abrasions) have been reported in hum ans exposed to amm o nia (Beare et al. 1988; Caplin 19 41; Clo se et al. 1980; Ferguson et al. 1977; Grant 1974; Hatton et al. 1979; Jarudi and Golden 1973; Kass et al. 1972; Latenser and Lucktong 2000; Legters et al. 1981; Levy et al. 1964; McGuinness 196 9; Montague and Macneil 1980; Price et al. 1983; Silverm an et al. 1949; Slot 193 8; Sob o ny a 1 977 ; Sto m b augh 19 69 ; Stroud 198 1 ; Verberk 197 7; Ward et al. 1983; Yang et al. 1987). Additional s tudies to examin e the dermal toxicity of amm onia are unlikel y t o provide new key inform ation.
Intermediate-Duration Exposure. Inform ation on the to xicityof inhaled ammonia in humans exposed for an interm ediat e duration is l i m ited to a case report of an indi vidual who develope d asthmalike sy m p toms following e xposure to ammonia gas for 5 m onths (Lee et al. 1993) and a study with volunteers exposed interm ittentl y for 5

– 6 weeks (F erguson et al. 1 977). T h e latter study foun dnoAMMONIA 105 3. HEALTH E FFE CTS significant changes in pul m onary function in su bjects exposed to up to 100 pp m ammonia, but e y e and throat irritation occurred at ≥ 50 ppm

. Be cause so me uncertainties r e garding the study design and reporting, th e Fergusson et al. (197 7) stu dy coul d not be used as basis for an interm ediate-dur ation inhalation M R L. Several anim al studies exam ined the toxicity of ammonia following interm ittent or continuous exposure to amm onia. As with acute -duration exposure, these studies suggest that th e respiratory tract is the m o st sensitive tar g et of toxici ty. Sy m p toms of irritation, nasal lesions, dy spnea, and pulm onary inflammation have been observed in s e veral animal species (Bro derson et al. 1976; Coon et al. 1970; D r ummond et al. 198 0; Gaafar et al. 1992; Sjöblom et al. 199 9; Stom baugh et al. 1 969). I n general, the concentrations used in these studies we re higher than the lowest adve rse effe ct lev e ls identified for acute-duration exposure. No intermediate-duration o r al MRL was derived for so me of the same reasons mentioned un der acute -duration exposur e. No hum an studies or reports of inter m ediateduration oral exposure to NH 4 + were located. Ani m a l studies have reported decrease s in body weight gain in rats exposed via drin kin g water (Gupta et al. 1979) or diet (Bo y ano-Adanez et al. 199 6). It should be mentioned th at Gupta et al. (197 9) adm i nistered am monium sulfa m ate to the rats. Ammonium sulfa m ate is an herbicide for which there is little toxicity in form ation in th e open literature. The EPA (IRIS 2004) has derived an oral RfD for the sulfa m at e m o iety b ased on the results of Gupta et al. (1979). Following gavage ad m i nistration of ammoniu m sal ts, bone, bl oo d pressure, adrenal gland, and renal effects have been observed in earl y studies of generally poor qual ity (Bodansky et al. 1932; Fazekas 1939; Seegal 1927). Addit i onal interm ediate-duration oral low to m oderate dose studies are unlikel y t o pr ovide new valuable infor m ation. No i n term ediate-duration de rm al exposure studies were identified. Based on th e irritant properties of a m m o nia, it is reasonable to assume that directcontact of the skin with ammonia for a prolonged ti me will produce irritation.
Chronic-Du ration Exposure and Cancer. Several studies have exam inedthe relationship between chronic expos ure to ammonia in the air and respirator y effects. Studies of farm ers working i ne n closed livestock facilities provide evidence that amm onia ma y contribute to transient respiratory distress (Choudat et al. 199 4; Cor m ier et al. 2000; Donh am et al. 1995, 2 000; Heederik et al. 199 0, 1991; Melbostad and Eduard 200 1; Reynol ds e t al. 199 6; Vo gelzang et al. 1997 , 20 00); however, co-exposure to total d u st, r espirable dust, carbon dio x i d e, tota l endo toxins, respir able endotoxi ns, fungi , bacteria, and/or m o lds co m p licates the interpretation of th ese studies. A study of workers at a fertilizer production facility found an associatio n between respirator y e ffects and amm o nia exposure at levels of ammonia higher than 2 5 ppm (Ballal et al. 1998)

. Another lon g - term study o f workers exposed to an av erage of 9.2 ppm ammonia did not f i nd respiratory effects (H ol ness et al. 1989). A chronic-duration inhalation MRL was der i ved based on the findings of Holness etal. (1989). Animal studies exam ining the chronicAMMONIA 106 3. HEALTH E FFE CTS
toxicity of inhaled amm o n i a were not identified. No chronic-durat ion oral or derm al data were located. A need for such studies is not apparent at this time.

There are li mited data to assess the carci nogenic potentia l of ammonia. Nasal cancer was rep o rted in an indivi dual accidentally exposed to a refrigeration-oil mixt ure, but th e role of amm onia, if any , is unknown (Shimk in et al. 195 4). Ani m al carcinogenicity data consist of several oral exposure studies. Amm onia was not found to increase the occurrence of tum o rs following oral e xposure to rel a tively l o w doses (Toth 1972; Uzvolg y i and Bojan 1980). Anot her study fo und evidence th at amm onia ad m i nistered as drinking fluid m ay act as a can cer prom oter (Tsujii et al. 1992a , 199 5). The dose of ammonia adm i nistered can be estimated at 200 m g /day , c o m p ared to th e estimated 0.36 m g /day fr om water ingestion for the general populati on ( W HO 1986). The relevance of these studies to expos ures in hum ans is unknown. The available inform ation does not sug g est th at amm onia is carcinogenic, but well-designed studie s in animals have not beenconducted an d m ay be warranted. Genotoxicity
. Dat aon the genotoxicity of amm o n i a in hum ans are li m ited to a study of workers at a fertilizer fact ory that found an increase in cl astogenic effects ( Y ad av and Kaushik 1997). In vivo ani m al data consist of a study in m i ce that found alterations in the occurrence of m i cronuclei (Yadav and Kaushik 199 7) and several studies in D. melanogaste r that resulted in a positive response for m u tagenic lethality (L obasov and Sm i rnov 1934) , but negative responses for sex-linked recessive lethal m u t a tions and dom inant lethality (Aue rbach and Robson 1947). In vitro studies reveal ed positive responses for genotoxicity i n E. coli(Demerec et al. 1951), an d chi c k (Ro senfeld 193 2) and m ouse (Capuco 197 7; Visek et al. 1972) fibr obla s ts. It would be valuable to further assess the genotoxicity of amm onia with
m

u t a genicity assay s in S. ty phimurium and in vitro an d/or in vivo te sts for chromosomal aberr a tions in
ma mmali an s y stem s. Reproducti ve Toxicity
. No information was located regardi ng reproductiv e effects of ammonia in hum ans. Rep r oductive to xi city data in animals are lim ited to a study in pigs exposed prior t o mating and until gestation day 30 (Diekman et al. 1993). T h is stud y did not fi nd alterations in fetus-to-corpus luteum ratio, num ber of live fetuses, or ovarian or uterine wei ghts (6 weeks of exposure onl y ). This st udy is not adequate for assessing reproductive toxi city because very l o w concentrations were used, there were no unexposed controls, and only femal es were exposed to amm onia. A dditional studies are need ed to assess
amm onia’s potential to in d u ce reproductive effects.AMMONIA 107 3. HEALTH E FFE CTS Developmental Toxicity
. No information was l o cated regardi ng develo pmental effects of amm onia in hum ans an d very lim ite d data were l o cated for anim als. No alte rations in num b er of live fetuses or fetal length were observed in a study of pigs exposed to a relatively low concentration of ammonia for 6 weeks prior to m a ting and until gestation day 30 (D i e k m an et al. 1993). A reduction in bo dyweight gain was observed in the offspring of rats orally expos ed to high doses of a mmonia, but no information was provided regarding the health of the dam s (Miñ ana et al. 1995). Developmental toxicit y s tudies are needed to assess the potential of a m m o n i a to damage the developing organism

. Immunotoxicity
. Seco ndary infection has been observed in humans who have r eceived s e vere burns from exposure to high l y co ncentrated aerosols deri ved from ammo nia (Sobo ny a 1977; Taplin et al. 1976). It is not known if this represents a pri m a ry effect on the immune s y stem in humans since nec r osis of exposed tissues facilitates infection by pathogenic orga nism s. Animal studies have shown that exposure to airborne ammonia may im pair imm u ne function ( B roderson et al. 1976; Gustin et al. 19 94 ; Richard et al. 1978a; Tar gowski et al. 1984). No or al imm unotoxicitydata were located. The available data provide suggestive evidence that ammonia may be an immunotoxicant. It would be val u able to assess the potential for i mmunotoxicity of amm onia witha battery of imm une function test s. Neurotoxicity
. Neurological effects have been ob served in humans who received extensive and serious burns from exposure to anhy dr ou s amm onia (G eorge et al. 2000; Hatton et al. 1979; L a tenser and Lucktong 2000; White 1971). These effects may be secondary t o tr au m a , rather t h an direct effects of
amm onia on the central nervous s y stem
. There are limited data on the potential of NH 4 + to i n duce overt neurological effects in ani m als. A decr ease in m o tor activity has been observed in rodents following an acute exposure to low levels of airborne amm onia (T epper et al. 19 85); n o overt signs of neur ological im pairment were observed following su b l ethal i nhalation exposure ( C oon et al. 1 970). Howev e r, num erous animal studies have found evi d ence that orally adm i nistered ammonia m ay disrupt norm a l energy production in the brain and im pai r neurotransmitter receptors (Bodega et al. 1991; Boy ano-Adánez et al. 1996; K i m u ra and Budka 1986; Kosenko et al. 1993; Kretzschmar et al. 1985; Miñana et al. 1989b; Sobel et al. 1981; S u árez et al. 1992). A dditional st udies following inhalation an d oral exposure would be useful to determ ine if the neurochem i cal alterations would result i n clinical im pairm e nt. No derm al studies exam ining neurolo g i cal end point s were identified. Epidemiological and Human Dosimetry Studies. Several studies have exam ined the toxicity of airborne ammonia in worke r s (Ballal et al. 199 8; Cho u d at et al. 199 4; Corm ier et al. 2000; Donh am et al. 1995, 2000; Heederik et al. 1990, 1991; Holness et al

. 1989; Melbostad and Eduard 2001; R e y n olds et al.AMMONIA 108 3. HEALTH E FFE CTS 1996; Vogelzang et al. 1997, 2000). T h ese studies have prim arily f o cused on the respiratory tr act, which is the m o st sensitive target of toxicity. Interpre tation of many of these studies is co m p licated by coexposure to other chem icals and m i croorganism s. In addition to th ese studies, there are reports of acuteduration expo sure to amm o nia via inhalation (Burns et al. 198 5; Clo se et al. 1980; Couturier et al. 1971; de la Hoz et a l . 1996; Ferguson et al. 1977; George et al. 2000; Hatton et al. 1979; Heifer 1971; Kass et al. 1972; Kerstein et al. 2001; Latenser and Lucktong2000; Leduc et al. 1992; Millea et al. 1989; M o rgan 1997; O’Kan e 1983; Price et al. 1983; S e kizawa and Tsubone 19 9 4 ; Sob o ny a 1 977; Tapli net al. 197 6; Verberk 1977 ; Weiser and Mackenroth 1 989), i ngestio n (Klein et al. 198 5; Klend s hoj and Rejent 19 66; Lopez et al. 1988), dermal contact (Amshel et al. 2000; da Fonseca et al. 1998; George et al. 2000; Kerstein et al. 200 1; Latenser and Luckto ng 2 000; Led u c et al. 1992 ; Rosenbaum et al. 1998; Weiser and Mackenroth 1 989), or ocular contact (Beare et al. 1988; Caplin 1 9 4 1 ; Close et al. 198 0; Fergus on et al. 1977; Grant 1 974; Hatton e t al. 197 9; Jarudi and Gol d en 1973 ; Latenser and Lucktong 20 00; Legters et al. 1981; Levy et al. 1964; McGuinness 1969; Monta gue and Macneil 1980; Pri ce et al. 1983; Silverman et al. 1949; Sl ot 19 38; S o b o ny a 19 77; S t om baugh 196 9; Strou d19 8 1 ; Verberk 19 77; Ward et al. 198 3; Yang et al. 1987). T h ese studies suggest that the m o stsensitive target is the site of contact. T h e carcinogenic potential of ammonia has not been assessed in hum ans. There are several subpopulations of indivi duals exposed to hig h er than nor mal levels of amm onia; these groups incl ude farm ers and
co mm unities living near fertilizer plants. Studies of th ese groups that involved e x am ination for a variety of potential e ffects could provide useful inform ation on the toxicity of amm onia i nhum ans. In addition, if the study gr oup i n cluded both chil dren and adults , these data woul d address the issue of age-r e lated differences in toxicity

.
Biomarkers of Exposure and Effect. Exposure

. There are no known specific biom arkers of exposure fo r amm onia in hum ans or an im als. Furtherm ore, no evidence for alterations in clinical indices of body ammonia or nitrogen levels after exposure to e xogeno us amm onia has been reported. It does not se em useful at this time to develop biom arkers of exposure for amm onia because after e xposure to low l e vels, ammonia is either rapidl y cleared fro m the body or m e tabolized to co m pounds f ound endoge nousl y at app r eciable levels. Exposure to hig hconcentrations is i mmediately and o v ertl y toxic, which eliminates the n eed for a m o re subtle biom arker.AMMONIA 109 3. HEALTH E FFE CTS Effect

. There are no known specific biomarkers of effect for ammonia in hu m a ns or anim als. Lesions produced b y exposure to h i gh concentrations of amm onia are sim i lar to those pr oduced b yother caustic substances. Absorption , Distribution, Metabolism, and Excretion. Measure mentof ammonia absorption is
co m p licated b y the apprec iable levels of endogeno us ly pro duced ammonia. Althoug h, m o st of the inhaled ammonia is retained in the tissu es of the uppe r respiratory tr act, inhalation exposure to low levels of amm onia can result in a sm all amount of abso rptio n(Silverman et al. 194 9). A s the amm onia concentration increases, the ability of the upper respir atory tract to retain amm o n i a is saturated , and a larger percentage is absorbed into th e bl ood stream (Silverm an et al. 194 9). Ab s o rptioninto th e sy stem ic circulation after oral exposure is lim ited (Metges et al. 199 9). Amm oniu m ions absorbed fro m the gastrointestinal tract travel s via the hepatic portal vein directly t o the liver where, in healthy i n dividuals,
m o st of it is converted to ur ea and glutamine. A lthou gh it has n o t been extensively stu d ied, d e rm al absorption of a m m onia doe s not occur to a great exte nt; WHO (1986) concluded that sy stem ic effects from skin and ey e exposure to amm onia are not quantitatively im portant. Data ar e not available to asses s the distributi on of amm o n i a in hum ans or anim als. Studies exam ining the d i strib u tion of ammonia would be useful for i d entif y i ng po tential targets of toxicity . Studies on en dogeno usl y p r oduced ammonia, however, indicate that it is distributed to m o st of th e organs and tissues of the body

. Extensive work has been co m p leted on the m e tabolism of ammonia and its participation in the glutam ine cy cle and the urea cy cle (Duda and Handler 1958; F ü rst et al. 1969; Richar ds et al. 1975; Vitti et a l . 1964). Dat aregarding excretion are lim ited but it is known that amm onia inhaled at low levels is excreted prim arily unchanged in the expired breath (Silverm an et al. 1949); NH 4 + abs o rbed from the gastroint estinal tract is excreted primarily in th e urine as urea and other urinar y nitr og en com pounds (Gay et al. 1969; Pitts 1971; Richards et al. 1975; S u mmerskill and Wol p ert 1970). No inf o rmation regarding excretio n after derm al exposure was locat ed. Comparativ e Toxicokinetics. Available data indicate that a mmonia has s i m ilar targets of toxicity in hum ans an d anim al s. Ammonia is most hazar dous as a site-of-contact toxicant; therefore, the respiratory s y stem is m o st vulnerable after inhala tion exposure, the gastrointestinal tract is m o st vulnerable after oral exposure, and the s k in and e y es are m o st vulnerable after d e rm al/ocular exposure. Li m ited human and anim a l data are avai lable for toxi cokinetics; however, these data indicate that hum ans and anim als are probabl y v e ry sim ilar regarding th e to xicokinetic di sposition of ammonia. Furtherm ore, it is reasonable to expect, especially give n the bioche mical i m porta nce of a m m o nia, that hum ans and anim als would handle this co m pound si milarly

.AMMONIA 110 3. HEALTH E FFE CTS

Methods fo r Reducing Toxic Effects. There are li m ited spe c ific data on reducing the toxic effects of amm onia. Many of the methods are generic appro aches, such as getting to anarea with fresh air and
rem oval of contam inated clothing

. No m e thods were identified for r e ducing the b o dy burden o r interfering with the m e chanism s of toxi city

. Studies designed to i d entif y m e thods for interfering with th e dam a ge associated with direct contact with ammonia would be use f ul. Children’s Susceptibility
. There are li m ited data on the toxic ity of amm o n i a in children and no inform ation on effects in a dults who were exposed as children. A higher incide nce of respira t ory diseases was found in school childr e n exposed to airborne am m onia and other chem icals (Go m zi 1999 ; Gomzi and Šari ć 1997). There is no in dication that children are m o re susceptible to the effects of amm o n i a than adults; studies of children and adults exposed to amm onia would be useful for asse ssing potential agerelated differ e nces in a m monia toxicity.

Child health data needs rel a ting to exposure are discu ssed in Section 6.8.1 Identification of Data Needs: Exposures of Children.

3.12.3 Ongoing Studies Ongoing stud ies pertaining to amm onia have b een identified and ar e shown in T a ble 3-5.AMMONIA 111 3. HEALTH E FFE CTS



### Table 3-5. Ongoing Studies on the Health Effects of Ammonia Investigator Affiliation Research d e scription Sponsor Seash o re MR Yale Unive r si ty Wall SM University of Texas Health Sci e n c e Center Matthews J B Univers i ty of Cinc innati

Wall SM University of Texas Health Sci e n c e Center Wein er ID University of Florid a

R a us he l F M Te xa s A&M U n ive r s i ty Sys t em Hamm on DS Utah State University, Animal Dai ry and Vet Sc ienc e Nag a mi GT Dep a rtme nt of Veterans Affairs, Medi cal Cente r We st Los An gele s , California Nag a mi GT Dep a rtme nt of Veterans Affairs, Medi cal Cente r We st Los An gele s , California Feldma n GM Dep a rtme nt of Veterans Affairs , Medical Ce nter Richmond, Virginia Wal s ch PJ University of Miami

Wein er ID Dep a rtme nt of Veterans Affairs , Medical Ce nter Gainesville, Florida Sastra sin h S Dep a rtme nt of Veterans Affairs, Medi cal Cente r East Ora nge, New Jer s ey Sodium ph en ylbutyrate tre a tment of inborn erro rs of ammonia metaboli s m NH 4 + tran spo rt in renal in n e r medulla ry coll ecting d u ct Intestinal secretion an d inflammation; impact of am monia Ren a l net aci d se cretio n a nd Na + /K + /2Cl- cotrans p orter Loc alization o f ammonia tra n sp orte rs in human live r Mech ani sm a nd co ntrol of urea biosynth esi s Gamete an d embryo toxic effects of ammoni um in cattle Effect of angiotensi n II on ammoni a prod uctio n by tubule cell s. Effect of acid osi s on renin-angi oten sin sy stem Ammonia p r o ductio n and transport by the proximal t ubule

Colo nic tra n sport of bica rb onate, ammoni um a nd small o r g a n ic ani on s

Me ch ani sm o f tolerance of extreme ammoni a Effect of ammonia on IM CD H-KATPase. Expressio n of an ammoni asen s itive prot ein in brai n that mediates ammoni a’s n eurol ogi cal ef fects Na + /H + antipo rt in renal mit o ch ond ria Nation al Cent er for Re sea r c h Re sou r c e s Nation al Institute of Diab etes a n d Dige stive and Kidney Disea s e s Nation al Institute of Diab etes a n d Dige stive and Kidney Disea s e s Nation al Institute of Diab etes a n d Dige stive and Kidney Disea s e s Nation al Institute of Diab etes a n d Dige stive and Kidney Disea s e s Nation al Institute of Diab etes a n d Dige stive and Kidney Disea s e s Animal He alth Award
Dep a rtme nt of Veterans Affairs, Re se arch and Develo pment , Wa shin gton, DC Dep a rtme nt of Veterans Affairs, Re se arch and Develo pment , Wa shin gton, DC Dep a rtme nt of Veterans Affairs, Re se arch and Develo pment , Wa shin gton, DC Nation al Institute of Environme n tal Health Sc ie nc es Dep a rtme nt of Veterans Affairs, Re se arch and Develo pment , Wa shin gton, DC Dep a rtme nt of Veterans Affairs, Re se arch and Develo pment , Wa shin gton, DC Source: F E DRI P (2003)AMMONIA 113



### 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY Data pertaining to the chemical identity of ammoni a are presented in Table 4-1. These data are for ammonia in its pure gaseous state (i.e., anhydrous ammonia). Ammonia is also commercially and commonly available as an aqueous solution; the mo st common commercial formulation is 28–30% NH 3 (Weast et al. 1988). At this concentration, ammonia fo rms a nearly saturated solution in water. Data on ammonia in aqueous solution, ammonium hydroxide, and ammonium ion are also included in Table 4-1 where appropriate.

4.2 PHYSICAL AND CHEMICAL PROPERTIES Ammonium hydroxide is a weak base that is partia lly ionized in water according to the equilibrium:

NH 3 + H 2 0 o [NH 4 OH] o NH 4 + + OH The dissociation constant, K b , is 1.774x10 5 at 25 °C (pK b is 4.751) and increases slightly with increasing temperature (Weast et al. 1988). At pH 9.25 half of the ammonia will be un-ionized (NH 3 ) and half will be ionized (NH 4 + ). At pH 8.25 and 7.25, 90, and 99% of the ammonia will be ionized, respectively. Therefore, at most environmentally significant pHs, ammonia will be largely ionized; the fraction of unionized ammonia will become increasingly more important at pHs above 7. As a result, many physical and chemical properties will be a function of pH. Fo r example, the solubility of ammonia in water will increase with decreasing pH. The volatility of ammonia increases with increasing pH; therefore, it volatilizes freely from solution at high pH values. Amm onium salts such as chloride, nitrate, and sulfate are strongly dissociated and very soluble in water (W east et al. 1988); therefore, changes in pH will not normally result in the formation of ammonium precipitates. The physical and chemical properties of ammonia are presented in Table 4-2. Also included are some chemical and physical properties of ammonia in soluti on. Ammonia in solution is widely available, and it is often referred to as ammonium hydroxide and has been also historically referred to as “spirit of hartshorn” (Windholz 1983).AMMONIA 114 4. CHEMICAL A ND PH YSICAL I N FORMATI O N



### Table 4-1. Chemical Identityof Ammonia
Characterist ic Information Reference Chemi c al n a m e Synonym(s)
Regi stered trade nam e(s) Chemi c al fo rmula Chemi c al stru cture

Identification numbe rs:

CAS Regi stry NIOSH RTE C S

anhydrou s a mmonia aque ou s sol u tion aqua am moni a EPA Haz a rdous Was t e OHM/TA DS DOT/ UN/ NA/IMCO shippi n g

anhydrou s solutio n (10

– 35%) solutio n (35

– 50%) solutio n (>50 %) HSDB NCI Ammonia Anhydro u s a mmonia, AM-FOL, Ammonia ga s, Liquid amm onia, Nitro-s il, R 717, Spirit of harts horn No data NH 3 

### H H HN

7664 -41
- 7 B00875 000 B00875 000 B00875 000 B00875 000 No data 7216 584
UN 1 005 UN 2 672 UN 2 073 UN 1 005 162 No data EPA 1987a; Windhol z 1983

HSDB 20 03 NIOSH 2 002 a

OHM

- TADS 1988
NIOSH 2 002 a

HSDB 20 03

CAS = Chemic al Abstracts Se rvices; DOT/UN/NA/IMCO = Dep a rtment of T r ansportation/ Unite d Natio n s / North America/Intern ation a l Maritim e Dan gero u s Goods C o d e ; EPA = Environme n tal Protectio n Agenc y ; HSDB = Hazar dous Su bstanc es Data Bank; NCI = Nationa l Canc er Institute; NIOS H = Na tiona l Institute for Occupatio na l Safet y a nd H ealt h ; OHM/T A DS = Oil and Ha za rdous Mater i al s/T e chnica l Assistance D a ta S y stem; RT ECS = Regi stry of T o xic Effects of Chemi c al Substa ncesAMMONIA 115 4. CHEMICAL A ND PH YSICAL I N FORMATI O N



### Table 4-2. Ph ysical and Ch emical Properties of Ammonia Property Value Reference Molecula r wei ght Colo r Physical state Melting point Boiling point Den s ity : Gas Aqueou s solu tion (28%) Liquid Vapor d e n s ity Specific g r avi t y (25 °C) Odor Odor th re shol d: Air

Wate r pKa Solubility: Wate r at 0 °C
at 15 °C at 20 °C
at 25 °C
at 30 °C at 50 °C Orga nic solve n t(s) at 0 °C at 25 °C

Partition co efficient s: Log K ow 17.03 Colo rle ss Gas at room tempe r ature -77.7 ° C -33.35 ° C 0.7710 g/L 0.8980 1 (20 ° C ) g/L 0.6818 g/L (-33.35 ° C , 1 atm) 0.5967 (air=1 ) 0.747 g/L Sharp, inten s ely irritating 25 ppm (18 mg/m 3 ) 48 ppm (34 mg/m 3 ) 53 ppm (38 mg/m 3 ) 1.5 ppm 9.25 (25 ° C)

42.8% (w/ w ) 47% (w/ w ) 38% (w/ w ) 33.1% (w/ w ) 34% (w/ w ) 34% (w/ w ) 31% (w/ w ) 28% (w/ w ) 18% (w/ w ) 20% (w/ w ) in absol ute etha nol 10% (w/ w ) in absol ute etha nol 16% (w/ w ) in methanol Soluble in chl o rofo rm and ether 0.23 (e stimat ed) LeBlan c et al. 1978 LeBlan c et al. 1978 LeBlan c et al. 1978 LeBlan c et al. 1978 LeBlan c et al. 1978
Wea s t et al. 1988 Wind hol z 198 3 Wind hol z 198 3 Wind hol z 198 3 Lide 19 98 Sax and Lewi s 198 7
Amoore a nd Hautal a 198 3 Leon ard o s et al. 1969 Budavari et al . 1996 Amoore a nd Hautal a 198 3 Lide 19 98

LeBlan c et al. 1978 Budavari et al . 1996 Budavari et al . 1996 LeBlan c et al. 1978 Budavari et al . 1996 LeBlan c et al. 1978 Budavari et al . 1996 Budavari et al . 1996 Budavari et al . 1996
Budavari et al . 1996 Budavari et al . 1996 Budavari et al . 1996 Budavari et al . 1996
EPIWIN 2000AMMONIA 116 4. CHEMICAL A ND PH YSICAL I N FORMATI O N


### Table 4-2. Ph ysical and Ch emical Properties of Ammonia Property Value Reference Log K oc Vapor p r e s su re: Anhydro u s NH 3 Aqueou s NH 3 (28%) Hen ry's la w consta nt

Autoignition tempe r ature Flash point Flammability limits in air Conve r si on factors ppm (v/v) to mg/m 3 in air (20 ° C ) mg/m 3 to ppm (v/v) in air (20 ° C ) pH in water

Explosive limi t s 1.155 (e stima t ed) 8.5 atm (20 ° C ) 10.2 atm (25 ° C) 2.9 atm (25 ° C ) 1.6x10 -5 atm-m 3 /mol (25 ° C ) 7.3x10 -6 atm-m 3 /mol (pH 7, 23.4 °C) a 1.60x10 -5 atm-m 3 /mol (25 ° C ) b 5.01x10 -6 atm-m 3 /mol (5 ° C ) 650 ° C Not available 16–2 5% 1 ppm (v/v) = 0.707 mg/m 3 1 mg/m 3 = 1.414 ppm (v/v) 11.6 (1 N) 11.1 (0.1 N) 10.6 (0.01 N) Not available EPIWIN 2000
Sax and Lewi s 198 7 Dau bert an d Dan ner 1 989 Dau bert an d Dan ner 1 989 Betterton 199 2 Ayers et al. 1985 Yoo et al. 1986 Brimble c om b e and Dawso n 1984 LeBlan c et al. 1978
LeBlan c et al. 1978
Versch ueren 1983

Wind hol z 198 3

a Unitless co nstant e x trapo late d from cited da ta. b Unconv erted v a lu e of 0.016 8 kg-atm/mol w a s calcul ated fro m equati on i n citation. pKa = T he diss ociati on co nsta nt of the conju gate aci dAMMONIA 117



### 5. PRODUCTION, IMPORT/E XPORT, USE, AND DISPOSAL

5.1 PRODUCTI O N
Amm onia is both a natural and a manufactured chemical. It is a key i n termediate in the nitrogen cy cle in nature, and microbial production is a m a jor source of a m m onia in the world. Recent reports, however, have em phasized the significant influence that hum ans are having o nthe glo b al n itrogen b udge t. At the beginnin g of the 20 thcentury , m o st nitrogen was fixed into usable forms (e.g., NH 3 ) b y li ghtn i ng strikes and m i crobial nitrogen fi xation, with an estimated 90– 130 teragrams (Tg; 1 teragram is equivalent to o n e million m e tric tons) fixed per y ear. Human producti on of fi xed ni trogen (NH 3 ) is now esti m a t ed to be 140 T g N per y ear, an am ount that is si milar to non- anthropogeni c sources (NS F 1999; Socolow 1999). This increase in hum an-rela ted a m m onia e m is sions is considerably higher than earlier esti m ates of the total annual commercial productionof ammonia, wherein the anthr opogenic em ission of ammonia represented approxim a tely 1–5% of nature's global amm onia emis si on budget (ApSim on et al. 1987; Buijsm an et al. 198 7; Crutz e n 1983 ; Galbally 19 85; R o sswall 1981; Socolow 19 9 9 ). The largest am ount of naturally pro duced amm onia is thoug ht to ar ise fro m soil. Amm onia from deco m posing anim al excreta probabl y ac counts for th e largest propo rtion of th e ammonia produced, with the decay of organic mater i als fro m plants, dead animals, and the like contributi n g significant am ounts (Crutzen 1983; Dawson 1977; Dawson and Farm er 1984; Galball y 1985; Irwin and William s 1988).

Manufacture of a m m onia within the United States ha s dec lined ste a dily over the past several y ears, with one of the o u t c o m es being the closure of several production plants. The U.S. annu al commercial production capacity f o r amm onia was 16.6 m illion metric tons in 1999 (CMR 1999), 15. 7 m illion m e tric tons in 2000 ( S RI 2000), but onl y 9. 5 million m e tric tons in 2001 ( K ramer 2002). Producti on levels increased slig htl y to 10.8 million m e tri c tons in 2002 (Kram e r 20 03). High nat u ral gas costs, along with weather-r elat ed decreas es i ndem ands, c ontributed to the lower production output in the y ears leading up to 2002. However, natural gas pr ices became lower in 2002, and amm onia production i n creased that y ear. In 1999, four plant closings eli m inated a co m b in ed production capacity of 1.2 m illion tons, some of which was replaced by ne w facilities ( C MR 1999). In 200 0, an a dditional seven plants were co m p letely shut down, and five plants were partially closed due t o m a rket conditions (Kramer 2000). In 2002 , the largest producer of a m m o n i a in the United Stat es filed for Chapter 11 bankr uptc y , leading t o th eAMMONIA 118 5. PRO D UCTION, IMPO RT/EXP O R T, USE, AND DISPO SAL

perm anent closing of th ree large product i on plants (wi th a com b ined prod uction capacity of ju st over 980, 000 m e tric tons) (Kramer 2003).

While a m m o nia production decreased o v er the past few y ears and so m e a mmon i a plants were closed, the states and co m p anies that have historically produced m o st of the ammonia re ma ined relatively constant. In 200 0, 2 0 0 1 , and 2 002 , Louisiana, Oklahom a, andTexas were the three m a jo r producin g st ates, contributi ng over 50% of th e total U.S. amm onia pr oduction. Six co m p anies (Farm l and Industries Inc., Terra Industries Inc., PCS Nitrogen Inc., Agrium Inc. , CF Industries Inc., and Ko ch Nitrogen) produced 73% of the nation ’ s ammonia in 200 2 (K ram e r 2003).
There are 2,338 facilities that manufacture or process amm onia in the United St ates (Table 5- 1). The
am ounts m an u factured or processed ran g e from rel a ti vely small production activities (from 0 to 99,999 pounds) in Hawaii t o ver y large f o rm ulati on and processing activities (up to 499,999,999 pounds) in Alaska, Florida, Iowa, Kansas, Louisiana, Ne bra s ka, and Texas (TRI01 2003). As m e ntioned previously , three stat es, Louisiana, Oklahom a, and Te xas, produce m o r e than 50% of the nation’s total NH 3 output. The major method for commercial production of anhy drou s ammonia is a m o d i fied Haber-Bosch process. This process was first demonstrated in 1909 (Krame r 2000), and w as co mmer c ially developed in 1913 i n Germ any . T h e first U.S. plant to use this process was built in Sy racuse, New York , in 1921 (DOI 1985). The basic Haber-Bosch m e thodol ogy was still responsible for 98% of the industrially produced ammonia in the United States in 1979 (EPA 1980; HSDB 2003)

. In this proc ess, nitrogen (obtained from the at m o sphere) and hy drogen (obtained fro m natural ga s ) are m i xed together in a 1 to 3 ratio and passed over a cataly s t at high pressure and hi gh tem p erature. The amm onia thus produced is collected by various means, and a ny unreacted feed gases ar e recirculat ed through the reactor.

S m all a m oun ts of a m m onia are produced industrially as a by -product of the coking of coal. The largest proporti on of industrial amm onia production occurs inareas where natural gas is cheap and plentiful because a mmonia is synthe sized using natural gas. Large pipelines stretching from Louisianato Nebraska andfrom Texas to Minnesota carry anh ydro u s amm onia from its site of producti on t o agricultural areas wher e it is used as fert ilizer (LeB lan c et al. 1978). These pipelines are capable of transporting o r storing 3 m i llion m e tric tons of amm o nia per y ear, and have a storage capacit yof 1.5 m illion metric tons (Kram e r 2000, 2003). Amm o nia can also be shipped in l arge refrigerated, lowAMMONIA 119 5. PRO D UCTION, IMPO RT/EXP O R T, USE, AND DISPO SAL



### Table 5-1. Facilities that Pr oduce, Process, or Use Ammonia Number Minimu m Maxi mum of amount on site amount on site State a facilit ies in pounds b in pounds b Activities an d uses c AK 6 1,000 499,99 9,999 1, 3, 4, 5, 6, 1 0 , 11, 12 AL 69 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 9, 10, 11, 12, 13 AR 45 100 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 AS 1 10,000 99,999 11 AZ 16 0 9,999,99 9 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12 CA 161 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 CO 15 0 999,99 9 1, 5, 6, 7, 9, 1 1 , 12 CT 24 0 999,99 9 1, 2, 3, 5, 6, 7 , 8, 10, 11, 12 DC 2 100,00 0 999,99 9 12 DE 14 0 999,99 9 1, 3, 5, 6, 7, 1 1 , 12 FL 54 100 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 GA 87 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 HI 6 0 99,999 1, 3, 5, 6, 10, 12, 13, 14 IA 54 100 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12 ID 16 100 49,999,9 99 1, 2, 3, 4, 5, 6 , 8, 9, 10, 11, 12, 13 IL 108 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 IN 72 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 KS 36 100 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 8, 10, 11, 12, 13, 14 KY 34 100 9,999,99 9 1, 2, 3, 5, 6, 7 , 9, 10, 11, 12, 13, 14 LA 73 0 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 10, 11, 12, 13, 14 MA 34 0 999,99 9 1, 2, 3, 5, 6, 7 , 10, 11, 12 MD 16 1,000 999,99 9 1, 3, 5, 6, 7, 8 , 10, 11, 12, 13, 14 ME 13 0 999,99 9 1, 2, 3, 5, 6, 1 0 , 11, 12, 13 MI 72 0 999,99 9 1, 2, 3, 5, 6, 7 , 8, 10, 11, 12, 13, 14 MN 39 0 9,999,99 9 1, 2, 3, 5, 6, 7 , 8, 9, 10, 11, 12, 13 MO 50 1,000 9,999,99 9 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12 MS 44 100 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 MT 12 0 9,999,99 9 1, 3, 5, 6, 10, 11, 12 NC 86 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 ND 7 0 999,99 9 1, 3, 5, 6, 10, 11, 12 NE 35 100 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12 NH 14 0 9,999,99 9 1, 3, 4, 5, 6, 7 , 10, 11, 12 NJ 58 0 9,999,99 9 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 NM 6 100 99,999 1, 5, 7, 11, 12 NV 11 100 9,999,99 9 1, 2, 3, 4, 5, 6 , 10, 11, 12, 13 NY 63 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 OH 123 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 OK 26 100 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 9, 10, 11, 12, 13, 14AMMONIA 120 5. PRO D UCTION, IMPO RT/EXP O R T, USE, AND DISPO SAL


### Table 5-1. Facilities that Pr oduce, Process, or Use Ammonia Number Minimu m Maxi mum of amount on site amount on site State a facilit ies in pounds b in pounds b Activities an d uses c OR 46 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 PA 108 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 PR 15 100 999,99 9 1, 2, 3, 4, 5, 6 , 7, 9, 10, 11, 12 RI 13 0 9,999,99 9 1, 2, 3, 4, 5, 6 , 7, 9, 10, 11, 12 SC 64 0 999,99 9 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 SD 4 1,000 999,99 9 1, 5, 10, 11 TN 56 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 TX 191 0 499,99 9,999 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 UT 28 100 9,999,99 9 1, 2, 3, 4, 5, 6 , 7, 9, 10, 11, 12 VA 57 0 49,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 1 100,00 0 999,99 9 1, 2, 3, 5, 6, 1 0 , 12 VT 2 1,000 99,999 1, 5, 11, 12 WA 38 0 99,999,9 99 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13 WI 68 100 999,99 9 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 1 1 , 12, 13, 14 WV 33 0 49,999,9 99 1, 3, 5, 6, 7, 9 , 10, 11, 12, 13 WY 12 0 99,999,9 99 1, 3, 4, 5, 6, 7 , 10, 13 Source: T R I01 200 3 (Data ar e from 2001)

a Post office state abbrev iati on s used b Amounts on si te reported b y f a ciliti e s in e a ch state cActivities/Uses: 1. Produce 6. Impurit y 11. Chemic al Processi ng Aid 2. Import 7. Reactant 12. Manufactu ring Ai d 3. Onsite use/process i ng 8. F o rmulation Compo nent 13. Ancill ary / O t her Uses 4. Sale/Distrib ution 9. Article Com pon ent 14. Process Impurit y 5. Bypro duct 10. Repack a g i ng VIAMMONIA 121 5. PRO D UCTION, IMPO RT/EXP O R T, USE, AND DISPO SAL pressure tanks (holding between 4 and 30 thousand to ns) or smaller (holding approxim a t e ly 210 tons), pressurized tanks (Farm Chem icals Handbook 1987). Ba rges ar e often used for r e frigerated sh ipments because of their lower cost

. Ammonia c an be stored in refrigerated tanks holding up to 36,000 tons for use in the amm onia market

. Sm all e r amounts of ammonia are stored in pressurized tanks. The suppl y of amm onia for dom estic uses has been hi storically m e t by dom e stic production. The ability to m e et the ammonia demand depends on the am ount of crop acres planted, the price of im po rted fertilizers, the cost of natur a l gas, and the ava ilability of amm onia via im port from abroad. In 2000, 3.9 m illion metric tons of anhy dr ous amm onia were i m ported; in 2001, th is am o unt increased to m o re than 5.5 m illion m e tric ton s . In 2000, domestic s ources supplied 15.7 m illion metric tons of ammonia, whereas international sources provided 3.9 m illion metr ic tons; imports represented 20% of the total suppl y . In 2001 by com p arison, dom estic production dropped to 9. 5 m illion m e tric tons, whil e im ports increased 5.5 million m e tri c tons; im ports in 2001 repr esented al m o st 37% of the suppl y of amm onia (Kramer 2002). The am o unt of amm o nia im ported in 20 02 held steady

—the am ount im ported was just under 5. 7 m i llion m e tric to ns (Kramer 2003)—while dom estic production r o se slightl y to 10. 8 m illion metric tons. Im ports in 2002 repr esented 35% of the domestic need. The increase s in im ported a m m onia, along with de creased domestic production, resulted in a substantial increase in reliance on foreign sources during these 3 y ears.

5.2 IMPORT/EXPORT
The im port and expor t of ammonia have fluctuated slightl y over the last few y ears. In 20 00, th e am ount of amm onia i m ported into the United St ates was slightlyless than 3.9 m illion metric tons. In both 2001 and 2002, th e am ount of ammonia im p o rted into the United States was slightly m o re than 5.5 m illion metric tons ( K ramer 2003). These y ears reflect a 41 % increase in the am ount of amm onia i m ported
co m p ared to 2000

. U.S. e xports of amm onia fell du ring the y ears following th e change in d o mestic production and im port from abroad. E xports in 2000 were approximately 0. 66 m illion m e tric tons, and in 2001, 0. 65 m illion m e tric tons were exported. Export s then dropped to 2/ 3 of those reported in the previous y ears. In 2002, wh en dom estic produc tion dr opped and imports in creased, onl y 0.44 million metric tons of amm onia were exported.AMMONIA 122 5. PRO D UCTION, IMPO RT/EXP O R T, USE, AND DISPO SAL
5.3 USE The largest and m o st significant use of amm oni a andamm oniu m com pounds is the agricultur a l application of fertilizers. Ammonia and amm oni u m com pounds used as fertilizer represent 89–90% of the commer c i a lly produced a m m onia, wi th plastics, s ynthetic fibers and resins, explosives, and other uses accounting for m o st of the rem a inder (Kram e r 2002, 2 004). Direct uses of amm o nia as fertilizer can be broken down into the following categories (percentag es based on mass of nitrogen in each com pound): anhy dro u s ammonia, 26% ; urea/ammonium nitrate solutions, 23 % ; urea, 20%; amm oniu m nitrate, 4.5% ; amm oniu m sulfate, 2%; other forms, 3%; and m u ltiple nutrient f o rms, 21% (Kramer 2003). Most
amm oniu m com pounds and nitric acid, which are produced from anhy dr ous amm onia, are used directly i n the production of fertilizers.

The sm all proportion of commercially produced ammonia not incor porated into f e rtilizers is used as a corrosion inhi bitor, inthe p u rification of water supp lie s, as a co m p o n ent of household cleaners, and as a refrigerant. It is also used in the pul p and pape r, m e tallurgy , r ubber , food and be verage, textile, and leather industries. Amm o n i a is used in th e manuf actu r e of pharmaceuticals and explosives, an d in the productio n of various chemical intermediates (LeBlanc et al. 1978 ; Sax and Le wis 1987).

5.4 DISPOSAL
Solutio ns of ammonia can be highl y dil uted with water, or alternatively, dil u ted with water an d neutralized with HCl and th en routed t o the sewer sy stem
. The amount released to the receiving stream should not exceed the established lim its for ammonia. Lim ited amounts of gaseous ammonia may be discharged to the at m o sphere. Federal, s t ate, and local guidelines sh ould be consu lted before di sposal. Disposal of liquefied ammonia or of large quantities of gaseous or aqueous ammonia directly into water is not desirable, because of the large a m ou nt of heat generated. This generation of heat could increas e exposure to personnel involved in th e pr ocess. Rec overy of ammo nia from aqueous waste sol u tions is a viable optio n for many i n d u stries (HSDB 2003).AMMONIA 123



### 6. PO TE NTI A L FO R HUMAN EXPOSURE

6.1 OVERVIEW
Amm onia has been identifi e d in at least 137 of the 1,647 hazardous waste sites th at have been proposed for inclusion on the EPA National Priorities List (N PL) (HazDat 2004). However, the num ber of sites evaluated for a m m onia is n o t known. The frequency of these sites can be seen i nFigure 6-1. Of these sites, 135 are located within the United States and 2 ar e located in the Commonwealth of Puerto Rico (not shown).

Amm onia is a naturally

- o ccurring com p ound that is an interm ediate in the glo b al nitrogen c y c l e. It is essential for many bi ologi cal processes and is a central co m pound in all living organism s. Ni trogen is converted fro m atm o spheric N 2 to other forms by different process es. Nitrogen fixation (the process of converting atm o spheric N 2 to NH 3 ) occurs naturally due to biologic a l processe s. Lightning strikes also “fix” atm o sp heric nitrogen , but th e y pro duce nitrogenoxides, n o t ammonia. The current am ount of nitrogen fixation that occurs by industrial processes equals that of natural, terrest rial nitrogen fixation. Both natural and anthropogenic s ources produce a tot a l of approxi mate ly 230–270 m illion metric tons of NH 3 per y ear.
Because of its role in natur a l processes and c y cles, amm onia is found at low concentrations in m o st environm ental media. When amm onia is found at a l o cal concentration that is h i gher than the se background l e vels, it is often a result of hum an infl uence. Amm o n i a is hazardous onl y when e xposure is to hig hlevels. In determ in ing the envir o nmental fate of amm onia, several factors should be c onsidered, the prim ary one being that amm onia is t h e m o st abunda nt alkaline gas in the environm ent. An acid-base reaction betw een water and a m m onia oc curs such th at the dom inant form of ammonia in water, at environm enta lly relevant pHs, is the a m m oniu m ion. In m e dia where wat e r is usually present, such as soil, plants, biological tissue, and water itself, a m m o nia and ammonium are in dy nam i c equi librium

.
Amm onia is a key i n termediate in the ni trogen c y cle, a natural cy cl e that is coupl ed with other im portant biolog ical cycles (i.e., the sulfur cy cle and carbon c y cle). An und erstanding of the role of amm onia in the nitrogen c y cle, at least on a generalized level, is i m portant in determining the environm ental f a te of
amm onia. A si m p lified schem a tic of the m i crobial processes of the nitrogen c y cle that invol ves amm onia can be found in Figure 6- 2. Microorgani sm s perform four processes in the nitrogen cy cle that result inAMMONIA 124 6. NTIAL FOR HUMAN EX POSURE 

### Figure 6-1. of NPL Si tes w i th A mmonia Contamination

1-2 3-4 5-6 7-8 9 16 Derived from HazDat 2004 Frequency of NPL Sites POTE 

### FrequencyAMMONIA 125 6. POTE NTIAL FOR HUMAN EX POSURE 

### Figure 6-2. Simplified Schematic for the Microbial Processes of the Nitrogen Cy cle



### ATMOSPH ERE

NH 4 + 

### NO 2 –



### SOI L , A Q UATIC ENVIRONMENTS Or gani c N (Biota) D e

n

i t ri

f i c

a

t i o

n 

### N 2 

### O

NO N

i t r i f i c

a

t i o

n 

### N 2 

### ATMOSPH ERE

NH 4 + 

### NO 2 –



### SOI L , A Q UATIC ENVIRONMENTS Or gani c N (Biota) Uptake

Ammon i fica ti on D e

n

i t ri

f i c

a

t i o

n 

### N 2 

### O

NO N

i t r i f i c

a

t i o

n 

### Nitrog en Fixati o n 

### N 2



### NO 3 –AMMONIA 126 6. POTE NTIAL FOR HUMAN EX POSURE productio n or transform a tion of amm o n i a: nitrogen f i xation, nitrifi cation, denitri f ication, and
amm onification. As part o f this cy cle, n itrogen g as and oxidized forms of nitrogen are transf ormed and returned to the biological world. Nitrogen fixati on is the process whereby atmo spheric nitrogen gas is converted to amm onia, wh ich is then assi m ilated into am ino acids; it has been found th at there is onl y a sm all proportion of all genera of m i croorganism s thatcan fix nitrogen. Denitrification is the process whereby the nitrogen oxides (i.e., nitrate and n itrite) are reduced under anaerobic conditions t o N 2 and N 2 O, which can escape to t h e at m o spher e . Nitrifi cati on is the biological oxidation of amm o n i acal nitrogen t o ni trate, with nitrite as the interm ediat e . Ammonificatio n (or nitr ogen m i neralizatio n) is the conversion of organic nitro g en into ammonia.

A m m onia ma y be released to the atm o sp here by volat ilization from the following sources: dec ay i ng organic matter; livestock excreta; fertili zers applied to soils; venti ng of gas, leaks, or spills during
co mmercial synthesis, pro duction, transportation, or refrigeration equipm ent fail ure; sewage o r waste water effluent; burni ng of coal, wood, an d other natura l prod ucts; and volcanic eruptions.

Amm onia may be released to water through effluent f

r om sewage treat ment plants, effluent from industrial processes, runoff from fertili zed fields, and r unoff from ar eas of concen trated livestock. This usually occurs when the organic N co mpounds presen t in th ese sources enter the water and are converted microbiologi cally to ammonia.

Amm onia may be released to soils by natural or s y nthetic fertilizer application, animal (including livestock) excrem ent degradation, decay of organic m a te rial fro m de ad plants and ani m als, and indirectly from natural f i xation of atm o spheric nitrogen. In this latter cas e, a mmonia rele a ses c an occur following nitrogen fi xation b yfree-living m i crobes and plants (those that are sy m b iotic nitr ogen-fixin g bacteria), which subsequentl y die and release amm onia (or co m pounds that are converted to amm onia) to the soils.

In the atm o sp here, amm oni a can be rem o ved by rain or snow washout. Reactions with acidic substances, such as H 2 SO 4 , HCl, HNO 3 , or N oxi des (all produced in hig hconcentrations fro m anthropoge nic activities) produce a m m oni um a e rosols, which can unde rgo dry or wet deposition. The gas phase rea c tion of amm onia with phot och e m i cally pr od uced hy dro x y l radicals is thought to con tribute about 1 0 % to the overall at m o s pheric re m oval process. The best esti m ate of the half-life of at m o s pheric a m m o nia is a few day s .AMMONIA 127 6. POTE NTIAL FOR HUMAN EX POSURE In water, amm onia volatilizes to the at mosphere, is transformed to other nitrogenous com pounds, or m ay be bound to materials in the water. Vo latilization is highl y pH-de p endent, and can also depend on other factors such a s te m p er ature , wind speed, and atm o sphe ric a m m onia concentration. Transforma tion of
a m m onia in water occurs primarily by the m i crobial processe s of nitrification and to lesser extents, denitrification. Nitrification y i elds n itr ate and nitr ite anions; the f o rmer speci es can be responsible for methem oglobinem i a in human infants if the contam in ated water is ingested. Rem oval of amm oniu m from water ca n also occur by adsorption to sediments or suspended organic materi al.
In soil, amm o nia may either volatilize to the atm o sphere, adsorb to particulate matter, or unde rgo microbial transformation to nitrate or ni trite anions

. Uptake by plants can also be a significant fate process. Amm onia at natu ral concentrat ions in soil is not believed t o have a ver ylong half-life. If
a m m onia is d i stributed to s o il in large concentr ations (e.g., followin g an application of an
amm onia- containing fertilizer), the natural biologi cal transform a tio n processes can be overwhel m ed, and the environm ental fate of ammonia will beco m e depe ndent upon th e phy s ical and chem ical properties of
amm onia, until the ammonia concentrat i on returns to background l e vels. Occupational exposure to ammonia may occur in ind u s tries involved in its s y nth esis, form ulation, processing, transportation, and use. Occ upational expo sure to ammonia can also occur during the use of an extensive num ber of cleaning pr oduct s that cont ain amm onia. Farm ers may be exposed duri ng the application of fertilizers co ntaining anhydrous amm o n i a or liqui d ammonia, or manures high in amm onia. Workers at cattle feedlots, poultr y confi n em ent bu ildi ngs, or other i ndustries that have a high concentration of anim al s may also be exposed. Exposure of th e general po pulation t o el evated leve ls of amm onia is m o st co mmonl y from the use of household cleaners that contain a m m onia

. People wh o live near farms or who vi sit farm s during the application of fertilizer thatcontain or rel ease amm onia m ay also be exposed. Pe ople living ne ar cattle feedlots, poul try confinem ent buil d ings, or other areas where anim al pop ulations are concentrated can also be exposed to ammonia, in addition to other gases generated by putrefaction. Amm onia has been identified at 137 out of 1,647 NPL hazardous waste si tes (HazDat 2 004).

6.2 RELEASES TO THE ENVIRONMENT
Amm onia is co mmercially produced f o r many pr ocesses, but m o st production is for agricultur a l uses, primarily crop fertilizer. As a result of m o st it be ing form ulated f o r agricultural practices, ammonia isAMMONIA 128 6. POTE NTIAL FOR HUMAN EX POSURE

co mm only di stributed to th e environm en t during its intended use as a crop fertilizer. Release data generated for the Toxics Release Inventory (TRI) (see Table 6-1) provide detaile d inform ation regarding environm ental releases related to industri a l activ ities, but shoul d be used with caution because onl y certain ty pes of facilities ar e required to report, and data from these reports do not represent an exhaustive list of all commercial releases. It should be noted th at for amm onia, since it is on e of the m o st widely

used agricultural fertilizer chem ical s in the United States, the TRI data represent onl y a sm all fraction of the environm ental release, and do not i n clude releas es that occur during farm ing or other agric u lture practices.

Table 6-1 shows the 2001 TRI releases of amm onia f r om manufacturing or proc essing faciliti es to different environm ental co m p artments. Most of th e ammonia rele a sed to the environm ent from the se facilities was the result of air rel eases, followed by rel eases via underground i n jection. The gr eatest air releases occu rred in the state of Louisiana (12,304, 532 pounds), whi c h was alm o st 2 m illion more pounds released than the second hi ghest releasin g state, Oh io (10,505,480 pounds). Texas released the m o st
amm onia via undergro und injection (15, 014, 490 poun d s), which was m o re than 3 times the second highest releasing state, Louisiana (4,446,211 pounds). For all on-sit e releases, the two states rel easing the
m o st ammonia were the adj acent states of Louisian a and Texas (Louisiana re leased 17,742,736 pounds and Texas released 21,354,611 pounds).

Release of ammonia fro m producti on and processing facilities has changed from y ear to y ear, with
am ounts generally decreasi ng since the early 1990s. Reported air releases have r anged from a high of 254,542,289 pounds in 19 89 to a l o w of 122,057,546 pounds in 2001. Surface water rel eases have ranged from a high of 48,138,279 pounds in 1990 to a l o w of 6,621,166 pounds in 2001. Land releases (surface releases) hav e shown a similar trend, with the hi ghest am ount (17,782,641 po unds) released in 1990, and the lowest amount ( 2 ,868,728 pounds) released in 1999. The gener a l trend is that less and less amm onia has been released to the envir onm ent each y ear, such that th e total am ount released in 2001 (158,521,046 pounds) was less than a third of the am o unt released in 1990 (548,828,735 pounds).

The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list.

In addition to releases rel a ted to agricult ural or ot her anthropogeni c usage, ammonia has been identified in several environm ental co m p art m ents including surf ace water, groundwater, soil, and sedi m ent collected at 135 of th e 1,647 current or f o rmer NPL hazardous waste sites in the United States, and inAMMONIA 129 6. POTE NTIAL FOR HUMAN EX POSURE



### Table 6-1. Releases to the Environment from Facilities that Produce, Process, or Use Amm onia a Reported amounts released in pou nds per year b Number Under- Total on- Total off- Total on and of State c facilit ies Air d Water ground injection Land site release e site release f off-site release AK 7 AL 75 AR 48 AS 1 AZ 18 CA 178 CO 19 CT 28 DC 2 DE 14 FL 72 GA 95 HI 7 IA 60 ID 16 IL 136 IN 82 KS 38 KY 40 LA 78 MA 48 MD 17 ME 15 MI 81 MN 56 MO 55 MS 49 MT 14 NC 101 ND 9 NE 38 NH 15 NJ 67 NM 5 NV 13 NY 71 1,427,01 1 32,428 5 95,950 1,555,39 4 0 1,555,39 4 3,192,61 5 180,70 3 0 57,288 3,430,60 6 145,30 5 3,575,91 1 3,672,62 1 209,12 2 0 372 3,882,11 5 18,078 3,900,19 3 6,920 No data 0 0 6,920 0 6,920 107,96 7 5 0 260 108,23 2 350 108,58 2 6,362,24 0 37,470 41,236 264, 00 4 6,704,95 0 18,728 6,723,67 8

291,92 2 12,899 0 4,019 308,84 0 148 308,98 8 169,07 1 10,035 0 0 179,10 6 8 179,11 4 0 487 0 0 487 0 487 109,35 6 3,804 0 7,937 121,09 7 0 121,09 7 5,646,49 6 148,22 6 293,10 6 124,91 4 6,212,74 2 122,75 5 6,335,49 7 8,291,37 1 171,67 0 0 13,140 8,476,18 1 154,58 2 8,630,76 3 47,492 660 2,059 30,368 80,579 0 80,579 4,686,90 0 133,40 3 0 3,829 4,824,13 2 166,22 3 4,990,35 5 2,705,63 9 5,874 0 182,36 9 2,893,88 2 21,731 2,915,61 3 2,366,35 6 56,440 0 68,423 2,491,21 9 1,108,62 1 3,599,84 0 1,294,43 1 55,681 824,98 4 61,545 2,236,64 1 23,002 2,259,64 3 3,285,06 4 36,461 22,555 270,45 9 3,614,53 9 42,129 3,656,66 8 1,218,86 9 83,020 0 4,000 1,305,88 9 1,483 1,307,37 2 12,304,5 32 917,88 3 4,446,21 1 4,816 17,673,4 42 69,294 17,742,7 36 591,58 9 6 0 0 591,59 5 33,235 624,83 0 482,93 4 25,246 0 18,569 526,74 9 4,587 531,33 6 813,19 8 39,047 0 0 852,24 5 0 852,24 5 1,579,68 0 141,34 6 40,307 68,851 1,830,18 4 12,981 1,843,16 5 1,790,28 8 43,283 0 36,315 1,869,88 6 3,315 1,873,20 1

548,48 5 319,68 5 0 11,624 879,79 4 34,796 914,59 0 4,452,54 0 394,83 7 0 46,552 4,893,92 9 255 4,894,18 4

543,33 2 10,920 0 9,685 563,93 7 0 563,93 7 3,054,43 5 287,55 5 0 30,750 3,372,74 0 18,711 3,391,45 1

305,28 3 17,106 0 88,654 411,04 3 340 411,38 3 804,87 2 245,58 7 0 377,53 9 1,427,99 8 243,32 7 1,671,32 5 128,42 0 551 0 0 128,97 1 966 129,93 7 1,144,70 2 165,64 2 0 0 1,310,34 4 18,406 1,328,75 0 9,780 5 29,497 670 39,952 0 39,952 428,88 0 2,710 0 311,81 0 743,40 0 0 743,40 0 1,387,98 2 61,780 0 8,266 1,458,02 8 1,540 1,459,56 8AMMONIA 130 6. POTE NTIAL FOR HUMAN EX POSURE


### Table 6-1. Releases to the Environment from Facilities that Produce, Process, or Use Amm onia a Reported amounts released in pou nds per year b Number Under- Total on- Total off- Total on and of State c facilit ies Air d Water ground injection Land site release e site release f off-site release OH 136 OK 28 OR 51 PA 131 PR 16 RI 22 SC 68 SD 9 TN 58 TX 209 UT 29 VA 64 1 VT 2 WA 45 WI 83 WV 36 WY 12 10,505,4 80 98,996 2,006,50 0 52,964 12,663,9 40 93,861 12,757,8 01 5,995,91 5 81,112 0 25,716 6,102,74 3 1,850 6,104,59 3 1,769,98 9 43,747 0 106,23 3 1,919,96 9 1,882 1,921,85 1 2,346,40 3 229,26 8 0 13,469 2,589,14 0 23,359 2,612,49 9 1,938,72 7 306 0 0 1,939,03 3 600 1,939,63 3 84,982 3,573 0 0 88,555 0 88,555 2,559,69 4 162,78 2 0 39,741 2,762,21 7 5,627 2,767,84 4 86,361 684 0 225 87,270 29,223 116,49 3 4,865,08 7 487,65 0 0 796 5,353,53 3 78,192 5,431,72 5 5,206,67 5 518,39 6 15,014,3 9 0 199,71 0 20,939,1 71 415,44 0 21,354,6 11

458,19 7 8,800 0 911,30 5 1,378,30 2 503 1,378,80 5 7,866,81 9 93,001 0 35,707 7,995,52 7 129,61 4 8,125,14 1 77,675 42,154 0 0 119,82 9 0 119,82 9 47,582 4,450 0 0 52,032 0 52,032 857,16 5 137,95 6 0 22,488 1,017,60 9 80,200 1,097,80 9 589,02 7 89,624 0 3,107 681,75 8 78,850 760,60 8 961,27 6 758,66 1 14,387 0 1,734,32 4 42,951 1,777,27 5 587,21 9 8,429 239,00 0 6,610 841,25 8 0 841,25 8 Total 2,668 122,05 7,546 6,621,16 6 22,974,2 3 7 3 ,621,04 9 155,27 3,998 3,247,04 8 158,52 1,046 Source: T R I01 2003 (D ata ar e from 2001)

a T he T R I data shou ld b e used w i th c autio n si nce on l y c e rtai n t y p e s of facili ties are req u ire d to report. T h is is not an exha ustive list. Data are rou n ded to n earest w h ol e num ber. b Data in T R I are maximum a m ounts rel eas ed b yeac h faci lit y
. c Post office state abbrev iati on s are used. d T he sum of fugitive a nd stac k releas es are i n clu ded i n rel e ases to air b ya given faci lit y
. e T he sum of all releas es of the chemic al to a i r, land, w a ter, and u n d e rgro u nd in jectio n w e lls. fT o ta l a mo u n t o f ch e mi c al tra n s fe rre d o ff-si te , i n cl ud i n g to p u b l i c lyo w ned tre a t me n t w o rks (PO T W ). VIAMMONIA 131 6. POTE NTIAL FOR HUMAN EX POSURE

groun dwater and soil sam p les at 2 sites in Puerto Rico (HazDat 2004). Furthermore, amm onia is a key interm ediate in nature' s nitrogen c y cle, and considerab le am ounts are released to the environm ent as a result of natural processes. As a result of input s from natural sources and from anthropogenic sources, amm onia con centrations in nature are in dy nam i c equilibrium

. When ammonia is found at elevated concentrations, however, it is usually a result of anthr opogenic acti v ity .

6.2.1 Air Large am ounts of amm onia are released t o the atm o sp here worldwide by dom e st icated farm animals (ApSim on et al. 1987; Asman and Janssen 1987; Bu i j sm an et al. 1 987; Kramer 2000 , 20 02; Ry denet al. 1987). Ammonia em i ssions due to the decay of livest ock m anure are a source for amm onia release in areas that hav e artificially high concentrations of anim als, such as cattle feedlots and poultry

- confinement buildi ngs (Brinson et al. 1 994; Hutchi n s on et al. 198 2; Langland 1 992; Liao an d Bundy 199 5; Olivier et al. 1998; Sunesson et al. 2001). I nGermany , over 90% of the measured NH 3 e m issions originated from agricultural sources (Strogies and Kallw eit 1996). In Russia, esti m ated NH 3 em i ssions from fertilizer applications and livestock s ources accou n ted for 94% of the total N H 3 em issions from all anthropogenic sources (Tsib u lski et al. 1996). The use of high n itrogen content feed for farm a n imals and the trend toward larger feedlots have been responsible for increased em i ssions in develope d countries. The application of fertilizer to soil, as ammonia, amm oniu m co mpounds, or ammonia precursors (such as urea), is a well docum ented source of ammonia relea se to the atm o sphere (ApSim on et al. 1987; Be y r outy et al. 1988; B u ijsman et al. 198 7; Kucey 198 8; Olivie r et al. 1998; Rey nol ds and Wolf 19 88). The rate of
amm onia emi ssion from gr ound sources, such as fresh ly fe rtilized fields and cattle feedlots, is dependent on variables such as the pH, tem p erature, soil characteristics, rainfall, method of a pplication, wi nd speed, etc. (Bouwmeester and Vlek 1981; Brunke et al. 198 8; Denmead et al. 1982; Hoff et al. 1981; Kucey 1988; Nason et al. 1988; R e y n olds and Wolf 1988). Amm onia can volatilize from sewage sludge that has been spread on the surface of the soil (B eaucham p et al. 1978; R y an and Keeney 1975) as wel l as fro m poultry litter (Brinson et al. 1994). In the latter case, co m posted pou ltry litter released far l ess volatile NH 3 to the atm o sphere (0–0.24% of applied) than did fresh poultr y litter (17–23%) (Brinson et al. 1994). In contrast, the crops the m s e lves are ofte n m i nor sources of at m o spheric NH 3 . Harper and Sharpe (1995) dem onstratedalm o st no net atm o spheric NH 3 flux in corn crops, due to their relatively sim ila r e m ission and uptake rates of NH 3 over the growing season.AMMONIA 132 6. POTE NTIAL FOR HUMAN EX POSURE
For m u ch of the histor y of th e Earth, biol ogical activ ity in soil and natural waters was the pri m ary global source of atmospheric amm onia (Dawson 1 977; Dawson and Farmer 1984; National Science Foundatio n 1999), but thi s has changed over the last century

. Cr ut zen (1983) suggested that the decay of organic materi al arisi ng from dead plant, anim al, and m i crobia l biom as s generates most of the at m o spheric
amm onia, wh ile Galbally ( 1985) and Ir win and Willi am s (1988) suggested that dom estic-animal excretions represent the dom inant source of at m o sp heric amm oni a. Lee et al. ( 1997) estim at ed that grasslands co ntributed 40% of the total global NH 3 e m issions, with dom estic anim al wastes contribut ing 42.3% of that. Recent studies, however, provided fairly uniform e s t i m ate s of ~40% of global NH 3 em issions being d u e to excreta fro m domestic anim als (Asman et al. 199 8; Bouw m an et al. 1 997; Olivier et al. 1998). Current measurem ents andestim ates, however, indicate that the amount of ammonia produced as a result of anthropogenic activities is equi valent to the am ount produced by natura l processes (National Science Foundation 1 999).

In addition to livestock-related rele ases, amm onia can be released t o the atm o sp here through the venting of gases during the pr oduc tion, storage, and transport a tion of ammonia, and duri ng its form ulation or incorporationinto secondary prod ucts (Buijsm an et al. 198 7). L o n g pipelines are used to transport
amm onia fro m it s site of manufacture t o agricultural areas where i t is used as fertilizer (Farm Chem ical s Handbook 1987; Kramer 2000; LeBlanc et al. 1978)

. Rele ases to the at m o sphere could occur at pum ping stations and points of transf er along these pipelines, or from leaks. Large refriger a ted tanks are used to store a m m oni a, and release to the environment can occur while venting the press ure in these tanks, or from le aks.

Amm onia can also enter the at m o spher e by volatiliz ati on from the wast e wat e r of industrial processes that involve its pr oduction or use, and from the volatilization from the effluent of waste water treatment plants (Buijsm an et al. 1987; Lan g land 1 992; Roy and Pori cha 1982; Wi lkin and F l emal 1980). Amm onia has been found in the exhaust of autom obile and diesel engines (Asman et al. 1998; Plerson and Brachaczek 1983). Release to the atm o sphere canoccur during th e burnin g of c o al (Bauer and Andren 1 9 8 5 ; Olivier et al. 1998). The latter process, however, is not though t to account for a significant proportion of the total anthropogeni c amm onia r e leased to the at m o sphere ( O livier et al. 1998; Strogie s and Kallwei t 1996).

Natural sourc es of a m m oni a e m is sions to the atm o sp here are volc anic eruptions, forest fires, and the deco m position of nitr ogen ous com pounds arising fro m microbially -fi xed nitr og en (Galbally 1985; Hegg et al. 1987; N a tional Science Foundatio n 19 99). E x cr eta fro m household pets, wild animals, and hum ans are also contributin g sourc es (Asman an d Drukker 19 88; Buijsm an et al. 1987; Crutzen 1983 ).AMMONIA 133 6. POTE NTIAL FOR HUMAN EX POSURE

6.2.2 Water The major point source of releas e to surface w a ters i s from the efflu e nts of waste water-tr eat me nt plants (Barica 1990; Crum pton and Isenhart 1988; Wilki nan d Flemal 1980). Amm onia can enter surface waters through the e ffluent of commercial processes in which amm onia i s used or produced (Effler et al. 2001; Huddleston et al. 2000; Matthews et al. 2000; Roy an d Poricha 1982). Runoff from fertilized farm land and from ar eas of concentrated livestock producti on c an also result in the transfer of ammonia to surface water (Corsi et al. 2000; Ji ngsheng et al. 2000; W ilki nand Flemal 1980). Surface water can absorb
a m m onia dire ctly from the at m o sphere n ear cattl e fee d lots, areas w h ere the local at m o spheric concentration may be hi gh (Fangmeier et al. 199 4; Hut c hinson and Viets 1969). Amm oniu m can also be releas ed to water when N 2 -fixing c y anobacteria ( a lso c a lled blue-green algae) die and are decom pos ed.

6.2.3 Soil
Amm onia ent e rs soil through different processes, prim arily hum an practices (e.g ., fertilizer applications, ani m al husbandry ) , and natural biological processes. Di rect application of fertilizers represent s a m a jor influx of amm onia into soils. Of the tot a l U.S. produ ction of anh y drous amm o n i a, 30% is applied directl y to the soil under pressure ( K ramer 2000). Approxim ately 80% of the U.S. production of amm onia is applied to soil in fertilizer form ulations designed to release ammoniacal nitrogen. Application of natural fertilizers obtained from li vestock excreta will also resu lt in the release of ammo nia to the soil (Asman et al. 1998; Beaucham p et al. 198 2; Hoff et al. 198 1; Oli v ier et al. 199 8). High leve ls of amm onia in soils can result from the deco mposition of ani m al wastes o n cattle feedl o ts or other c onfinem ent ar eas, as well as fro m the la nd disposal of livestock and poultry wast e. A m m oniain soil can also arise fro m the decay of organic m a terial arising from plant, animal, and m i crobial b y pro ducts and bio m ass (Dawso n 19 77; Dawson and Farm er 1984). Microbial fi xation of nitr oge n from the atm o sphere is a natural and continual source of a m m onia in soil, which can be releas ed to soil after the microorganisms die (Galb a lly 1985; National Science Foundati on 1 999).
In nature, the r e are many pathway s for incorporation of a m m onia i n to soil. Natural sources include microbial decom position of dead plants and anim als, and hy dr ol y s i s or breakdo wn of urea and nitrogeno us waste products in animal excretions

. Several species of m i croorganism s can prod uce amm onia by th e fixation of N 2 , and th ese organism s ar e widely dispersed throughout the soil ( A tlas andAMMONIA 134 6. POTE NTIAL FOR HUMAN EX POSURE Bartha 1998; Crutzen 1983); amm onia is released to the soil onl y aft e r these m i cr oorganism s d i e. While several species of m i crobes can perform nitrogen fi xation, this capability woul d not be one that is considered common for m o st m i croorganism s.

6.3 ENVIRONMENTAL FAT E In considering the environmental fate of a m m onia, it is neces sary to e m phasiz e that a m m onia i s very i m portant in nature and in nature' s biological cy cl es. In our lim ited understanding of fluxes between these cy cles, a m m o nia is considered a key interm ediate

. N a ture has incorporated many mechanis ms and “rules” for alt e ring the distr i bution of amm onia through the biologic a l sy stem , as circu m st ances dictate. An in-depth discussion of these phenomena is outsi de the scope of this docum en t; however, it is im portant to understand th at for amm o n i a, all organisms contribute, either directly or in directly, to th e direction and distribution of the various environm enta l-fate process es.
An im portantconsideration that affects the transpor t and partitioni ng of amm o n i a in the envir onm ent is that a m m oniais a base. As a base, the phy s ical and che m ical properties of a m monia are pH-dependent, and thus, environm ental-f a t e processes that in fluence the transport and partitioning of NH 3 will also be pH-dependent. For som e e nvironm ental fate process es , a change in pH may only affect the rela tive rate of a process, while for others, it could change the dir ection or overall result of that process. The influence of pH on the environm ental fate of ammonia will be discussed wher e appropriate. Tem p eratur e is also an im portant con s ideration in th e envir onm ental fate of ammonia. Tem p erature, althoug h to a les ser extent than pH, affects the ammo nia-amm oniu m equilibrium

.

6.3.1 Transport and Partitioning
Atm o spheric amm onia can be readily re m oved fro m th e air b y rain or snow washout (Adam o wicz 1979; Asman et al. 1998; Kum ar 1985). It can dissolve in th e water found in clouds (A sm an et al. 1998; Brim bleco m b e and Dawso n19 84; Spre nger and Bachmann 198 7) or fog (Jo hns on et al. 19 87 ). Amm onia can be rem oved from the at m o sphere through the dire ct absorption by surface wa ters in areas where the local at m o spheric concentration is high ( H utchinson and Viets 1969) and by wet deposition onto soils and surface w a ter s (As m an et a l . 1998; Cuesta-Santos et a l . 1998; Goulding et al. 1998). Uptake of atm o spheric ammonia by di fferent species of plants also occurs (Harper and Sharp e 1995; Naso n et al. 1988; Rogers and Aneja 19 80). Dependi ng o nthe loc a l atm o spheric concentration, h o wever, plants canAMMONIA 135 6. POTE NTIAL FOR HUMAN EX POSURE
also release ammonia to the atm o sphere (Harper and Sharpe 1995 ; Lee et al. 1997; O' Deen an d Porter 1986; Parton et al. 1988). By use of 15 NH 3 , it has been dem onstrat ed that m i ner a ls and dry soil can rapidly and effectively adsorb NH 3 from air containing trace quantities of this gas (Bremn er 1965). A m m onia is t h e predom ina n t basic gas in the atm o sp he re (Allen etal. 1989). A s such, it is capable of rapidl y reacting with atm o spheric H 2 SO 4 , HNO 3 , or HCl, form ing amm oniu m aerosols, which can then undergo dr y deposition (A llen et al . 1989; Irwin and William s 1988).

If released to surface water , amm onia can volatilize to the at m o sphere or be take n up by aquatic plants. The rate of volatilization of amm onia fr om wate r will increase with increasing pH (generally only im portant abo v e pH values of ~7.0) an d t e m p erature, and can be infl uenced b y other environmental factors. Gaseous or liquid amm onia add e d to wate r will increase th e pH of the medium ; the rat e of volatilization may increase dram atically i f large am ounts are released to relativel y sm all stati c bodies of water, such as rice paddies (DeDatta 1995). Agitation w ill also increase the rate of volatilization. Georgii and Gravenhorst (1977) calculated the equilibri um co n centration of amm onia ab ove the Pacific Ocean. Using a constant concentration of 3 pm ol/L, the am monia concentration above th e ocean as a result of increased volatilization was calculated t o change from approxim a t e ly 2.8 to 7 ppb as the pH was increased fro m 8.1 to 8.4 ( a t 25 °C). Volatilization of amm onia fr om flooded rice paddies was found to increase with increasing a m m onia cal nitrogen concentration, pH, te m p erature, an d wind velocity (Bouwm e ester and Vlek 19 81; DeDatta 1995; Tian et al. 2001)

. Ammonia can also be taken up b y aquatic plants as a source o f nutrients (Kem p and Dodds 200 2). In water, adsorptionof amm onia to sediment and suspended organ i c m a terial can be im portant under proper condit i ons (Ankle y et al. 1990). Adsorption t o sedi m ent should increase with increasi ng organic content, increased metal ion content, and decreasing pH. A m m onia, however, can be produced in, and subsequently releas ed fro m, sedi m ent (Jones et al. 1982; Malcolm e t al. 1986). The uptake of amm onia by fish can also occur under th e proper conditions (Hargreaves 1998; Mitz and Giesy 198 5). Amm onia is the final breakdown pr odu ct of nitrogen ous-com pound m e tabolism for catfish, and it is norm a lly released through the gi lls into the surroundi ng water, driven by a concentration gradient. If th e water concentration is abnorm a lly hi gh, the direction of passive amm onia tran sport is reversed.

A co m p lete d i scussion of the factors influencing th e tr ansport and partitioning of amm onia in soil is outside the scope of this do cu m e nt. Adsorptionof amm onia occur s in m o st m o is t or dry soils, andAMMONIA 136 6. POTE NTIAL FOR HUMAN EX POSURE

amm onia is p r edom inantly , but not exclusively , helda s the amm oni um ion. Generally , adsorption will increase with increasing organic- m a tter content of the soil, and will decreas e wit hincreasing pH. Other factors that influence the adsorption of ammonia to soil are the pres ence of m e tal lic ions, the predom inant microbial populations and c o mmunities present, and its rate of uptake by plants. The a m m onia concentration, te m p erature, and wind spe e d can also subtly affect the adsorption process by influencing the rate of vol atilization (Bouwman et al. 1997; Bouw meester and Vlek 1981; B r unke et al. 1988; Den m ead et al. 198 2; Galb ally 198 5; Go ulding et al. 1 998; Hoff et a l . 198 1; Kucey 19 88; Nason et al. 1988; Reynol ds and Wolf 1988; Socolow 1999). To dem onstrate the influence of pH on th e volatilization of amm onia ( w hich, as indi cated above, influences the potential for amm onia adsorption) , amm onia loss
was measured in greenh o u se experiments using soils th at had been adjusted to different pH values. Following th e application of manure to the soil surf ace, ammonia volatilization was found to be 14% of the applied ammoniu m at a soil pH of 6

. 4 (m anure p H =6.4). At a soil pH of 7. 0 (manure pH=7.8), 65% was lost by volatilization (Hoff et al. 1981). In a study of the effects of SO 2 depo sition onsoils, it was found that the threshold pH at which amm onia volatilization from soil was drastically reduced did not occur until the pH was redu ced to between pH 3.5 an d 4.0 (Mahendrappa 1982). This is a relatively unrealistic and unrepresentative pH value for m o st soils; the results, however, indicate that volatilization will be an important process that affect s the trans port and partitioning of amm o n i a in m o st soi l s. Because ammonia, as ammonium ion, is the nutrien t of choice for many plants ( K ramer 2000; Rosswall 1981), uptake of soil amm o nia by li ving plants is an im portant fate process. The rate of uptake by plants varies with the growing season. At norm a l environm e n tal concentrations, a m m o nia does not have a very long residence tim e in soil. It is either rapidl y taken u p b y plants, b i oconverted b ythe m i crobial populati on, or volatilized t o the atm o sp here. Becau se of these processes, and because ammo nia generally exists in soils as NH 4 + (which binds to soils particles), amm oni a does not leach readily through soil; thus, it is rarely fo und as a cont am inant of groundwater (Barry et al. 1 9 9 3 ). In soil , ammonia that results fro m the application of fertilizers is usually f o und i nthe top 10 inches of the soil (Beaucham p et al. 1982). However, nitrate derived from a m m onia may leach to groundwater.

6.3.2 Transforma tion and Degradation 6.3.2.1 Air In air, a dom i n ant fate process for a mmo nia is the reac tion with acid air pollutants

. Form ation of particulate NH 4 + com pounds by reactions with HNO 3 and H 2 SO 4 i s rapid (Bouwm an et al. 1 997; IrwinAMMONIA 137 6. POTE NTIAL FOR HUMAN EX POSURE and Williams 1988). The e x tent to whic h this pr ocess serves as a rem oval mechanism depends on the concentrations of these aci dic com pounds (Goulding et al. 1998). Thus, it is likely m o re i m p o rtant in areas of high industrial activity or a high density of autom obile traff i c, but of lesser i m portance over rural
areas. These amm oniu m com pounds can thenbe removed by dr y or wet deposition. The vapor-phase reaction of amm onia wi th photoc hemically pr oduc ed hy droxy l r a dicals is known to
occur. The rate constants for this reac tion have been d e term ined to be 1.6x 10 -1 3 cm 3 / m ole c ule- sec, which translates to a calculated half-life of 100 day s at a hydr ox y l radical concentration of 5x1 0 5 m o l ecules/c m 3 (Graedel 1978). This pr ocess reportedly rem oves 10% of at m o spheric ammonia (Crutzen 1983). Since
amm onia is v e ry soluble in water, rain washout is ex pected to be a dom inant fate process. The half-life for amm onia in the atm o sp here was estimated to be a few day s (Brim b leco m b e and Dawson 1984; Crutzen 1983; Dawson 1977; Galbally and Roy 1983; Moller and Schiefer decker 1985). The r eaction of at m o spheric a mmonia with acidic substa nces in the ai r results in the formation of a m m oniu m a e rosols that can subsequentl y be r e m oved fro m the atm o s phere by dr y or wet depositi on. In general, dr y deposition pr ocesses predominate wher e there are high am ounts of NH 3 e m is sions; where N H 3 em issions are lower, wet deposition of particulate NH 4 + predominates (As m a net al. 1998).

6.3.2.2 Water In surface water, groundwater, or sediment, amm onia can undergo s e quential transform a tion by two processe s in the nitrogen c y cle, nitrification and de nitrification, which would produce ionic nitrogen
co m pounds, and from these, elem ental nitrogen. T h e ionic nitro g en co m pounds f o rmed fro m the aerobic

- process of nitrification, NO 2 and NO 3 , can leach through the sediment or be taken up by aquatic plants or other organis m s. High concentrations of nitrate in g r oundwater can cause methem oglobine mia in infants when contaminated water i s ingested (Messinga et al. 2003, Pay n e 1981). Elemental nitrogen formed from the anaerobic process of denitrification is lost by volatilization to the atm o sp here.
In water, amm onia is in equilibri um wi th the amm o n i um ion, NH 4 +

. The amm o nia-amm oniu m ion equilibrium is highly dependent on the pH and, to a lesser extent, the tem p eratur e of the medium

. In acidic wat e rs and neutral waters, the e quilibrium favors the amm oni um ion.AMMONIA 138 6. POTE NTIAL FOR HUMAN EX POSURE
6.3.2.3 Sediment and Soil In soil, amm o nia can serve as a nutrient source for plants, which can be taken up b y plants an d microorganisms and converted to organi c-nitroge n co m pounds. Ammonia in soil can be rapidl y transform e d to nitrate b y th e m i crobial populatio n th r oughnitrification (Atlas and Bartha 199 8; Pay n e 1981). The nitrate form ed will either leach throu gh the soil or be taken up by plants or other microorganisms. Very high localized concentrations of a m m onia, such as those that m i ght occur after a spill, or an excessive application, of ammonia-c ontaining fertilizers can be toxic to plants, other organisms, or m i crobiota, which if inhi bited or ki lled, will result i na decrease of the rates of any related nitrogen trans f ormation processes. Under these conditions , other fat e processes dictated by th e phy s ical and chem ical properties of amm onia will dom inate until the ammonia concentrati on returns to a background level. These phy s ical and che m ical proc esse s include binding to soil particles (including organic carbon) or undergoing volatilization to the atmosphere.

6.3.2.4 Other Media No data exist for the transformation or degradati on of amm onia in other media, apart from biological tissues. Thes e transform a ti ons are discu ssed in m o re detail in Chapter 3.

6.4 LEVELS MONIT O RE D OR ESTI M ATED IN THE ENVIRONMENT In discussing the concentration of amm o nia m onitored inthe envir o nment, it is im portant to consider both
amm onia andits conjugate acid, the amm oniu m ion. Independent determ in ation of these co mpounds cannot always be achieved. In an anal y s is of th e literature, it is diffi cult to separate aqueous ammonia concentration from aqueous a m m onia- a mmoniu m co ncen trations unless the investigators m a de a special effort to determine the am o unt of un-ioni zed amm oni a. In this section of th e doc ument, amm o nia will refer to the ammonia and amm oniu m concentration, and un-i onized ammonia will refer speci fically to the
a m m onia con centration.

In the atm o sp here, a m m oni a can exist in its gaseous st ate, be dissolved in rain, th e water of fog, or clou ds, or be found a s a m m oniu m in particulates and aerosol s. These spec ies can be an a l y zed separately

. For this reason, atm o spheric ammonia concentrations reporte d in this document will refer to the concentration of gaseous ammonia, and not to the con centrations of amm oniu m com pounds.AMMONIA 139 6. POTE NTIAL FOR HUMAN EX POSURE

6.4.1 Air
Amm onia has a worldwide atm o spheric backgroun d c oncentration. Esti m a te s of the average global
amm onia con centration are approxim a tely 0.6 –3 ppb ( A neja et al. 1998; Crutzen 1983; Georgii and Gravenhorst 1977). Dawson and Farm er (1984) repo rted that the average concentration of ammonia in the southwestern United States is 0.9 ppb, which m ay be considered a representa tive background value because at th e site of these mea s ure m ents, the prev alent winds ca me fro m the Pa cific Oc ean a nd there were no known urban or a g ricultural ammonia sources n earby

. Fangmeier et a l . (1994) reported si m ilar values in a review of effect s of at m o spheric a m m onia on vegetation. Values m e a s ured at sea o r at high altitude provi ded a background range of 0.06–1. 0 ppb (n=9 reports). When atm o spheric ammonia levels have been determ ined to be above background leve ls, the measur e ments can often be correlated with industrial, agr i cultural, or other activities that m i ght occur in nearby areas (F ang m eier et al. 1994).

The concentrations of amm onia in the at m o sphere v ary across the United States, with concentrations being higher in the Midwest as co m p aredto either the west or east c o asts. Bas e d on early data on the concentration of ammonia in rain, Lau an d Charls on (1 977) determ ined a trend fo r the atm o spheric
a m m onia con centration acr oss the United States. The esti m ation of at m o spheric a m m onia con t ent increased progressively starting from the east coast to the m i d-west and on t o the western st ates. Upon reaching the Pacific coast, the at m o spheric amm onia c oncentration decreases. Itshould be noted that the values obtained in this study (ppt levels over the eastern seaboard and pacific coasts, and low ppb levels in the m i dwest and western United Stat es) tend to be lower than those determ ined by m o re recent experi m e nts. For exam ple, Aneja et al. ( 1998) m easur e d concentrations of both NH 3 and NH 4 + at Mount Mitchell (North Carolina) o v er 2 y ears; concentrations averaged 1–2 pp b. Fang meier et al. (1994) provided atmospheric amm onia values derived from five studies conducted i nth e United States, with an average NH 3 concentration of 3.3 pp b. The general c onclusion of Lau and Charlson (19 77) h o wever, appears valid, and is indicat ive of the tren ds found for th e amm onia concentrations in the atm o sphere. At m o spheric a m m onia con centrations ar e expected to be highest ne ar intense agricultural or li vestock production areas because o f amm onia emissions from f

e rtilizer and anim al ex creta, respecti v ely. Lower concentrations are generall y expected in m o r e i ndustrialized areas because of di minished sourc es of agricultural emissions and the atm o spheric reaction of amm onia with acidic co mpoun ds kn own to be produced ini ndustrial em issions and autom obile exha ust. Data su mmarized in Fangmeier et al. (1994) indicate that industrial regi ons m ay have significan t ammonia concentrations, but these are or ders of magnitude lo wer than concentrations in regions with so m e agricultural applications. ConcentrationsAMMONIA 140 6. POTE NTIAL FOR HUMAN EX POSURE
determ ined near industrial sources in Germ any (10.3– 39.1 ppb) wer e in the sam e order of m a g n itude as concentrations near m anure heaps (89 p pb), b u t were three orders of magnitude lower than emissions near pigpens (4. 7 x 1 0 4 pp b).

Ground-level amm onia con centrations taken at urba n Ham p ton and rural Langley, Virginia, r anged from 0.2 to 4.0 and from 1.5 to 4

. 0 pp b, respectivel y , in th e fall of 197 9 ( H arward et al. 198 2). Amm onia concentrations obtained in December of 1979 on L o n g Island, New York, ranged from approximately 80 to 200 nmol/m 3 (1.9–4. 8 pp b) (Tann e r 1982). Th e ground level amm onia co ncentrations in Clarem ont, Los Angeles, and Anahei m, California, were <25 ppb (Russell et al . 1988). In Riverside and Rubidoux, California, areas near dairy feedlots, the ground level amm onia con centra tions were 37–132 ppb and approxim a tel y10–100 ppb, respectively

. Rural-area c oncentrations, however, in Massa chusett s and New York were co nsiderably lo wer (0.2–1.1 ppb) (Fangm eier et al. 1994).

The am bient concentrations of amm onia determ ined at Whiteface Mountain, Ne w York, in 1982 ranged from approxi mately 0.3 t o 5 pp b, with th e hourl y m e dian and m e an values both d e term ined as 2.2 p pb (Kelly et al. 1 984). Amm o nia concentrations in rural Thurber, Nevada, ranged from approximately 0. 5 to 2 pp b (Farmer and Dawson 198 2). In th e atm o sphere over the worl d' s oceans, ammonia concentrations ranged from approxim a tely 0.2 8 to 5. 6 ppb (Georgii and Gravenhorst 197 7).

Several inves tigators have studied the seasonal variati on of amm o n i a concentrations in the atm o sphere. In Ham p ton, Virginia, the groun d level amm onia con centrations during th e spring and summer were 10 and 1 pp b, respectively (Levine et al. 1980). The d i fference in concentration may have been due to volatilization of amm onia r esulting from springtim e application of fertilizer in nearby agricultural areas. In Warren, Michigan, the av erage ammo nia concentrations m e asured duri ng the s u mmer, fall, winter, and spring were 0.85, 0.37 , 0. 1 0 , and 0

. 16 p pb, respectively. The difference in concentrations was attributed to fluctuations in e m issions fro m livestock excreta, si nce natural ammonia e m is sions are m u c hhigher in the summer than in the wi nter (Cadle 1985; NRC 19 79). Addi tio nally, in col d er weather, microbial activity would be expected to decrease, and thus, amm onia e m is si ons from the decay of organic matter would also be expected to decre ase. A m m onia e m is si ons from ani m al excr etions also fluctuate with the time of day ( B eaucham p et al. 198 2; Br unke et al. 19 88).

The concentration of ammonia in th e atm o sphere decr eases with al titude. Levine et al. (1980) found that
an amm onia concentration of 10 ppb m e asured at gr ound level dec r eased to a co ncentration of 1.5–3 ppb at a height of 10 km

. In a historical m odeling study on the European production of a m m onia, levels basedAMMONIA 141 6. POTE NTIAL FOR HUMAN EX POSURE

on amm onia release fro m livestock, fertilizer productio n and application, hum an and dom e stic animals, and sewage sludge resulted in average atm o spheric ammonia concentrations ranging from 0.6 to 1. 4 pp b for 197 0 and from 0.7 to 5. 6 pp b for 1 9 8 0

. The greatest increase occurred between 1950 and 1980 , when sy nthetic fertilizer applicati on and high nitrogen conte n t feed grains were widely used (Asman and Drukker 1988). The ammo nia concentration over a field duri ng th e application of gaseous amm onia fertilizer was as high as 300 ppb (Denmead et al. 198 2). Over cattle feedlots, atm o spheric ammonia concentrations have been measured at 520–2 ,16 0 pp b (Hutchinson et al. 1982).

6.4.2 Water
The concentration of ammonia in th e Ochlocknee Rive r at the head of Ochlock n ee Bay , Flor ida, ranged from approxi mately 31 t o 43 p pb, and concentrations of appro x imately 8. 5 to 2 6 pp b were determ ined at the m outh of the bay (Seitzinger 19 87). The con centration determ i n ed in the Ochlocknee River is consistent with levels reported fo r un poll u ted tropical rivers (Mey b eck 1982). T ypical amm o nia levels in the South Sk unk River, I o wa, upstream from a m uni cipal sewage-treatment facility were <1 ppm (Cru m p ton and Isenhart 1988). Downstr e am of the facility , ammonia levels peak ed at approxi mately 16 m g /L (16 ppm ), with levels of un-io n i zed amm onia ranging fro m <1.0 to 2. 2 ppm . The levels of undissociated amm onia were directly rel a ted to pH flu c tuations in th e river. The authors did n o t discuss why the upstr eam concentration was so high. In the s a m e study , it was noted that amm oniu m and unionized ammonia concentrations fluctuated in a diur nal pattern in th e river, with peaks in amm onia (approxim a tely 1 m g /L) occurring aroun d no on, and l o w concentrations (0.5 m g /L) occurring usually after m i dnight (Crum p ton and Isenhart 1988). The meanammon i a concentration in th ree Illinois rivers ranged from 0.28 m g /L (0. 28 p p m ) to 6.08 m g /L (6.0 8 ppm ). The lower values were a ssociat ed with agricultural sa m p ling points and the higher values we re associ ated with urban sam pling points (Wilkin and Flemal 1980).

The amm onia concentration m e asured in Ham ilton Harbour, Ontario, Canada was ty picall y 0

. 1–3 m g /L (0 .1

– 3 p p m ) inth e early 1 9 8 0 s . Th is body o f water is u sedfo r water tran sp o rtatio n(e.g ., b o a t an db arg e traffic), as a source for industrial cooling water, and as a receptor for waste wat e r disposal (Snodgrass and Ng 1985)

. Measurements made a few years lat e r (1987–1988), in contrast, showed m u ch lower concentrations. Measured concentrations, however, were still great er than the International Joint Co mm ission objective of 2 0 : g/L (20 ppb) for m o re than half the y ear, and concentrations ofte n exceeded the chronic to xicity thresho l d of 3 00 : g/ L (300 ppb) ( B arica 1990). This work r e ported that ammoniaAMMONIA 142 6. POTE NTIAL FOR HUMAN EX POSURE loadings int o Ham ilton Har bor had decreased over the late 1970s and 1980s, and the measur e d concentrations m ay reflect that change. Some representative data regarding the concentrati on of ammonia in groundwater indicate that natural concentrations are generall y low, but that agricultura l practices can, at times, leadto higher levels. Low levels of amm onia have b een f ound i n groundwater wells under cattle and poul try feed lots, and in shallow wells. Wells 3–6 m deep showed little variati on in amm onia concentration over a 3- year period where vary ing am ounts of chicken manure were spread over agricul tural plots, except when excessive
am ounts (54– 179 m e tric to n/ha) were ap plied (Liebhardt et al. 197 9 ). Groundwat er levels of ammonia were also determ ined in an area in Idaho that ha d prev iousl y been n o ted as havin g hig hnitr og enous co m pound co ncentrations in the water. In this study, ammoniu m co ncentrations varied from 2

. 5 pp b in a
m

unicipal drinking water well to 3.25 p p m in a deep , private well (Wicherski 2000). S h allow wells in North Carolin a had ty pical amm onia con centrations of 0.1– 1 p p m , which were independent o f land use, plant ty pe, and am ount of fertilization (Gilliam et al. 1974). Water sam p les fro m wells on four school y ards i nMichigan th at used septic tank sewag e sy stems had amm onia co ncentrations ranging from 0 to 7 33 ppb (Rajagopal 1978). I nthe Netherlands, the amm onium concentration detected in sam p le cups buried 1. 2 m in the gro und near forests ranged fro m 0 to 2.3 ppm (Krajenbrink et al. 198 8), b ut no a m m onia w a s detected in deeper well s ( 12.6 m e ters) analy zed in this study

. T h e high adsorp tivity of
amm oniu m to soil and th e rapid conver s ion of amm o nia to nitrate b y m i crobial action are both consistent with the usual findin g of v e ry low a mmonia concentrations in gro undwater.

Amm onia was m e asured in rain and sno wsam p les from three sites in north ern Michigan in 1978 –19 79. Concentrations ranged from 23.8 to 3, 500 ppb, with mean values f o r each site of 816, 572, and 632 ppb, respectively

. Concentrations were gener a lly greatestin the spring and fall and w e re lowest during the winter (Mung er 1982). Ammonia concentrations in bulk precipitation o b tained in the Netherlands had median values ranging from 1.33 ppm i nocean areas to 5.09 ppm in bodies of water near he avily agricultural areas (Schuurkes et al. 1988).

A m m onia co ncentrations in the influent to sewage- treatm ent plants, and thus the effluent from sewer sy stems, ty p i cally range fr om 10 to 20 p p m (Englande et al. 1978; Hauser 1984; U.S. Army C o rps of Engineers 1980). Waste water-treat men t plant efflue nt is one of the few ty pes of point sources of
a m m onia e m i ssions to surface w a ter. In a study of se veral wast e w a ter-treat men t plants, eight of nine plants exceed ed the guideline a m m onia concentration (0.5 m g /L), with measur e d m e dian val u es at these sites ranging from 0.08 to 15 m g /L (0.0 8–15 ppm ) (Englande et al. 197 8).AMMONIA 143 6. POTE NTIAL FOR HUMAN EX POSURE

No data were located in the available literature regard ing amm onia concentrations in drinki ng water. This may be attrib uted to th e rapid reaction b e tween ammo nia (and ammonium ) and the chlorinatin g agents used in water treatment plants (Morris 1 978).

6.4.3 Sediment and Soil A 4-y ear study on amm onia levels in the soil (0–1 0 c m deep) of an open field (s am ples obtained in early May of each y ear) showed that a m m onia concentrati ons ranged from 1 to 5 ppm ( B eau cha mp et al. 1982). The day after application of a slurry of li quid cow m a nure, the soil concentration ranged from 2 to 3,34 9 ppm

. Five day s after application, the concen tration of ammonium ranged from 2 to 84 8 ppm

. The greatest ammonia concentration was in the upperm ost 4 cm of soil.

Amm onia was found at 1 3 7 of 1, 647 ha zardous waste sites on the NPL of highe st priority site s for possible rem e dial action (HazDat 2004).

6.4.4 Other Environmental Media
The amm onia concentrations measured in the plum es of seven forest fires in the western Unite d States ranged from 7 to 1 30 ppb; the median value of the 13 measurements was 37 ppb (Hegg et al. 1987, 198 8). Fangmeier et al. (1994) rep o rted a slightl yhig h er va lu e for sm oke from a forest fire in Canada, 250 ppb

. Amm onia has been found i nthe exhaust of autom obile and diesel engines (Plerson and Brachaczek 1983). Amm onia has also been determ ined to be a co m ponent of tobacco and cigarette sm oke (Sloan and Morie 1974).

6.5 GEN E RAL POP U LATI ON A ND OCCUP ATIONAL EX POSURE
The m o st pro b able routes b y which the general popul ati on is expos ed to ammonia are by the i nhalation of
amm onia that has volatilized from co mmon household cleaning products and thr ough dermal contact during the us e of these products. Inhalation exposu re to amm onia by som e mem b ers of the rural populati on may occur for those who are near agricultural areas during the fertilizer-application period, those near animal fe edlots or confinem e n t areas, and those who apply anhydrous a m m onia or a mmoniaproducing fertilizers to fields. There is also the po ssibility for exposure to amm o nia via water and foodAMMONIA 144 6. POTE NTIAL FOR HUMAN EX POSURE ingestion. If untreated surface w a ter is i ngested, the average uptake would be 0.36 m g /day (assum i ng an amm onia con centration in untreated water of 0.18 m g /L and a consum ption of 2 L/day ) (WHO 1986). Food i ngestio n could lead t o an exposure to amm onia, primarily fro m the use of various ammonium salts as stabilizers; the estim atedexposure from th ese food additives is 18 m g /day (W HO 1986). In the National Occupational Haz ard Survey (NOHS) of 1972–1974, it was statistically estimated that 2,52 4,67 8 wo rkers are exp o sed to ammonia in th e United States (RTECS 1988 ). According to the National Occupational Exp o sure Surve y (NOES), in 1989, 681 ,78 0 workers (231, 208 of whom were fem a le) were estimated to be exposed to amm onia (NOES 1989). A correlation of data from the EPA Air Toxics Em ission Inventor y with indus tri a l source codes (SIC codes) s hows that volatile em issions of
amm onia ar e associat ed wi th 212 different industrial classifications (EPA 1987b)

. Workers in swine- and poultr y - confine m ent buildings may be exposed to elevated levels of a m m onia (Attwood et al. 198 7; Croo k et al. 199 1; Donham and Popendorf 19 85; Jones et al. 198 4; Leon ard et al. 1984; Liao an d Bundy 19 9 5 ). Average amm onia con centrations in the air of the se buildings d e pend on
num erous factors; represen tative values ranged from 0.28 t o 42.2 ppm (280–42,200 ppb) (Attwood et al. 1987; Fangmeier et al. 1994), but in buil dings with sl ow ventilation rates, concentrations exceeded 80 ppm (Liao and Bundy 1995). It s hould be noted that workers in th ese buildings may also be exposed to other m a te rials in addition to amm onia, includi ng particulate mat e rial (s mall dessic a ted m an u re particles), en dotoxi n, and others which may lead to c o m b ined exposures.

Amm onia lev e ls in air at an ammoniu m phosphate fertilizer-production plant ranged from 3 to 75 ppm (3,000 –75 ,00 0 pp b) (NIOSH 1987). In a Finnish pl y w ood factor y , s hort-term amm onia concen trations during the m i xing of urea-formaldehy de glue were 50–70 ppm (50,000– 70, 000 p pb) (Kauppin e n 1986)

. Amm onia co ncentrations at 42 facilities using a blue-l ine printing s y stem were 1–40 ppm (1,000– 40,0 00 p pb) ( T uskes et al. 1988). Work ers at coal-g asification unit s m ay be exp o sed occupationall y to
amm onia (Jin et al. 1999; Van Hoesen et al. 1984). Workers at ammonia transportation and storage facilities can be exposed to amm onia during the transf er between facilities, fro m the venting of built-up pressure in tanks, and during leaks or spills.

Farm ers can be exposed to amm onia wh en appl y i ng f e rtilizer. The amm onia co ncentration over a field during the application of gaseous anhy dr ous amm onia fertilizer was as high as 213 μg/m 3 (30 0 pp b) (Den m e ad et al. 1982)

. W o rkers at cattle production f acilities (e.g., feedlots, farms) and those who work under condi ti ons where volatilization from animal ex cr eta would be enhanced may be occupationall yAMMONIA 145 6. POTE NTIAL FOR HUMAN EX POSURE exposed to ammonia. Over cattle feedlots, at m o sphe ric amm onia concentrations have been measured at 373– 1,5 40 μg /m 3 (520 –2,1 60 p pb) (Hut chinson et al. 1982). Exp o s ure to amm o nia can occur b y inhalation in th e liquid m an u re-storage facilities of sw i n e-confinement buil d ings. Am bient air l e vels have been measured at up t o 50 ppm (50,000 ppb) i nthese facilities (Do nham et al. 1982).

6.6 EXPOSURE S OF CHILDREN This section focuses on exposures from conception to maturity at 18 y ears in humans. Differ e nces fro m adults in susceptibility t o hazardous substances ar e discussed in Section 3.7 Chil dren’ s Susceptibility .
Children are not sm all adu lts. A child’s exposure m ay differ from an adult ’ s exposure in m a ny way s . Children drink m o re fluids, eat m o re food, breathe m o re air per kilogram of body weight, and have a larger skin surface in proportion t o their body vol um e. A child’ s di et often differs fro m that of adults. The developing hum an’ s s ource of nutrition changes withage: from pla cental n ourishm ent to breast m ilk or form ula to the diet of ol d e r children who eat m o re o f certain ty pe s of foods thanadults. A c h ild ’s behavior and lifesty l e also influence exposure. Childr e n crawl on the floor, p u t th ings in their m ouths,
so m e times eat inappro p riate things (suchas dirt or pai n t chips), and spend m o re tim e outdoors. Children also are closer to the gr ound, and th e y do not u se the judgm ent of adults to avoid hazards (NRC 1993).

Three recent studies focused on the ex posure of children to ammonia or the effects that exposure m ay have on children, all of which noted littl e effect on the children’s health (Go m zi 1999; Gom z i and Saric 1997; Suh et al. 1992)

. On e of the studi es focused on the respiratory effects am o ng peop le livi ng near a fertilizer plant, another study investigated the effects of living in anurban vs. rural area, and a third study investigated the general eff ects of acid a e rosols on ch ildren living in a se m i -rural area. In general, these studies noted that exposure to low levels of ammonia ha d ver y little im pact on the health of the children. The studies did find th at other factors, such as parental sm oking, h a d m o re profound effects on the children’ s respiratory health. One study com p ared the effects of livin g near a fertilizer factory on the respiratory health of 8–9- y ear-old children (Gomzi and Saric 1997). Th e s tudy f ound that the air quality near a fertilizer plant was within acceptable li mits for m o stof the m e asu rem e nt peri od, with onl y a f e w fluctuations beyond acceptable lim it s. While these fluctuations correlated somewhat with health para meters me asured on children living nearby , the rate of respiratory disease w a s m o re infl uenced by indoor air pollution sources than byAMMONIA 146 6. POTE NTIAL FOR HUMAN EX POSURE
outdo or sourc es. No significant effect was observed due to exposur e to amm onia at the concentrations seen in the study

.
A second study of 223 ch il dren (8–1 0 y e ars old) livin g in Croatia f ound that in d oor air quality had a slightly greater effect on re spiratory health in urba n areas co m p aredto those living in rural areas (Go m zi 1999). The d i fferences, however, were not significan t. The stud y f ound no i n flu e nce of ammonia on th e children’s respirator y health , but did f i n dthat parental sm oking ha d a significant negative impact on their respiratory he alth.

A third study evaluated SO 4 2- and H + exp o sure to 24 c h ildren (ages were not prov ided) livin g i n Uniontown, P e nnsy l vania (Suh et al. 19 9 2 ). This study did not f o cu s on ammonia exposure per se , but on other airborn e contam inant concentrations in aerosols found out do ors, indo ors, and b y personal m onitors. It sought t o determ ine how personal exposures to these aerosols corr elated with indoor and out door concentrations. A m m onia concentrations were me asu red in order to asses s their potential for neutralizing H + found in a e rosols. Amm onia concen trations were found to be hi ghest near the children (det ected by the personal m onitors), followed b y in d oor concentra tions, and we re m i nim a l o u tdoors. It was proposed that a large proportio n of th e H + found i nindo or aerosols are neutralized b y NH 3 , and would thus lower the children ’ s exposure to a c id aerosols. The authors n o ted that m o re research is needed to full y m odel the influence of factors, including NH 3 , o nind oor acid aerosol exposure.

6.7 POP U LATI ONS WIT H POTE NTIALLY HIGH EXPOSURE S Workers in industries that commonly use a m m onia, es pecially if there are no adequate safety and/or venting s y ste m s, may be at risk for pote n tiall y hig h e xposure to ammonia. Exam ples of these m i ght include farm workers who are em ploy ed in in adequately -ventilated, enclosed spaces with high concentrations of animals. Other exa m pl es incl ude workers who process a m m oni a or transfer it from shipping cont ainers to pipelines. The general populati on is at risk t o hig hlevels of exposure if cleaning products cont aining concen trated solutio ns of ammoni a are used in sm all, enclosed, or unventi l ated
room s.AMMONIA 147 6. POTE NTIAL FOR HUMAN EX POSURE
6.8 ADE QUA C Y OF THE DATA BASE Section 104(i )(5) of CERCLA, as amended, directs the Adm i nistrator of ATSDR (in consultatio n with the Ad m i nistrator of EPA and agencies and program s of t h e Public Health Service) to asses s whe ther adequate inform ation on the health e ffec t s of a m m onia is available. Where adequate inform at ion is not available, AT SDR, in conjunction w ith the National Toxicology Program ( N TP) , is required to assure the initiation of a program of resear ch designed to determin e the health effects ( and techniques for developing methods to d e term ine such health effects) of amm onia. The following categories of possible data needs have been identified by a j o int te am of scientists from ATSDR, NTP, and EPA. They are defi ned as substan ce-specific i n form ational needs that if met would reduce the uncertainties of hum an health assessment. This definition shoul d not be interpreted to m e an that all data needs discussed in this secti on m u st be f illed. In the future, the id entified data needs will be evaluated and prioritized, and a substance-sp ecific research agenda will be proposed.

6.8.1 Identification of Data Needs
Ph y s ical an d Chemical Properties. The phy s ic al and chem ical properties of amm onia have all been well documented, and there do no t appear to be any data needs in this area. Production, Import/Export, Use, Re lease, and Disposal. The large amounts of ammonia produced inn a ture and in h ousehold pro ducts indi cate that the risk f o r hum an exposure to ammonia exists. Data regarding the co mmercial p r oduction , dis posal, and us e of amm onia are well understood. Data regardin g the pro ducti on of amm o n i a b y natural organisms, and its glo b al and regio n al concentrations are not as well understood, nor are the influences of different process str a tegies on livestock amm onia emissions. This inf o rmation wou l d be useful i ndeterm ining the contribut ion of anthropo geni c amm onia to the global bu dget of this c o m pound, wh ich would hel p in determ in ing the hum an influence on the gl obal c y cle. According to the Emergency Plannin g an d Comm un ity Right-to-Kn ow Act of 19 86 (EPCRA), (§313) , (Pub. L. 99-499, Title III, 9313), industries are require d to subm it release information to th e EPA. The TRI contains release information for 2001. T h is database is be updated y early and provides a m o re reliable estimate of industri a l productio n and em ission.AMMONIA 148 6. POTE NTIAL FOR HUMAN EX POSURE
Environmental Fate. Since a m m o n i a is a key interm ediat e inthe nitrogen c y cle, the environm ental fate of amm o nia should be interprete d interm s of its involvem e nt in this c y cle. Inform ation available on the environm ental fate of ammonia is su fficient to defi ne the basic trends, and data are availabl e regarding the direction of changes in these trends resulting fro m changes in the key variables. There are many subtle facets of the fate of a m m onia in the envir onm e n t that depend on nature and its c y cles. Thus, accurately predicting the environm ental fate of a mm o nia is not possible with our present knowledge. An understanding of the environm ental fate of amm o n i a is im portant when consid ering that human contributi on t o the glo b al ammonia budg et has grow n over the y ears. A co m p lete understanding of th e environm ental fate of ammonia will then allow an understanding of any changes that m i ght occur from the role of amm onia in the nitrogen c y cle. Since a ll living organis m s depend onthe nitrogen cy cle, either directly or indirectly , th is i n form ation would allow any decisions concerning amm onia to be made in an inform ed andprudent m anner. Bioavailabilityfrom En vironmental Media. The bioavailability of amm o nia from air and water has been examined rather extensivel y i nanimals. Bioavailability fr om soil has n o t been studie d , although it is not a like l y source of exposure.
Food Chain Bioaccumulation. Ammonia is a naturally

- o ccurring com pound and a ke y interm ediate i nthe nitrogen cy cle. Since it is continually recy cled in the environm ent, bioaccum u l a tion, as it is usually considered, does not occur. Thus, data on this process are not warr anted. Exposure Levels in Environmental Media. As an interm ed iate in the nitr ogen c y cle, ammonia is naturally present in environmental media

. Measure me nts of ammonia in environmental mediaare sufficient to d i stinguish betw een background concentr ati ons and elevated concentrations. Data regarding
a m m onia lev e ls in soil sam pl es, however, appear not to be as complete as the database for ai r and water.

Determ ining low level concentrations of at m o sphe ric a mmonia in the presence of a m m oniu m s a lts is difficult. Recently, investigators have been establishi ng new m e th ods for the analy s is of amm onia in the presence of ammoniu m co m pounds (see Chapter 7, Anal y t ical Methods). If highl y accurate values for low levels of amm onia ar e necessary , then a re-evalu ation of older literature values m i ght be necessary

. Exposure Levels in Humans. Data regarding th e exposure levels of amm o nia are sufficient for understanding the sources and approxim a te m a gnitudes of hum an exposure. Quan titative m onitoring dataAMMONIA 149 6. POTE NTIAL FOR HUMAN EX POSURE for specific ci rcu m stances, occupations, or events , as reported in the current literature, m i ght be considered to be lacking. Monitoring data for a m m o nia concentrations in the average household are generally ade quate. Reports indicate that while b ackground ind oor concentrations of chem icals such as
amm onia are so m e times higher inside th an outside the hom e, the levels of expos ure do n o t ge nerally have effects on residents. This exposure, ho wever, would be expected to be hig h er when ammonia-containing cleaning prod ucts are used, or when othe r amm onia-co ntaining com poun ds are used in the h ous ehold, and effects under these conditions would depend on th e exposure concentration and duration. Exposures of Children. Data regarding th e expo sure levels of amm onia to children were not extensive enough for evaluating the sour ces and approxima te exposures to childr e n. As was f ound with data in the section for Exposure Levels in Hum a ns above, quantitat i ve m onitoring data m i ght be considered lacking. A few recent studies indicate th at exposures to, and effects of, amm onia on children are generally minim a l, and do n o t infl uence the respirat ory health of the children studied. However, m o re studies could be conducted to verif y thes e findings.

Child health data needs rel a ting to susceptibility are discussed in Section 3.12.2 Identification of Data Needs: Children’ s Susceptibility

. Exposure Registries. No exposure registries for amm onia were located. This co m pound is not currently one of the com pounds for whic h a subregis try has been established in th e National Exposure Registry (Agency for Toxi c Substances and Disease Regi stry 1999). The compound will be considered in the future when che m ic al s e lection is m a de for subreg i s tries to be established. The information that is
am assed in the National Exposure Registry facilitat es the epidem iol ogical r esear ch needed to a ssess adverse health outcom es that may be related to expos ure to this co m pound.

6.8.2 Ongoing Studies The Federal Research in Progress (FEDRIP 2003) da tabase and Current Resear ch Inform atio n Sy stem (CRIS) database (US DA 2 003) pr ovide additional in f o rmation obta i nable from a few ongoing studies that may fill som e of the data needs identified in Sec tion 6.8.1. These studies are su mmarized below and in Table 6-2. M o st of the stu d ies are investigating appr o aches that redu ce exposures to amm onia, em issions of amm onia during agricult ural practices, and no vel s y stems to reduce those em issions.AMMONIA 150 6. POTE NTIAL FOR HUMAN EX POSURE



### Table 6-2. Ongoing Studi es on Environmental Fate and the Potential for Human Exposure to Ammonia Investigator Affiliation Research d e scription Sponsor Baz e mor e RA; Che n TC

Harper LA; Sharp e RR

Hristov AN

Wal sh JL Jr. Missi s sippi State University
ARS, Athens, Georgia

University of Idaho

Georgia Institute of Tech nolo g y

Wilhelm L R e tal. University of Tenne ssee at Knoxville Evaluation of effectivene ss of five substa nce s Hatch (co ppe r chlorophyllin comp lex, chitosa n , activated carbon, ke naf, and pap er mill slud ge) in redu cin g a mmonia emi s sion s from a n i mal wa ste com p o s t. Investigation of the genera t ion and de po sition of USDA ammoni a aerosol s from swine wa ste, wh ich is in-ho u se then com p a r e d to meteorol ogical fluxes, with the obje c tive bein g to redu ce short-te rm an d longterm ammo ni a losse s that affect the local environ ment. This p r op osal see ks, throu gh dietary me ans, NRI comp. better capture of ruminal a mmonia
- nitro gen into grant microbe s an d con s eq uentl yinto milk. This will increa se the efficien cy of utilization of feed N and re du cing N excretion s in the dairy co w. The obje c tive is to develop an integrate d
- optics U.S. DOE (IO) sen s o r capabl e of measu r ing g a se ous ammoni a co n c entration s in the range of 100 pp b. This will be u s e d to measu r e l o sse s from ag ricultu r al cropl and s after appli c ati on of nitroge n fertili zers. Emissi on dat a and produ ct ion inform atio n will be Hatch gathered fro m facilities co untry-wide for poultry and swin e bui lding s
. Evaluation of factors related to am monia emi s si ons will be co ndu cted, and cost-effective approa ches for red u ci ng emission s co nsid ere d and evaluated. Source: CRIS 200 3; F E DRIP 200 3 ARS = Agricult ural R e searc h Service; NRI = Natio nal R e se ar ch Institute; USDA = U.S. Dep a rtment of Agricult ure; U.S. DOE = U.S. D epartment of Energ yAMMONIA 151 6. POTE NTIAL FOR HUMAN EX POSURE Several studies are being conducted t o l essen exposures to amm oni a. Researchers at the University of Kentucky are investigating methods to r e duce em i ssi ons of amm o nia from poultry houses by im proving manure handling. In a different approach, researcher s at the University of Idaho are investigating changes in anim al dietas a means t o im prove the abilities of li vestock to more co m p letel yincorporate rum i nal
amm onia nitr ogen int o m i l k and pr otein. If successf ul , both will result in l o wer exposures to e x creted
amm onia. Furtherm ore, both approaches will l ead to m o re knowledge regarding the efficient transform a tio n of amm onia into useful pr oducts, either com postable manure or food pro ducts.

A considerable num ber of studies are being cond ucted to pro v ide be tter determ inations of atm o spheric transport and deposition of a m m onia, eit h er on a local scale or a global scale, andfor reducing a m m onia effluents from ani m al waste. The U.S. Depart ment of Agriculture (USDA) at W a tkinsville and Athens, Georgia, in conjuncti on wi th the Univer sity of Tenne ssee at Knoxville, is investigating appr oaches to reduce ammo nia em issions from poultry, dairy, and s w ine facilities, with the objective being to reduce short- and long-term ammo nia losses that affect indoor and out door air quality . The USDA in Fay e tteville, Arkansas is t esting different approach es to reduce amm onia emissi ons from poultry, swine, and dair y facilities via evaluation of th e efficacy of al um treat m ents. Other research efforts being conducted by the USDA include the evaluation of th e best use and application pra c tices of ani m al manures that contain ammonia to reduc e em issions and favor nutrient transfer to crop soils. Mississippi State University researcher s are ev aluati ng the quality of poultry ef fluents and swine litter for use as manure-based fertilizers for crops, wherein the effi ciency of m anu re nutrient (including ammonia) transfer to the crop soils is being evaluat e d. Resear ch is also being conducted at Mississippi State University to evaluate the use of cellulosic m a te rials (i. e ., kenaf) to decre ase a mmonia and odor e m issions from poultry waste. K e naf has several a ttractive ch ar acteristi cs as a biosorbent for a m m onia, and is therefore being evaluated for the rem oval of od ors and amm onia fro m waste streams. In anoth e r study being conducted at Mississ ippi State University , five treat ments (co pper chlorophy llin, chitosan, activated carbon, kenaf, and paper mill sludge) are being com p ared for their effects on reducing em issions fro m poultr y litter. The findings indicate that the materials have different efficiencies for reducing overall odor
em issions, but no report has been provid e d about their specific effects on amm o nia em issions.AMMONIA 153



### 7. ANALYTICAL METHODS The purpose of this chapter is to describe the analy tic al m e thods that are availab l e for detecting, measuring, and/or m onitor i ng amm onia, its metabolites, and other biom arkers of exposure and effect to
amm onia. The intent is not to pro v ide anexhaustive lis t of analy tic al m e thods. Rather, the intention is to identif y well-established methods that are used as th e standard methods of anal ysis. Many of the analy tical m e thods used fo r environm en tal sam p les are the m e thods approved b y federal agencies and organizations such as EPA and the National Institute fo r Occupational Safety and Health (NIOSH). Other methods presented in this c h apter are those that are ap proved by gr oups such as the Associati on of Official Anal y tical Chem is ts (AOA C) a nd the Am eri can Public Health Associ a tion (APHA). Additionall y , analy tical m e thods are included that m odif y previ ousl yused m e tho d s to obtai n l o wer detection lim its and/or to i m prove accuracy and precision.

7.1 BIOL OGICAL MAT ERI ALS
When amm o nia is found i nbiol ogical materials at p hy s iological pH (7.2), m o st of it (99%) will be found as ammonium ion, due to its pK aof 9. 2. This is an i m portant cons ideration for any subsequent analy s is. The determ ination of ammonia (as dissolved NH 3 and amm oniu m ion) in bloo d, plasm a , or serum is of value in detecting existing or im pending hepatic co m aand Rey es S yndrom e (Mey erh o ff and R obins 1980; Tietz 1970). T h e de term ination of amm onia in urine had hist orically been used as an indicator of the kidne y ' s ability t o produce amm onia; however, thi s procedure has been replaced by m o re m odern and accurate t ests for kidne y function. Procedures for th e determ ination of ammonia in biological sa m p les a re found in Tabl e 7-1. Amm o nia is also tested for incalculi (abnorm a l concretions in the bo dy f o rm ed of mineral deposits, often found in th e gall bladder, kidn e y , or bladder ) (Tietz 1970) ; however, th e test described therein is not quantitative and is not included in Table 7-1.

The am ount o f amm onia in collected blood, uri n e, saliva, or other b i ological flui d sam p les can be affected by several m e chanis m s thatmay lead to erroneous a m m onia concen tration determinations. These effe cts can be m i nimized b y pro p er sam p le storage and ha ndl ing. T h e amm onia conten t of freshl y dr awn blood rises rapidly on standing because of the dea m ination of labile a m ides such as gluta m ine (H enry 1964); at
room tem p erature, the ammonia content can increase b y a factor of two or three in several hours. Therefore, it is im portant to both keep th e specime n cold (o n ice) and perform the analy s is as soon as possible. If th e sam p le cannot be analyzed quickl y , i t may be froz e n (-20 ° C). The amm onia content ofAMMONIA 154 7. ANAL Y T ICAL METHODS



### Table 7-1. Anal y t ical Methods for De termining Ammonia in Biological Samples Sample Analytical Sample matrix Preparation method method detection limit Urin e 24-Hou r spe c imen, add Colo rimetri c Not rep o rte d HCl , r e fr i g er ate (Berthel ot rea c tion ) Urin e 24-Hou r spe c imen Indoph enol No t r e po rt ed analyzed im mediately, or rea c tion store d up to 8 wee ks at -20 °C Saliva Free ze at -20 °C for up to Membrane No t r e po rt ed 2 wee k s, or store for 1 ho u r based at 4 °C, or an alyze ammoni aimmediately sele ctive electrode Ser u m, Free ze, then store at -15 °C Colo rimetri c No t r e po rt ed plasm a , for seve ral da ys, or store assay ba sed whol e blood on ice (4 °C) for 30– on indo phen o l 60 minute s , or analyze prod uctio n immediately Ser u m, Free ze, then store at -15 °C Titration Not rep o rte d plasm a , for seve ral da ys, or store whol e blood on ice (4 °C) for 30– 60 minute s , or analyze immediately Ser u m, Free ze at -30 °C or store Membrane Not rep o rte d plasm a , on ice, or a n a l yze based whol e blood immediately ammoni aPercent recovery Reference Not rep o rte d Tietz 197 0
No t r e po rt ed Hu iz e n g a e t al. 1994
No t r e po rt ed Hu iz e n g a e t al. 1994

No t r e po rt ed Hu iz e n g a e t al. 1994

Not rep o rte d Hui z en ga et al. 1994

-7.0–1 4% er r o r, Meyerhoff 102% averag e and Robin s r e covery 1980 sele ctive electrodeAMMONIA 155 7. ANAL Y T ICAL METHODS iced (4 ° C) blood sam ples rem a ins constant for up to 60 m i nutes, whereas the ammonia content of frozen (-20 °C) bloo d sam p les remains constant for several day s (Huizen ga et al. 1994 ; Tietz 1970). For bl ood
sam p les collected fro m a healthy person (and stored on ice), the amm onia conten t should be measured within 30–60 minutes of collection. For persons suspected of suffering from liver disease, how ever, the blood sam p les should be an aly zed withi n15 m i nutes (H uizenga et al. 1994)

. This m o re rapid assessment is neces sary because so m e l i ver disease s result in high levels of γ -gluta my l transferase, an enzy m e that hy droly zes glutam ine; the enzy m e ’ s acti v ity will incr ease the concentration of ammonia in the sam p le to levels higher than was present at the time of collec tion (Huizenga et al. 1994). Other erroneously hig h
mea s ured a m m onia level s can result from a mmonia c ontam ination of reagents or pick-up of ammonia from the at mosphere, including from te chnicians that have recently sm oked a ci garette (Huiz e nga et al. 1994). The presence and activities of bacteria in sampl es can also cause changes inthe concentrations of
a m m onia. The natural presence of bacte r ia present inso m e s a m p les (e.g., saliva) or their presence in infected tissues (e.g., bladder infecti ons) can lead to erroneousl y h i g hammonia concentrations, due to th e presence of bacterial ureases that hydrol y ze urea present in the bi ol ogical sam p les. This reacti on is the chief cause fo r the form atio n of amm onia in unacidifie durine o nstanding (Henry 196 4). Furth e rm ore, conta m ination of sam ple s by environm e n tal bacteria f o llowing the collection of the sa m p le ma y also lead to increases i nammonia c oncentrations. Therefore, u se of sterile collection bottles for sa m p l e collection and storage is reco mmende d if there is potential for st orage of the sa m p le prior to analy s is (Huizenga et al. 1994)

.
In the determination of amm onia or amm oniu m ion inbiological sa m p les, a mmonia is first liberated by distillation, a e ration, ion-e x change chromatography, microdiffusion, or depr oteinization (Hui zenga et al. 1994). Deproteinization methods involve treat ment of bl ood or plasma fluids with trichloroacetic acid (or perchloric acid or tungstate-sulfuric acid), followed by centrifugation. The protein-free supern atant can be assay ed colorimetrically for ammonia. Traditionall y, Kjeldahl di stillation m e t hods have be en used to determ ine amm onia levels in biol ogical t i ssue, but oth e r m e thods (e.g., colorim e tric or ion-spe c ific electrodes) are also availab l e. In the Kjeldahl di stillati on, amm onia is distille d and subsequentl ytrapped in acid and analy zed titrametrically or colorimetri cally

. High values someti mes result because of the cleavage of protein am ino groups and also the form ati on of amm o n i a by deam in ation reactions (Parris and Foglia 1983). Other te chniques use the a m m onia- selective el ec trode and enz y m a tic as say s. Discrepan cie s have been reported between results using electrodes and those usi ng m o re specific enzy m a tic procedures because the ammonia electr ode responds to both amm onia and volatile am ines (Parris and Foglia 1983). Chromatographic sep aration of amm onia and volatile am ines after derivatization has also been used to o b tain specifi city ( H uizenga et al. 199 4; Parri s 1984). Amm onia inAMMONIA 156 7. ANAL Y T ICAL METHODS
urine has been m e asured by Nessleri zati on, as we ll as by enz y m a ti c ass ay s and chromatographic approaches (Huizenga et al. 199 4).

7.2 ENVIRONMENTAL SAMPLES Water and waste water samples can be analy zed fo r ammonia by E P A Test Methods 1 689 (E PA 2001a), 1690 (EPA 2 001b), and 3 4 9 .0 (EPA 19 9 7 ). Analog o u s procedures (i.e., Method APHA 4500) have been approved and published joi n tl y b ythe A m erican Publ ic Health As s o ciation, American Water Works Association, and Water Pollution C ontr o l Association. These met hods are suitable for drinki ng, surface, and saline wa ters, and domestic and i ndustrial effluent, and can be app lied to bios olids. These and other methods for d e term ining ammonia in environm ental sam p les are listed in Table 7

- 2. Amm onia is reported as ammonia nitrogen. Two m e thods that are suitable for water employ colorim e tric techniques, Nessl erizatio n, and phenate m e thods. Nessler 's reag ent, an alkaline m i xture of mercuric and potassiu m iodide, produces a y e llow to brown color with a m m o nia, whereas t h e phenate reagent, alkaline phenol, and hy pochlorite produce a blue color (E PA 2001a, 20 01b; Greenberg et al. 1985). In the titri m etric method, the distillate is titrated with standard sulfur ic acid with an appropriate indicator. The amm onia electrode emplo y s a hydro phobic gas-perm eable memb rane to separate the sam p le solution fr om an internal ammonium chloride solution: amm onia diff using thr oug hthe mem b ran e changes the pH of the internal soluti on and is sen sed by a pH electrode. For determ ining NH 3 -N concentrations abo v e 5 m g /L, the titrimetric and ammonia-selective el ectrode m e th ods are preferred. In contr ast, gas chromatography / mass spectro metry m e thods have been developed that perm it NH 3 detection at concentrations near 20 μg/L for environm ental waters (Mishra et al. 2001)

. Methods for determ ini ng amm onia in water and soil measure a m m onia cal nitrogen, the su m of NH 3 and NH 4 +

. In the determ inat ion of amm o niacal nitrogen i nso il, exchangeable amm onium should be distinguished from nonexchangeable amm oniu m . The former is usually defined as that which can be extracted with K C l (or K 2 SO 4 ) at room te m p erature (Bremn er 1965). Nonexchangeable amm oniu m ion is defined as nitrogen held by clay s and not displaced b y 2M KCl ( B remn er 1965). In th e determ inati on of nonexchange able amm onium , organic forms of
amm onia are first rem oved , the m i nerals cont aining th e nonexchang eable ammonium are then deco m posed with HF, and the amm onium ions released

. In colorimetric procedures, turbidity and sam ple color m ay lead to interference. To elim i n ate interfe re nce, the pH of the sa m p le may be raised and the
amm onia dist illed. Care should be taken to prev ent l o sses in wat e r sam p les due to volatilization and microbial transformation. To prevent such losses, sam p l es should be acidified soon after coll ection and refrigerated. Care should also be taken d u ring storage and treatm e nt of soil sam ples to prevent amm oniaAMMONIA 157 7. ANAL Y T ICAL METHODS



### Table 7-2. Anal y t ical Methods for Determining Ammonia in Environmental Samples Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference A i r P a ssiv e colle ction Method 67 01, ion No bia s between usin g 0.01 N H 2 SO 4 chromato gra phy, 6.9 and 48 p p m ; in liquid sorb ent c o nd uc ti vi ty +19% at badg e detectio n 148 ppm 1 μg NH 3 /sample NIOSH 1987

A i r A i r sampl e s fr om stac k emi s sio n s colle cted thro ugh an in-sta c k filter to remove p a rticulates and amm oniu m salts, an d the n bubbl ed thro u gh 0.1 N H 2 SO 4 EPA Method 30; ion ch rom a tograp hy 1 μg NH 3 /sample 98.5±1.3%; B i as of 0.996 ppm for a spi k ed sam p le of 6.43 ppm. Corre c tion fa ctor of 0.87 need s to be appli ed Eaton et al. 1996

Air 0.8 μm prefilter may be used; am monia trappe d on su lfuric acid silica gel NIOSH meth od 6015, Colori metric determi nation of indo phenol b y visible light spe c tro photo m etry 0.5 μg NH 3 /sample Not determin ed NIOSH 1994

Air 0.8 μm prefilter may be used; am monia trappe d on su lfuric acid silica gel NIOSH meth od 6016. Ion chromato gra phy 2 μg NH 3 /sample 102±3.8% NIOSH 1996

Air Chromatomembr a ne cell s pre e xtra ct and pre c on ce ntrat e sampl e Ion chromato
grap hy with c o nd uc ti vi ty detectio n 6 μg NH 3 /sample Not rep o rte d Erxleben et al. 2000

Air Colle ction in H 2 SO 4 - coate d activa ted carbon b ead s in sampli ng tub e Ion chromato
grap hy 2 μg NH 3 /sample 95–1 10% r e covery Bishop et al. 1986

Air Known volu m e of air dra w n throug h prefilter a nd H 2 SO 4 - treated silica gel NIOSH S34 7 , ammoni a-spe c ific electrode Not rep o rte d 97.6% mean r e covery SRI 1988

Wate r Sample mixe d with borate b u ffer Method 16 89, ion sele ctive pro be 0.1 mg/L Not reported EPA 2001aAMMONIA 158 7. ANAL Y T ICAL METHODS


### Table 7-2. Anal y t ical Methods for Determining Ammonia in Environmental Samples Sample Preparation Analytical Sample matrix method method detection limit Wate r Sample colle cted, Method 16 90, 0.2 mg/L pre s e rved wit h colo rimetri c H 2 SO 4 , and chilled determi nation of to 4 °C. Samples indop henol bl ue, sho u ld not be stored following reaction for >2 8 days of any ammo nia with alkaline phen ol and h y pochlo rite Wate r Non e Method 35 0.1 0.1 mg/L colo ri metric, automated phen ate

Estuari ne an d Sample s filtered Method 34 9.0 , 0.3 μg/L coastal water throug h 0.45 μm automated membrane filter, colo rimetri c refrig erate d a nd determi nation by analyzed with in rea c tion s that form 3 hours indo phenol bl ue Wate r Removal of resid ual Method 35 0.2 0.05 mg N/L f o r chlo rine with sodi um Ne ssi e r reag ent, colo ri metric a nd thiosulfate, colorimetric, potentio metri c ; distillation titrimetric; or 1.0 mg N/L fo r ammoni a sp e c ific titrametri c electrode Wate r Non e Method 35 0.3 ion 0.03 mg N/L sele ctive ele c trode

Soil, exchang e- E x t ract soil wi th 2N Method 84 -3, Not rep o rte d able KCl steam di stillation ammoni um with MgO, titration Soil, non- Pretreat soil with Method 84 -7, Not rep o rte d excha nge abl e KOBr-KO H , shake steam di stillation (fixed) with 5 N H F -1 N H Cl with KOH, titration ammoni um for 24 hou rs Percent recovery Not reported

107 an d 99% r e cover i es at 0.16 and 1.44 mg NH 3 -N/L, r e spec tively 92.2–1 09.1% r e covery , n=14

28.12 to -0.4 6R b i a s be tw ee n 0.21 and 1.92 mg N/L

96 and 9 1 % r e cover i es at 0.19 and 0.13 mg N/L, r e spec tively Not rep o rte d
Not rep o rte d Reference EPA 2001b

EPA 1983

EPA 1997a

EPA 1983

EPA 1983

B r emne r 1965 B r emne r 1965AMMONIA 159 7. ANAL Y T ICAL METHODS loss or gain. It has been dem onstr ated that dry so il can rapidly ads o rb trace a m o unts of amm o nia from the atm o sphere and that extens ive am ounts of amm onia can be lost dur ing air dr y i ng (Bremn er 1965). Additionally , in sa m p les co ntaining both a m m oniu m a nd nitrite, losses during air dry i ng m ay occur due to the reaction between these ions and the r esulting fo rmation and release of nitrogen gas (Bremn er 1965).

The detection lim it of analy tical m e thods for determ ining amm onia in air depends on the am ount of air collected in a liquid or solid adsorbent. Sa m p ling is perform ed wit hpassive sa mplers or by drawing a volum e of air throu gh the a d sorbent usin g a pum p. Particulate conta m inants suc has a m m oni um s a lts may be rem o ved b y a prefi lter. For determ ination of amm onia in the am bient atm o sphere, larger volum es of air m u st be sa m p led than those appropriate for determinations of amm oni a in occupational settings (e.g., ind u strial, agricultural) where ammonia levels are higher. Improvem e nts in m e thodolog ies have led to developm ent of techniq u es that perm it continu ous m onitoring of atm o spheric amm onia down to 0.1 μg/m 3 (Pranitis and Mey e rhoff 1987). Several passive m onitoring s y stems report detection lim it s of 0.05 –1.0 μg/m 3 and have collection rates ranging fro m 2.7 to 2,00 0 m L /minute (Kirchner et al. 199 9). One m e thod used for am bient atm o spheric sam p ling em ploy s a sp ecially design ed flow-throu gh,
amm onia- sel ective electrode with a sniffer tube, wher eas the methods used for oc cupational settings often use passive collectors with media (usual ly acids im pr egnated onto filters) housed within pr ot ective cases. Amm onia co ncentrations on these passive collectors ar e then determined by a wide range of methods, includin g col o rimetric assay s (e.g. , ind o phenol determination), the Berthelot reaction, or io n chromatography (Kirchner et al. 1999).

A m m onia ma y be present in air in both the vapor phase as a mmoniagas and in the particulate phase as
amm oniu m salts. While some analy tical methods may distinguish between these phases, m o st standard methods do not. Methods have been developed that determ ine gaseous amm oni a alone or gaseous and particulate form s of ammo niacal nitrogen separately

. These methods use filter packs or sam p l i ng tubes coated with a selective adso rbent (denude r tube) to sep arate the phases (Dimmockand Marshall 198 6; Knapp et al. 1986; Rapsomanikis et al. 1988). In th ese methods, gaseous ammonia is trapped by acids that act as adsorbents (e.g., citric acid, oxalic acid, phosphoric acid) on a coated filter or denude r tube (Kirchner et al. 199 9). Infi lter m e thods, errors m a y arise due to amm onia interactions occurrin g on th e filter and vol atilization of retained ammonium salt (Di m m o ck and Marshall 1986; Rapsomanikis et al. 1988). There is evidence that amm onium nitrate in particulate matter is in equili brium with ammonia. The presence of a m m onium nitrat e m ay lead to overesti m ation of the actual concentration of a m m onia, but underestimation of the concentra tion of ammonium (Doy le et al. 197 9). F o r additional rev i ew of theAMMONIA 160 7. ANAL Y T ICAL METHODS methodologie s for determ i n ing amm oni a in water an d air, see MacCarthy et al. (1987) and Fox (1987), respectively

.

7.3 ADE QUA C Y OF THE DATA BASE Section 104(i )(5) of CERCLA, as amended, directs the Adm i nistrator of ATSDR (in consultatio n with the Ad m i nistrator of EPA and agencies and program s of t h e Public Health Service) to asses s whe ther adequate inform ation on the health e ffec t s of a m m onia is available. Where adequate inform at ion is not available, AT SDR, in conjunction w ith the National Toxicology Program ( N TP) , is required to assure the initiation of a program of resear ch designed to determin e the health effects ( and techniques for developing methods to d e term ine such health effects) of amm onia. The following categories of possible data needs have been identified by a j o int te am of scientists from ATSDR, NTP, and EPA. They are defi ned as substan ce-specific i n form ational needs that if met would reduce the uncertainties of hum an health assessment. This definition shoul d not be interpreted to m e an that all data needs discussed in this secti on m u st be f illed. In the future, the id entified data needs will be evaluated and prioritized, and a substance-sp ecific research agenda will be proposed.

7.3.1 Identification of Data Needs
Methods fo r Determini ng Biomarkers of Exposure and Effect. No k nown un ique biom arkers for exposure or effects exist for amm o n i a. Un til one has been identified, methodology for th e determ ination of biom arker s m u st be preceded by an experimental determ ination of a unique biomarker of hum an exposure or effect.
Methods fo r Determini ng Parent Compounds and Degradation Products in Environmental Media. Methods for determ ining ammoniacal nitrogen inenvironmental media are well developed and adequate. Standardized methods are available from EP A, NIOSH, and other sour ces. Analy tical m e thods are also well developed for oxidatio n pr oducts of amm onia. Since there are m u l tiple sources of these
co m pounds i nthe enviro nm ent, their analy s is is not g e nerally used to study the d i sappearance of
amm onia.AMMONIA 161 7. ANAL Y T ICAL METHODS
7.3.2 Ongoing Studies The Federal Research in Progress (FEDRIP 2003) da tabase provides additional inform ation obtainable from a few o ngoing studie s that m ay fill some of the data needs identified in Section 7.3.1. These studies
are su mmarized below and in Table 7-3. By an d large, m o st of the studies that were reported were related to the detection and m easu re m e nt of at m o spheric a mmonia conc entrations. Many of these focused on the developm ent of novel sens o r devices, which would pr ovide better data for esti m ating amm onia em ission and deposition rates. A com p any i nAtl anta, Georgia is developing an optical ammonia sensor to m e asure agricultural emissions. This sensor is capable of de tecting ammonia concentrations at the 10 0 ppb ran g e and above. S i m ilarly , the Georgia Institute of Techno logy is devel oping an opt i cal sensor that will perm it measurements of amm onia in the atm o sphere at the 100 p pb range. Another co m p any i nBur lingto n , Massa chusett s is developing a diode laser abso rption re m o te sensor for measuring a m m onia at t r ace concentrations, but no detection ranges have beenspecified. Another co m p any in Massachus etts is developing a solid-state ele c troche m i c a l sensor that is based on ionomer (i.e., an ion-containing poly m er)
mem b rane technolog y. T h is technolog y, however, is not inten d ed f o r atm o spheric amm onia sam p ling, but for i n strument m onitoring where amm onia gas ma y have negati ve im pact s. This particular application seeks to produce these m onit o rs for use in fuel cell sy stems, where fr e e a m m onia ca n negatively impact perform ance.AMMONIA 162 7. ANAL Y T ICAL METHODS



### Table 7-3. Ongoing Studies on the Development of Anal y t ical Approach es to the Studyof Ammonia Investigator Affiliation Research d e scription Sponsor Attar AJ Perfect View, Inc., Ralei gh, No rth Carolina
Edwa rd s J Photonic Se n s ors, Atlanta, Georgia
Gold stein N Spectral Scie nce s , Burlingto n , Massachuset t s
Laconti AB Giner, In c., Waltham, Massachuset t s Oz an i c h RM No rt hw es t In str u me n t Systems, Ri chland, Wa shin gton Wal sh JL Jr. Georgia Instit ute of Tech nolo g y, Atlanta, Georgia Develo pment of a low-cost ammonia d e tector (a sm all dete c tor pa nel, ab out the size o f a cre d it ca rd, that chan ge s color in respon se to ammoni a in the atmosphe re) for u s e in a n imal prod uctio n facilities. Develo pment of an optical ammoni a se n s or to measure agri c ultural emi s sions. Thi s se nso r is ca pabl e of detectin g am monia con c e n tration s at the 100 p pb ran ge. Develo pment of a diode la ser a b sorptio n sen s o r for me asu r em ent of trace con c e n tration s of ammoni a , for potential appli c ation s in atmosp he ri c ch emist ry and pollution mo n i toring. Develo pment of a solid-sta te electro c h e m ical sen s o r that is base d on ion o mer me mbrane techn o logy fo r instrument monitori ng where ammoni a ga s may have negative impact s
. Develo pment of an online system for analyzi ng am monia (and ot her nitroge n contai ning ch emical s) in water sy stems. Develo pment of an optical ammoni a se n s or to measure agri c ultural emi s sions. Thi s se nso r is ca pabl e of detectin g am monia con c e n tration s at the 100 p pb ran ge, an d woul d be u s e f ul for real-tim e monitori ng of the injectio n of anhydro u s a m monia fertili zer onto cro p s. SBIR

Coo perative Agreem ent
U.S. DOE

SBIR

SBIR
U.S. DOE

Source: F E DRI P 2002, 2 003 SBIR = Small Busin e ss Innov ative Res earch ; U.S. DOE = U

. S. Department of Energ yAMMONIA 163



### 8. REGULATIONS AND ADVISORIES International guidelines for ammonia were not located . National and state regulations and guidelines pertinent to human exposure to ammonia are summarized in Table 8-1.

ATSDR has derived an acute-dura tion inhalation MRL of 1.7 ppm for ammonia based on a minimal LOAEL of 50 ppm for eye, nose, and throat irritation in a study with volunteers (Verberk et al. 1977). No NOAEL was identified in that study. An uncertainty factor of 30 (3 for the use of a minimal LOAEL and 10 to protect sensitive individuals) was applied to the LOAEL.

ATSDR has derived a chronic-duration inhalation MRL of 0.1 ppm for ammonia based on a NOAEL of 9.2 ppm for sense of smell, prevalence of respir atory symptoms (cough, bronchitis, wheeze, dyspnea, etc.), eye and throat irritation, and pulmonary func tion parameters in workers exposed for approximately 12 years in a soda ash plant (Holness et al. 1989). No LOAEL was defined in that study. The NOAEL was duration-adjusted, and divided by an uncertainty factor of 10 to protect sensitive individuals. A modifying factor of 3 was added for the lack of reproductive and developmental studies. This MRL supersedes the previous chronic inhalation MRL of 0. 3 ppm derived in the 2002 draft for public comment version of this profile.

EPA derived an inhalation reference concentration (RfC) of 1E-1 mg/m 3 (0.14 ppm) for ammonia based on a NOAEL of 6.4 mg/m 3 (9.2 ppm) defined in the Holness et al. (1989) study (IRIS 2004). EPA used an uncertainty factor of 30 (10 to protect sens itive individuals and 3 for data base deficiencies). Ammonia has not undergone a complete evaluation under EPA’s IRIS program for evidence of human carcinogenic potential. Ammonium ion is regulated by the Clean Water Effl uent Guidelines for the following industrial point sources: ferroalloy manufacturing; fertilizer manufact uring; glass manufacturing; inorganic chemicals; iron and steelmaking; landfills; nonfe rrous metals manufacturing; nonfe rrous metals forming and metal powder; paper and paperboard; petr oleum refining; pharmaceutical manufacturing; pulp, meat products; and transportation equipment cleaning (EPA 2002j).AMMONIA 164 8. REGULATIONS AND ADVISORIES The FDA (1973) determined that concentrations of ammonia and ammonium compounds normally present in food do not suggest a health risk; ammonia and ammonium ions are recognized to be integral components of normal metabolic processes. However, so me restrictions have been placed on levels of ammonium salts allowable in processed of foods. Maximum allowable levels in processed foods are as follows: 0.04–3.2% ammonium bicarbonate in baked goods, grain, snack, foods and reconstituted vegetables; 2.0% ammonium carbonate in baked goods, gelatins and puddings; 0.001% ammonium chloride in baked goods and 0.8% in condiments and relishes; 0.6–0.8% ammonium hydroxide in baked goods, cheeses, gelatins and puddings; 0.01% monobasi c ammonium phosphate in baked goods; and 1.1% dibasic ammonium phosphate in baked goods, 0.003% in nonalcoholic beverages, and 0.012% for condiments and relishes.AMMONIA 165 8. REG U LATI ONS AND ADVIS O RIES



### Table 8-1. Regulations and Gu idelines Applicable t o Ammonia Agency Description Information References INTERNATIONAL Gu i d e l in es :

IARC WHO

NATIONA L Carcin oge nici ty classifi cati on Drin kin g wate r quality guid e line

Ammonia

Thre sh old od or co ncentration Thre sh old taste con c entration Health -ba s e d guideline Reg u lation s a nd Guid eline s : a. Air

ACGIH TLV ( 8 -hour TWA) Ammonia Ammonium chlorid e fume STEL (15

- mi nute TWA )

Ammonia Ammonia chl o ride fum e EPA Ac c i dental release pr evention; toxic endp oin t

Ammonia (an h ydrou s ) Ammonia (>2 0 % con c ent ra tion) Re gu l a te d toxi cs u bs ta nc e fo r accide ntal rel ease preve n tion unde r Sectio n 112(r) of th e Clea n Air Act; threshold qu antity

Ammonia (an h ydrou s ) Ammonia (>2 0 % con c ent ra tion) AEGL 1 (interim) NIOSH REL (1 0-h o u r TWA) Ammonia Ammonium chlorid e fume STEL (15

- mi nute TWA )

Ammonia Ammonium chlorid e fume IDLH

Ammonia Ammonium chlorid e fume OS HA P E L (8-h our TWA ) for g e n e ral indu stry

Ammonia No data
1.5 mg/L 35 mg/L Non e pro p o s ed

25 ppm 10 mg/m 3 35 ppm 20 mg/m 3
0.14 mg/L 0.14 mg/L

10,000 p oun d s 20,000 p oun d s 30 ppm 25 ppm 10 mg/m 3 35 ppm 20 mg/m 3 300 ppm No data

50 ppm WHO 200 2

ACGIH 2001

ACGIH 2 001

EPA 2002b 40CF R6 8 , Appendix A EPA 2002a

40CF R6 8 .13 0 , Table 1 EPA 2004 NIOSH 2 002 b

NIOSH 2 002 b

NIOSH 2 002 b

OSHA 200 2d 29CF R1 910. 1000, Table Z
- 1AMMONIA 166 8. REG U LATI ONS AND ADVIS O RIES


### Table 8-1. Regulations and Gu idelines Applicable t o Ammonia Agency Description Information References NATIONA L (cont.)

OS HA P E L (8-h our TWA ) for con s tru c tion indu stry

Ammonia P E L (8-h our TWA ) for ship y a rd indu stry

Ammonia Highly ha za rd ous chemi c al, toxic, and re active for gen eral ind u stry; threshold quantity a

Ammonia Ammonia sol u tions (>4 4 % of ammoni a by weig ht) Highly ha za rd ous chemi c al, toxic, and re active for co nst r u c tio n indu stry; thre shol d qua ntity a

Ammonia Ammonia sol u tions (>4 4 % of ammoni a by weig ht) Occup a tional safety and he alth stand ard s ; st orag e and h a ndling of anhydro u s ammoni a Occup a tion s involved in agri c ultu re th at are pa rticul arly hazard o u s for the employm ent of child ren b e lo w the age of 16 Safety and health reg u lati ons for con s tru c tion; blastin g and use of explosive s ; common bl asti ng agent is a mi xture of amm onium nitrate and ca rbon aceou s comb ustibl es b. Water

EPA Hazardous s ubstance designated pursua n t to Section 3 11(b)(2)(A) of the Clean Wate r Act Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide EPA Reportable quantity of hazardous s u bs ta nc es de s i gn a t e d pu rs u a n t to Section 31 1 of the Clea n Wate r Ac t

Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide 50 ppm

50 ppm

10,000 p oun d s 15,000 p oun d s

10,000 p oun d s 15,000 p oun d s

Tran sp orting, transfe rring, or applyin g anhydrou s a mmonia

100 po und s 5,000 po und s 100 po und s 1,000 po und s OSHA 200 2c 29CF R1 926. 55, Appendix A OSHA 200 2a 29CF R1 915. 1000 OSHA 200 2e 29CF R1 910. 119, Appendix A

OSHA 200 2f 29CF R1 926. 64, Appendix A

OSHA 200 2g 29CF R1 910. 111 OSHA 199 8 29CF R5 70.7 1 (a )(1 1)

OSHA 200 2b 29CF R1 926. 914(e)

EPA 2002h 40CF R1 16.4, Table A

EPA 2002i 40CF R1 17.3AMMONIA 167 8. REG U LATI ONS AND ADVIS O RIES


### Table 8-1. Regulations and Gu idelines Applicable t o Ammonia Agency Description Information References NATIONA L (cont.)

USC Assu ra nces o f availability of Ammonia adeq uate sup p lies of chemi c al s necessa ry for treatment of water c. Food

EPA Res i dues fr om ammonium chlo ride, am monium hyd r oxide, and amm oniu m sulfate are exempted fro m the requi re ment of a toleran c e when u s ed in accordan ce with goo d agricultural pra c tice a s in ert (o r occa si onally inactive) in gredient s in pe sticid e formulatio ns applie d to gro w ing c r op s or to r a wa g r ic u l tur a l comm oditie s after harve st Ammonium ni trate is exem pt from the requi rem ent of a tolera nce whe n used in accord an ce with good a g ri cult ural p r a c tice as ine rt (or o c ca sion a lly active) ingredient s in pesti cide fo rmulatio ns a p p lied to gro w ing crop s only The fungi cide ammonia i s exempted fro m the requi re ment of USC 20 02a 42US C 30 0j

EPA 2002e 40CF R1 80.1 001(c)

EPA 2002e 40CF R1 80.1 001(d)

EPA 2002f 40CF R1 80.1 003

FDA 200 1a 21CF R1 84.1 138 FDA 200 1b 21CF R1 84.1 139 FDA 200 1c 21CF R1 84.1 143 FDA 200 1d 21CF R3 10.5 45(a )

FDA 200 1e 21CF R5 73.1 80 FDA 200 1f 21CF R5 82.1 139 a toleran c e when u s ed afte r harve st on the raw a g ri cult ural comm oditie s grap efruit, le mons, oran ge s, and corn grain for feed use o n ly FDA Dire ct food substa nces aff i rmed as ge nerally reco gni zed a s safe Dire ct food substa nces aff i rmed as ge nerally reco gni zed a s safe FDA Dire ct food substa nces aff i rmed as ge nerally reco gni zed a s safe Dru g produ ct s co ntainin g certain active ingredi ents offered o v erthe-counte r Expectorant drug p r o d u c t Fever bli s ter and cold sore treatment d r u g prod uct Ammonium chlorid e Ammonium h y droxide Ammonium sulfate Ammonium chlorid e
Ammonia sol u tion Ammonia sol u tion and Inse ct bite an d sting drug p r odu cts A mmonium h y droxide Food ad ditives permitted in feed Anhydro u s a mmonia and dri n ki ng water of ani m a ls Substan c e g e nerally recog n ize d Ammonium h y droxide as safe wh en used in a c co rdan ce with goo d ma nufactu ring o r feeding p r a c tice sAMMONIA 168 8. REG U LATI ONS AND ADVIS O RIES


### Table 8-1. Regulations and Gu idelines Applicable t o Ammonia Agency Description Information References NATIONA L (cont.) Substan c e g e nerally recog n ize d as safe wh en used in a c co rdan ce with goo d ma nufactu ring o r feeding p r a c tice s d. Other

CPSC Fede ral Cau s tic Poison A c t Ammonia water and a n y prep aration containin g free or chemi c ally un combi ned ammoni a, including am mo nium hydroxide a n d “ha rtsh o rn ”, in a con c e n tration of 5% or more EPA Ammonia Carcin oge nici ty classifi cati on RfC RfD CERCLA ha zardo u s sub s t ance desi gnate d p u rsuant to Section 31 1(b)(4) of the Cl ean Wate r Act Rep o rtabl e q uantity

Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide EPA Extremely hazardous substance Ammonia

Rep o rtabl e q uantity Thre sh old pla nning q uantit y Toxic chemi c al relea s e rep o rting; Comm unity right-to-kn ow; effective date for repo rting

Ammonia b Ammonium ni trate (solution ) USC Imposition of Superfu nd ta x on any taxable chemical sol d by the manufa c turer, produ ce r, or importe r

Ammonia Refun d or cre d it of Superfu nd tax paid when a mmonia i s used as a fertilize r Superfu nd ta xable su bsta nce STATE Reg u lation s a nd Guid eline s : a. Air Ammonium sulfate FDA 200 1g 21CF R5 82.1 143

CPSC 20 01 16CF R1 500. 129(1)

IRIS 2004 No data 1x10 -1 mg/m 3 No data EPA 2002d

40CF R3 02.4 ( a) 100 po und s 5,000 po und s 100 po und s 1,000 po und s EPA 2002c 40CF R3 55, 100 po und s Appendix A 500 po und s EPA 2002g

01/01/87 40CF R3 72.6 5 (a ) 01/01/87 c USC 20 02d
$2.64 pe r ton 26US C 46 61 USC 20 02b 26US C 46 62 Ammonium ni trate USC 20 02 c 26US C 46 72

No dataAMMONIA 169 8. REG U LATI ONS AND ADVIS O RIES


### Table 8-1. Regulations and Gu idelines Applicable t o Ammonia Agency Description Information References STATE (cont. ) b. Water c. Food d. Other

Florid a Toxic substa nce Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium ni trate Ammonium sulfate Massa c hu set t s Ha zardou s substa nce Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide Ammonium ni trate Ammonium sulfate Minne sota Ha zardou s substa nce Ammonia No data No data No data BLR 200 2

BLR 200 2

BLR 200 2

BLR 200 2 BLR 200 2

BLR 200 2 Ammonium chlorid e , fume Ne w Je rsey Ha zardou s substa nce Ammonia Ne w York Ha zardou s substa nce Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide Pennsylvani a Ha zardou s substa nce Ammonia Ammonium chlorid e Ammonium fl uorid e Ammonium h y droxide

a Potential for a catastroph ic ev ent at or abov e the threshol d qua ntit y
. b Ammonia: inc l udes a n h y d r ou s ammoni a, aq ueo us ammon i a from w a t e r, dissocia b l e am moni um salts, and oth e r sources; 10 % of total aqu eou s ammoni a is reporta ble und e r this listing. cAmmoni um nit r ate (soluti on) i s removed fro m this listi ng; the remov a l is e ffectiv e 07/02/9 5 , for the 1995 reporti ng ye ar
. ACGIH = American C onfere n c e of Governme ntal Industri a l H y gie n ists; AEGL = acute exp o sure g u id el ine value: BLR = Busines s & Legal R e p o rts, Inc. CERCLA = Compre hens ive Envir o nmenta l Resp o n se, Comp ens ation, an d Lia b il it y Act; CF R = Code of F edera l Reg u l a tions; CPSC = Consumer Pr otection Saf e t yCommissio n ; EPA = Environ m ental Protecti on Age n c y ; FD A = Food and Dr ug Adm i nistr a tion; IARC = Internati o n a l Ag enc yfor Rese arch on C ancer; IDLH = i mmediat el y da nger ous to lif e and h e a l th; IRIS = Integrated Risk Informatio n S y stem; NIOSH = National Institute of Occ upatio na l Safet y a nd H ealt h ; OSHA = Occupati o n a l Saf e t y a nd He alth Administr a tion; PEL = permissible e x pos ure l i m it; ppm = parts per milli on; R E L = recomme nde d e x p o sure limit; RfC = inhal atio n referenc e co ncentra ti on; RfD = oral refere nce dos e; ST EL = short-term expos ure lim it; T L V = threshol d limit val ue; T W A = time- w e i ghted av er a ge; USC = United States Code; W H O = W o rld Healt h Organiz a tionAMMONIA 171



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### 10
. GL OSSARY
Absorption— The taking up of liquids by solids, or of gases by s o lids or liquids. Acute Expos u re— Exposure to a chem i cal for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption— The adhesi on in an extremely thin layer of m o le cu les (as of gase s, solutes, or liquids) to the surface s of solid bodies or liquids with wh ich the y are in contact. Adsorption Coefficient ( K oc )— The ratio of the am ount of a chemical adsorbed per unit weig ht of organic carbon in the soil o r sedim ent to the concentr ation of th e ch em ical in solution at equ ili brium

. Adsorption Ratio (Kd)— The am ount of a chem ical adsorbed by sediment or soil (i.e., the solid phase) divided by th e am ount of chem ical in the solution phase, which is in equilibri um with the solid phase, at a fixed solid/solution ratio. It is generally expressed in microgra m s of che m ic al sorbed per gram of soil or sedi m ent. Bench m ark Dose (BMD)— Usually de fined as the lower confidence li m it on the dose that produces a specified m a g n itude of changes in a specified adverse response. For exa m ple, a BMD10 woul d be the dose at the 95% lower conf idence li m it on a 10% res ponse, and the benchmark response (BMR) would be 10%

. The BMD is determined b y m odeling the dose response curve in the regi on of the dose response relationship where biologically observable data are f easible. Bench m ark Dose Model

— A statisti ca l dose-response m odel applied to either experimental toxicological or epidem iological data to calculate a B M D. Bioconcentration Factor (BCF)— The quotient of the concentrati on of a chem i cal in aquatic organisms at a specific time or during a discrete time period of exposure divi ded b y th e concentration in th e surroundi ng water at the sam e time or during th e same period. Biom arkers—Broadly defined as indicators signaling events in bi ologic s y stems or sam p les. They have been classifi ed as m arkers of exposure, marker s of ef fect, and m ark ers of susceptibility. Cancer Eff e c t Level (CEL )— The lowes t dose of chemical in a stu dy , or group of studies, that produces significant increas es in the incidence of cancer (o r tum o rs) between the exposed pop ulation and its appropriate control. Carcinogen— A chem ical capable of inducing cancer. Case-Contro l Study—A type of epide m iological study th at examines the rel a tionship between a particular out co m e (disease or conditio n ) and a variety of potential causative age n ts (such as toxic che m ic als). I na case- controlled study, a group of pe ople with a specified and well-defined outco m e is identified and com p ared to a sim ilar group of peo p le without outco me. Case Report

— Describes a single individual with a particular disease or exposure. These m a y suggest so m e potential topics for scientific rese ar ch, but are not actual rese ar ch studies.AMMONIA 218 10. G L O SSARY
Case Seri es — Des c ribes t h e experience of a s m all num b e r of indiv i duals with th e same disease or exposure. These may suggest potential topics for scien tific resear ch, but are not actual research studies. Ceiling Value— A concent r ation of a substance that shoul d not be exceeded, ev en instantaneousl y . Chronic Exposure— Exposure to a chemical for 365 day s or m o re, as specified in the Tox i cological Profiles. Cohort Study— A type of epidem iologi cal study of a speci fic group or gr oups o f people who have had a co mm on insult (e.g., exposure to an agent suspected of causing dis ease or a co mm on disea se) and are followed for w ard fro m ex posure to o u t c o m e. At leas t one exposed grou p is co m p ared to on e unexposed group. Cross- sectio nal Study— A type of epi d em iological study of a gr o up or grou ps of people that exam ines the relationship between exposure and o u tcome to a ch em ical or to chem icals at one poi nt in t i m e . Data Needs

— Substance- specific informational nee d s that if m e t would reduce the uncertainties of hum an health asse ss ment. Developm ental Toxicity

— The occurrence of adverse effe cts on the developing organism that m ay result from exposure to a chem ical prior to co nception (e ith er parent), during prenatal developm ent, or postnatall y to the tim e of sexual maturation. Adverse developm ental eff ect s m a y be detected at any point in the life span of the organis m . Dose-R esponse Relations h ip— The quantitative relationship between the am ount of exposur e to a toxicant and the incidence of the adverse effect s. Em bryotoxicity and Fetot oxicity—Any toxic effect on the concept u s as a result of prenatal exposure to a chem ical; the distinguis h ing feature b e tween the two terms is the stage of developm ent during which the insult occurs. The term s, a s used here, include m a lformations and variati ons, altered growth, and in utero death. Environmen tal Protection Agency (EPA) Health Advisory— An esti m at e of acceptable d r inking water levels for a c h e m ical subst ance based o nhealth effect s inform atio n. A health advisory is not a legally enforceable f e deral standar d , but serves as technical g u id ance to assist federal, st ate, and local officials. Epidem iology—Refers to the investigation of factors that determ ine the frequency and distrib u tion of disease or other health-relat e d conditions within a de fi ned hum an population dur ing a specified period. Genotoxicity— A specifi c adverse effe cton the genome of living c e lls that, upo n the du plication of affect ed cells, can be expressed as a mutagenic, cl asto g enic, or carcinogenic event because of specific alteration of the m o le cular structure of the genom e. Half-life— A measure of rate for the time required to elim inate one half of a quantity of a che m ical fro m the body or e nvironm ental media. Immediately Dangerous to Life or Health (IDLH)

— The m a ximum environ m ental concentration of a conta m inant from which one could escape within 30 m i nutes without any escape-i m p a iring sy m p tom s or irreversible health effect s.AMMONIA 219 10. G L O SSARY
Imm unologic Toxicity— The occurrence of adverse effects on th e immune sy ste m that m ay result from exposure to e nvironm ental agents such as chem icals. Immunological Effects

— Functional changes in the immune respo n se. Incidenc e— The ratio of i ndividuals in a population who develop a specified co ndition to th e total num ber of individuals inth at pop ulatio n who coul d have develop e d that condit i on in a speci fied time period. Inter m ediate Exposure— Exposure to a chem ical for a duration of 15–3 64 day s , as specified in the Toxicological Profiles. In Vitro

— Iso l ated from th e living organism and artifi c ially m a intai n ed, as in a test tube. In Vivo

— Occurring withi nthe livi ng o r ganism

. Lethal Concentration(Lo) (LC Lo )— The lowest conc entration of a che m ic al in air that has been reported to have caused death in humans or ani m als. Lethal Concentration(50) (LC 50 )— A calculated co ncentration of a chem ical in air to which exposure for a specific len g th of tim e is expected to cause death in 50% of a defined experimental animal populatio n. Lethal Dose( Lo) (LD Lo )— The lowest dose of a che m ical introduced b y a ro ute o ther than inha lation that has been reported to have caused death in hum ans or ani m als. Lethal Dose(50) (LD 50 )— The dose of a che m ic al that has been cal culated to cause death in 50% of a defined experim e ntal animal populatio n. Lethal Tim e (50) (LT 50 )— A calculat e d period of tim e within which a specific c oncentration of a chem ical is expected to cause death in 5 0 % of a defined experim e n t al anim al population. Lowest- O bserved-Adverse-Effect Lev e l (LOAEL)

— The lowest exposure lev e l of chem ical in a study, or group of studies, that produces st atist i cally or biologically significan t increas es in frequency or severity of adverse effects between the exposed p opulatio n and its appropriat e control. Lymphoretic ular Effects

—Represent m o rphological effects involving l y m phatic tissues such as the ly m ph no des, spleen, and thy m us. Malform a tions— Perm ane n t structural changes that may adve rsely affect surviva l , developm e n t, or function. Minimal Risk Level (MRL)— An esti m ate of daily hum an exposure to a hazardous substance that is likel y to be without anappr eciable risk of adver se noncancer health effects over a specified route and duration of exposure. Modifying F a ctor (MF)— A value (greater than zer o) that is appl ied to the deri vation of a M i nim a l Risk Level (MRL) to reflect additional concerns about th e database that are not covered by th e uncertainty factors. The default value for a MF is 1. Morbidity— State of being diseased; m o rbidity rate is the incidence or prevalence of disease in a specific populati on.AMMONIA 220 10. G L O SSARY
Mortality—Death; m o rtal ity rate is a measure of the num be r of deaths in a population during a specified interval of ti me. Mutagen— A substance that cause s m u t a tions. A m u tation is a change in the D NA sequence of a cell’ s DNA. Mutat i ons can lead to birth defects, m i sc arriag es, or cancer. Necropsy— The gross examination of the organs and tissu es of a dead body to determ ine the cause of death or path ological cond itions. Neurotoxicity— The occurrence of adverse effects on the nervous s y stem following exposure t o a che m ic al. No-Obse r ve d-Adverse -E ffect Level ( N OA EL)— T h e dose of a che m ical at w h ich there were no statistically or biologically significant increas es in fre quenc y or severity of adverse effe cts s e e nbetween the exposed p opulatio n and its appropriat e control. Eff ects may be p r oduced at thi s dose, but th ey are not considered to be adverse. Octanol-Water Partition Coefficient ( K ow )— The equilibri um rat i o of the concentrations of a chem i cal in n -octanol and water, in dilute solution. Odds Ratio (OR)—A means of m e asuri ng the association between an exposure (such as toxic substances and a disease or conditi on) that represent s the best esti m at e of relati ve risk (risk as a ratio of the incidence am ong subjects exposed to a particular risk factor di vi ded b y th e in cidence am on g subjects who were not exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of diseas e in the exposed grou p com p ared to the unexpos ed group

. Organophosphate or Organophosphorus Compou nd— A phosp horus-contain i ng or ganic com pound and especiall ya pesticide that acts by i nhibiting choli n esterase. Permi ssible Exposure Li mit (PEL)—An Occupational Safety an d Health Administration (OSHA) allowable exposure level in workplace air averagedover an 8-hour s h ift of a 40-hour workweek. Pesticide— G e neral cla ssifi cation of chemical s specifi cally develo p e d and pro du ced for use in the control of agricultural and public health pests. Pharmacokinetics— The dy nam i c behavior of a m a terial inthe body, used to predict the fate (disposition) of an exogenous substance in an or ganism

. Utilizing co m putational techniques, i t provi des the means of study i ng the absorption, distribution, m e tabolism , andexcretion of che m ic als by the body. Pharmacokinetic Model— A set of equations that can be used to describe the ti m e course of a parent chem ical or metabolite in an animal sy stem
. Ther e are two types of pharm acokinetic m odels: data-based and phy s iologically -based. A data-base d m odel divides the ani m al sy stem into a series of co mpart m ents, which, in general, do not re present real, i d entif iable anato m ic regions of the body, whereas the phy s iologically -based m o d e l co m p art m e n ts represent real anato m ic regions of the body

. Physiologica lly Based Pharm acodynam ic (PBPD) Model— A type of phy s iologically based doseresponse m odel that quantitatively describes the rela ti onship between target tissue dose and toxic end points. These m odels advance the i m portance of phy s iologically ba sed m odels in that the y clearly describe the biological effect (response) produced by th e sy stem fol l owing exposure to an exogenous substance.AMMONIA 221 10. G L O SSARY
Physiologically Based Pharmacokinet ic (PBPK) M o del— Co m p rised of a serie s of com p art m ents representing organs or tissue groups withrealistic weights and blood flows. These m odels r e quire a variety of phy s iol ogical in formation: ti ssue volum es, bloo d flow r a tes to tissues, cardiac output, alveolar ventilation rat es, and possibl y m e m b rane perm eabilities. The m odels also utilize biochem i cal inform ation, such as air/blood partition coefficients, and m e tabolic parameters. PBPK m odels are also called biologically based tissue dosi m etrym odels. Prevalence

— The num ber of cases of a disease or co ndition in a population at one point in ti me. Prospective Study—A type of cohort s tudy i nwhichthe pe rtinent observations are made on events occurring after the start of the study . A group is follo wed over time. q1*— The up per-boun d estim ate of the low-dose slope of the dose-response curve as determined b y the m

u ltist a ge procedure. The q 1 * can be us ed to calculate an estimate of carcinogenic potenc y , th e increm ental excess cancer risk per unit of exposure (u sually μg/L f o r water, m g / kg/day f o r food, and μg/m 3 for air)

. Reco mmend e d Exposure Limit (RE L)

—A National Institute for Occ upational Safety and H ealth (NIOSH) ti me-weighted a v erage (TWA ) concentrati on for u p to a 10-ho ur work day duri ng a 40-ho ur workweek. Reference Concentration (RfC)— An esti m ate (wit h uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to th e hum an population (inc luding sensitive subgroups) that is likel y t o be without an appreciable risk of deleterious noncan cer health effects during a lifetim e. The inhalatio n reference concentration i s for c ontinu o u s inhalation exposures and is appropriately expressed in units of m g /m 3 or ppm . Reference Dose (RfD)—An esti m at e ( w ith uncertainty spanning pe rhaps an order of m a gnitude) of the daily exposur e of the hum an population t o a potential hazar d that is likel y to be without risk of deleterious effects during a lifeti m e. T h e RfD is operationallyder i ved from the no-observe d- adverse-effect level (NOAEL, fro m ani m al andhum an studies) by a consistent application of uncertainty factors that reflect various ty pes of data used to esti m ate R f Ds and an additional m odify i ng factor, which is based on a professional judgm ent of the entire database on the chem ical. The RfDs ar e not applicable to nonthreshol d effects such as cancer. Reportable Quantity (RQ)— The quantity of a hazardous substance that is considered reportable under the Com p reh e nsive Environmental Resp onse, Com p en sation, and Liability Act (CERCLA). Reportable quantities are (1) 1 pound or greater or (2) for select ed substances, an am ount established by r e gulation either under CERCLA or under Section 311 of the Cl ean Water Act. Quantities are measured over a 24-ho ur perio d

. Reproductiv e Toxicity— The occurrence of adverse effects on the reproductive sy stem that may result from exposure to a chem ical. The toxici ty m ay be di r ected to the reproductive o r gans and/or th e related endocrine sy s t em . The m a nifestation of such toxici ty may be noted as alterations in sexual beh avior, fertility , pregnancy outcomes, or m odifications in othe r functions that are dependent on the i n tegrity of this sy stem
.AMMONIA 222 10. G L O SSARY Retrosp ectiv e Study—A type of cohort study based on a grou p of persons known to have been exposed at so m e ti me in the past. D a ta are colle ct ed from routinely recorded events, up to the time the s tudy is undertaken. Retrospective studies are limited to cau sal factors thatcan be ascert a ined from ex isting records and/or exam ining survivors of th e cohort. Risk— The possibility or c h ance that some adverse effect will result from a given exposure to a chem ical. Risk Factor

— An aspect of personal b e havior or lif esty l e, an env i ronm ental ex posure, or an inbornor inherited characteristi c that is associat ed with an increased occurren ce of diseas e or other health-related event or cond ition. Risk Ratio— The ratio of th e risk am ong persons with specific risk factors co mpared to the ri sk am ong persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed group com p ared to the un exposed gro up . Short-Term Exposure Li mit (STEL)

— The American Conference of Governmental Industrial Hy gienists ( A CGIH) m a x i m u m concen tration to whi c h workers can be exposed for up t o 15 minutes continually

. No m o r e than four excursions are a llowe d per day , and there m u st be at least 60 minutes between exposure periods. The dail y Threshold Li m i t Value-Tim e Weighted Average (TLV-TWA) m ay not be exceeded. Standardiz ed Mortality Ratio (SMR)— A ratio of the observed num b er of deat hs and the expected num ber of deaths in a specific standard populati on. Target Orga n Toxicity— This term covers a broad range of adverse effects on target organs or phy s iological sy stem s ( e .g., renal, cardiovascular) ex tending from those arising through a singl e li m ited exposure to those assu med over a lifetime of exposure to a chem i cal. Teratogen—A che m i cal t h at causes stru ctural defect s that affect t h e developm e n t of an organis m . Threshold L i mit Value ( TLV)—An Am erican Co nference of Gove rnm e ntal Industrial H y g i enists (ACGIH) concentration of a substance to which m o stworkers can be exposed without adverse effect. The TLV m a y be expressed as a Ti m e Weighted Average (TWA) , as a Short-Term Exposure Lim it (STEL), or as a ceiling lim i t (CL). Time- W eigh ted Average (TWA)— An allowable exposure concentration averaged over a nor mal 8-hour workday or 4 0 -hour wor k

week. Toxic Dose(50) (TD50)—A calculat e d dose of a chemical, introducedb y a rout e other than i nhalation, which is expected to cause a specific toxic effect in50% of a defined experimental anim al population. Toxicokinetic— The absorption, distrib u tion, an d eli m ination of t oxic com pounds in the li vi ng organ i sm .AMMONIA 223 10. G L O SSARY Uncertainty Factor (UF)— A factor used in operatio nally derivin g the Minim a l Risk Level (MRL) or Referen ce Do se (RfD) or Reference Concentration (R fC) fro m experim e ntal data. UFs are intended to account for (1) the variation in sensitivity am ong the mem b ers of the hum an population, (2) th e uncertainty in extrapolating animal data t o the case of hum an, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifeti m e ex posure, and (4) the uncertainty in using lowestobserved-adverse- effect le vel (LOAEL) data rather than no-observed-adverse-ef fect level (N OAEL) data. A default for each individual UF is 10; if com p let e cer tainty in data exists, a value of 1 can be used; however, a reduced UF of 3 m ay be used on a case-by -case basis, 3 being the approxim a te logarithm i c average of 10 and 1. Xenobiotic

— Any chem i cal that is foreign to the biological s y stem
.AMMONIA A-1



### APPENDI X A. ATSDR MI NIM A L RISK LE VE LS AND WORKSHEETS
The Com p reh e nsive Environmental Resp onse, Com p en sation, and Liability Act (CERCLA) [42 U.S.C. 9601 et seq.] , as amended b y the Su perfund Am end m en ts and Reauthorization Act (SARA) [ P ub. L. 99– 499] , requires that the Agency f o r Toxic Substances and Disease Registry (ATSDR) develop jointl y with the U.S. Envi ronm ental Pr otection Agency (EPA), i norder of pri o rity, a list of hazardous substances m o st
co mm only found at faciliti es on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each substance included on the priority list of hazardous substances; and assure the initiation of a resear ch program to fill identified data needs asso ciated with the substances. The toxicological profiles include an examination, summary , and i n terpretation of available toxicological inform ation and epidem iologic evaluations of a hazardous substance. During the developm en t of toxicological profiles, Minimal Risk Lev e ls (MRLs) a r e derived when reliable and sufficient data exist to identify the target organ(s) of effect or the m o st sen siti ve health effect(s) for a specific duration for a given route of exposure. An MRL is an esti m ate of the dail y hum an exposure t o a hazardous substance that is likel y t o be without appreciable risk of a dverse noncancer health effects o v er a specified duratio n of exposure. MRLs are based on noncancer health effects only and are not based on a consi d eration of cancer eff ect s . These substance-spe c ific esti m ates, wh ich are intended to serve as screening levels, are used by ATSDR health ass essors to identify contam in ants and pote n tial health effects that ma y be of concern at hazardous wast e sites. It is im portant to note that MRLs are not intended to define clean-up or action levels.

MRLs are der i ved for hazardous substances using the no- observed- adverse-eff e ct level/uncertainty factor approach. They are below levels that m i ght cause a dverse health effects in the people m o st sensitive to such chem ical-induced effects. MRLs are derived fo r acute (1–14 d ay s ), interm ediate (15–3 64 day s ), an d chronic (365 day s and lon g e r) durations and for the or al and inhalation ro utes of exposure. Currently, MRLs for the derm al route of exposure are not derived because ATS D R has not yet identified a method suitable for this route of exposure. MRLs are gene rally based on th e m o st sensi tive chem ical -induced end point co nsidered to be of r e levance to humans. Seri ous health effects (such as irreparable damage to the liver or kidn ey s, or birth de fects) are not used as a basis for establishing MRLs. E xposure to a l e vel above the M R L does not mean that ad verse health effects will occur.AMMONIA A-2 APPENDIX A
MRLs are int e nded only to serve as a scr eening tool to help public health professi onals decide where to look m o re closely

. T h e y may also be viewed as a mechanism to identif y those hazardous wast e sites that are not expected to cause a dverse health effects. MostMRLs contain a degree of uncertainty because of the lack of pr ecise toxicological inform ation on th e pe ople who m i ght be m o st sensitive (e.g., i n fants, elderly , nutrit i onall y or imm unologically com p ro m i sed) to the effects of hazard ous substances. ATSDR
uses a conservative (i.e., protective) approach to addre ss this uncertainty consistent with the public health principle of prevention. Al though hum a n data are pr eferred, MRLs often m u st be based on ani m al studies because rel e vant hum an studies are lack ing. In th e absence of evidence to the contrary , ATSDR assu mes that hum ans a re m o re sensi tive to the effects of hazard ous substance than anim al s and that certain persons may be particularly sensitive. Thus, th e resulting MRL may be as m u ch as 100-fold below le vels that have been shown to be n o n toxic inlabo ratory anim als. Proposed MRLs undergo a rigorous revie wprocess: Health Effects/ MRL Workgr oup reviews within the Division of T oxicolog y , expert panel peer reviews, an d agency -wid e MRL Workgroup review s, with participation from other federal agencies and comment s from the public. The y ar e subject to change as new information becom es available conco m itant with updatin g the toxicolo gical profiles. Thu s , MRLs in the m o st r ece nt toxicologic a l profiles supersede prev iousl y p ublish e d levels. For additional i n form ation regarding MRLs, please c ontact the Division of To xicology , Age n cy for Toxic Substances a nd Disease Registry , 1 6 0 0 Clifton Roa dNE, Mailstop F-3 2 , Atlanta, Georgia 3033 3.AMMONIA A-3 APPENDIX A 

### MINIM A L RISK LE V E L (M R L ) WO RK SH EE T
Chem ical Name: Amm onia CAS Nu m b er: 7664- 41-7 Date: July 20 04 Profile Status: Third Draft Post-Public Route: [ X ] Inhalation [ ] Oral Du ra t i o n : [ X ] A c u t e [ ] In t e rm ed i a t e [ ] Ch ro n i c Graph Key : 14 Species: Hu m an Minimal Risk Level : 1.7 [ ] m g /kg/day [ X ] p p m Referen c e : Verberk MM. 1977

. Effects of ammonia in vol unteers. Int Arch Occup Environ H ealth 39:73- 81. Experimental design : The study exam in ed the effects of exposure t o ammonia in a group of 16 volunteers. Eight of the m (experts) knew the e ffects of amm onia fro m the literature, but had had no personal contact, whereas the rem a ining eight subj ects (non-experts ) were studen t s from a non -science faculty and were not fa m ili ar with a m m o nia or expe riments in laboratory situations. All me mbers of a group were exposed onthe same day t o one of the co n centrations tested (50, 80, 110, or 1 40 ppm ). The testing was repeated with a 1-week interval. Immedi ately before and after exposure, vital capacity , forced expirator y volume, and forced inspiratory vol um e wer e m e asured. During expos ure, each subject recorded subjective feelings every 15 m i nutes as no sensation (0), just perceptible (1), distinctly perceptible (2), nuisance (3), offensiv e (4), or unbearable (5). No st atistical analy s is wa s performed and there was no group exposed to air o n l y . A few weeks af ter the experim e nts, the subjects were tested to measure (pre-existing) no n- specific reactivity of th e airway s to exo g e nous stim uli. Effects noted in study an d c o rrespondin g doses : None of the participants was hypersusceptible to nonspecific irritants. Results of the pulm onary f unctiontests after exposure were not statistically significantl y different from pr e-exposure values. For the non-experts, there was a clear incr ease in the num ber of reported s y m p toms for sm ell, ey e irritatio n, throat irritation, cou gh, and general di sco m f ort as the exposure concentration increased. The latter w as not as clear f o r the experts. The num ber of sy m p toms rec o rded with a score >3 (nuisance) for s m ell, ey e irritat i on, n o se, thr o at, and urge to coug h for the 50, 80, 11 0, and 1 40 pp m exposure groups was 2, 2, 7, an d 11 , respectively , for the expert s and 6, 1 2 , 18, and 29, re spectively , for the non-experts. It s houl d also be m e n tioned that th e subjective responses appeared m o re pronounced in the n on-expert group th an in the expe rt group
. Dose and end point used fo r MRL derivation : 50 ppm for m ild irritation to th e ey es, nose, and throat in hum ans exposed to amm o nia gas for 2 hours. Becaus e the e ffects observe d were local i rritation e ffec t s, they were not tim e-depe ndent (but rather concentration-dependent), an adjustment to 24- hour e xposure was not necessary
. [ ] NO AEL [ X ] LO AE LAMMONIA A-4 APPENDIX A Uncertainty Factors used in MRL derivation : [ X ] 3 for u se of a m i nimal LOAEL [ ] 10 for extrapolation from ani m als to hum ans [ X ] 10 for hum an variab ility Was a conversion used fro m pp m in food or water to a m g /body w e ight dose ? N/A If an inhalation study in an imals, list the conversion factors used in determ ining hum an equivalent dose : N/A Other additional studies or pertinent info rm ation which lend suppor t to this MRL : Althoug h th e Verberk et al. (1977) s tudy has lim itations (no statistical an aly s is, subjective end poi nts, n o control gro up), it dem onstrates that concentrations of 50 p p m am m onia can produce minim a l discom fort in healthy mem b ers of the general po pulation an d th erefore, shoul d be avoi ded. Additi onal relevant info rm ation is provided b y a study b yFer guson et al. ( 1977). In t h at study , a gr o up of six health y v o lunteer s, not previousl y accusto m ed to working i nan amm onia en vironm ent, were exposed 5 day s /week to 25 ppm (2 hours/day ) , 50 ppm (4 hours/day ) , or 100 ppm (6 hour s/day ) of ammonia, or to 50 ppm of ammonia 6 ho urs/day f o r 6 weeks. End p o ints monitored i n cluded subjective and objective mea s ures of ey e and throat irritation as well as p u lse rate, resp iration rate, pulm onary function (FVC, FEV), asse ss ment of neurological f unction (reflex, balan ce, and coordi natio n), and b o dy weight. The exposure prot ocol consisted of a pre-exposure evaluation b ya phy s ician, 3 ho urs of exposure (this conflicts with exposure data on table 2 of the stu dyand m e ntioned above), a mid-point p hy sician ’s obs ervation, lunc h break, 3 additional hours of exposure, and a thir d phy s ic ian’ s observation 30 m i nutes aft e r exposure ceased. The conjunctiva and m u cosa of the nose and throat were e x a m ined by a phy s ician be fore and after each daily exposure and the degree of irritation note dwas descr ib ed as m ild, moderate, or marked. Expos ure to amm onia hadno significan t effect on the measures of respiratory function or i nth e neurolog ical tests conducted. T h e results of the evaluation s of irr itation conducted b ythe phy s icianshowed no si gnificant differences b e tween the ex posure groups, including th e 0 ppm exposure group (pre-exposure). All subjects expe rienced so m e watering of the ey es and a sensation of dry n ess in the nose and throat and there was one observation of definite redness in the m u co sa of the nose after a 6-hour e xposure to 100 ppm during which time, there w as an excursi on to 200 ppm a mmonia. No redness w as observed in this subject the following m o rning. Throughout th e study , the phy s ician observed 6 cases of ey e irritation, 20 of nose irritation, and 9 of throat irritation, and m o st cas es ap peared to have occurred the first week o f the study during expos ure to 50 ppm

. It is difficul t to dete rm ine in this study a NOAEL or LOAEL for irritation due to the dif f erent exposure durations experienced by the subjects, but it would appear that an exposure concentration of 10 0 ppm ammonia for 6 hours caused no significan t changes in th e vital functi ons mea s ured and that 50 ppm can cause ey e, nose, and throat irritation. NIOSH (1974) reviewed 15 studies of c ase reports in which subjects were exposed to ver y high, but unquantified, concentrations of amm onia. The 15 reports provided a representativ e array of documented clinical findings including death, perma n ent e y e l esions, and chronic respiratory sy m p toms, as well as acute lower and upper respiratory s y m p t o ms. The onl y quantitative inform ation available was that a worker died 6 hours after estim ated exposure to 10,0 0 0 ppm amm o nia for an uns pecified tim e (Mulder and Van der Zalm 1967). Studies with volunteers, also reviewed by NIOSH (1974), generall y used concentrations of amm onia m u ch higher than those in the studies b yVerberk et al. (197 7) or Fe rguson et al. (1977) an d / or exposure durations of o n l y m i nutes. For exam ple, exposure to a concentration of 500 ppm for 30 m i nutes caused respiratory irritation g r aded as severe by 2 o u t 7 subjects (Silverm an et al. 1949). Fo ur out of 6 v o lunteers exposed to 5 0 p p m ammonia for 10 m i nutes graded the irritation as “m oderate” and none described it as “disco m f orting” or “painful” ( M acEwen et al. 1970)

. All of theAMMONIA A-5 APPENDIX A subjects ratedthe odor as “highl y penetr ating” at 50 p p m and 3 subjects gave the same rating to 30 ppm . IBT (1973) e xposed 10 subjects to 32, 50, 72, and 134 ppm for 5 minutes and the frequency of positive findings was as follows: at 32 ppm , 1 subject co m p lai n ed of dryness of the nose; at 50 ppm , 2 subjects co m p lained of dry n ess of the nose; at 72 ppm , 3 subject s experienc e d ey e irritation, 2 had nas a l irritation, and 3 had thr o at irritation; and at 134 pp m , 5 subjects had signs of l acrimation, 5 had ey e irritat i on, 7 had nasal irritation, 8 had throatirritation, and 1 had chest irritation. Collectively , the available inform ation from studies in hum ans supports the 50 p p m exposure level from the Verberk e t al. (1977) study as a m i ni mal LOAEL for irritation i nacute studies. In general, studies in anim als have used higher e xposure conc entrations. F o r amm onia, a corrosive irritant gas that affects the portal of entr y and pr oduc es irritation of the ey es an d respiratory tr act, use of human data should be preferred over animal studies. Agency Contact (Che m i cal Manager) : Nickolette Roney , MPHAMMONIA A-6 APPENDIX A 

### MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: Ammonia and Ammonium Compounds CAS Number: 7664-41-7 Date: July 2004 Profile Status: Third Draft Post Public Route: [ X ] Inhalation [ ] Oral Duration: [ ] Acute [ ] Intermediate [ X ] Chronic Graph Key: 47 Species: Humans Minimal Risk Level : 0.1 [ ] mg/kg/day [ X ] ppm Reference : Holness DL, Purdham JT, Nethercott JR. 1989. Acute and chronic respiratory effects of occupational exposure to ammonia. Am Ind Hyg Assoc J 50:646-650. Experimental design : The study evaluated sense of smell, prevalence of respiratory symptoms (cough, bronchitis, wheeze, dyspnea, and others), eye and thro at irritation, and lung function parameters (FVC, FEV 1 , FEV 1 /FVC, FEF 50 , and FEF 75 ) in humans exposed for an average of 12.2 years in a soda ash plant (Holness et al. 1989). The cohort consisted of 52 wo rkers and 35 controls. The subjects were assessed on two workdays: on the first workday of their workweek and on the last workday of their workweek. Spirometry was performed at the begi nning and end of each work shift, so that each worker had four tests done. To determine the exposure levels, exposed and control workers were sampled over one work shift; the average sample collection period was 8.4 hours. All of the participants in the study were males. Effects noted in study and corresponding doses : Analysis of the results showed no significant differences in the prevalence of reported symptoms, but the ex posed workers reported that exposure in the plant aggravated some of their reported symptoms (cough, wh eeze, nasal complaints, eye irritation, and throat discomfort). Odor threshold was not affected by exposure to ammonia and there were no significant differences in baseline lung functions between exposedand control subjects. Analysis of each worker separately showed no significant relationship between th e level of ammonia exposure and changes in lung function. Also, when the workers were divided into groups of individuals that were exposed to low (<6.25 ppm), medium (6.25–12.5 ppm), and high (>12 .5 ppm) ammonia levels, no significant association was found between reporting of symptoms, decline in baseline function, or increasing decline in function over the work shift and exposure to ammonia. Furthermore, no association was evident between increasing years of exposure and decreasing lung func tion. However, the power of the indices of both level and length of exposure is low because only eight workers were in areas with relatively high ammonia exposure. The MRL was calculated by adjusting the NOAEL of 9.2 ppm (the mean TWA exposure concentration) for continuous exposure (9.2 x 8/24 hours x 5/7 days) and dividing by an uncertainty factor of 10 for the protection of sensitive individuals. A modifying factor of 3 was used for the lack of reproductive and developmental studies. Dose and end point used for MRL derivation : 9.2 ppm for no significant alterations in lung function in chronically exposed workers. [ X ] NOAEL [ ] LOAELAMMONIA A-7 APPENDIX A Uncertainty Factors used in MRL derivation : [ ] 10 for use of a LOAEL [ ] 10 for extrapolation from animals to humans [X] 10 for human variability Modifying Factors used in MRL derivation : [X] 3 for lack of reproductive and developmental studies Was a conversion used from ppm in food or water to a mg/body weight dose ? N/A. If an inhalation study in animals, list the conversion factors used in determining human equivalent dose : N/A. Other additional studies or pertinent info rmation which lend support to this MRL : Earlier studies summarized by NIOSH (1974) found that workers accustomed to 20 ppm ammonia did not complain of irritation symptoms, but showed slight redness in the conjunctiva. Those not accustomed had eye and respiratory discomfort and irritation. Another report st ated that air levels below 5 ppm were associated with barely noticeable eye irritation. In yet an add itional report, concentrations of 15–28 ppm in the work area produced slight eye irritation. More recent datareported respiratory effects associated with chronicduration exposure to pollutants, in cluding ammonia, in livestock confin ement buildings and an increase in respiratory symptoms (such as bronchial reactivity/hyperresponsiveness, inflammation, cough, wheezing, or shortness of breath) and/or a decrease in lung f unction (such as forced expiratory volume in the first second [FEV 1.0 ], maximum expiratory flow rates [MEF 50 and MEF 75 ], and maximal mid-expiratory flow rate [MMEF]) in farmers exposed to ammonia levels of 2.3–20.7 ppm (Choudat et al. 1994; Cormier et al. 2000; Donham et al. 1995, 2000; Heederik et al. 1990; Reynolds et al. 1996; Vogelzang et al. 1997, 2000). The farmers were also exposed to other possibl e respiratory toxins, such as dust and endotoxins. A cross-sectional study of male workers at two fertilizer factories in Saudi Arabia showed a significant association between exposure to ammonia gas and resp iratory symptoms and bronchial asthma (Ballal et al. 1998). No continuous exposure levels could be calculated for these workers because the number of days worked per week was not provided. There we re no chronic-duration inhalation studies in animals. Agency Contact (Chemical Manager) : Nickolette Roney, MPHAMMONIA B-1



### APPENDI X B. USER'S GUI D E Chapter 1 Public Health Statement This chapter of the profile is a health effects su mmary written in non-technical language. Its i n tended audience is the general public, especially people livi n g in the vicini tyof a hazardous waste site or che m ic al rele ase. If the Public Health State m ent were re m oved from the r est of the docum ent, it would still co mm unicate to the lay public essential inform atio n about th e chem ical. The major headings in th e Public H ealth State m ent ar e useful to findspecific topics of concern. The topics are wri tten in a question and answ er form at. The answer to e ach questi on includes a sentence that will direct the reader to chapters in the pr ofile th at will provi de m o re information on the given topic. Chapter 2 Relevance to Public Health This chapter provides a he alth effects su mma ry based on evaluations of existing toxicologic, epide m iologic, and toxicokinetic in formation. This su mmary is desi gned to present interpre tive, weightof-evidence discussions for hum an healt hend po ints by addressing the following questions: 1. What effects are known to occur in hum ans? 2. What effects observed in an imals are lik ely to be of c oncern to humans? 3. What exposur e conditions ar e likely t o be of concern to hum ans, especially around hazardous waste sites? The chapter covers end points in the same order that they appear within the Discussion of Health Effects by Route of E xposure section, by route (inhalation, or al, and dermal) and within route by effect. Hum an data are presented first, the nanim al dat a . Both ar e organized by duration (acute, intermediate , chronic). In vitro data and data from parenteral routes (intram u sc ular, intravenous, subcutan eous, etc.) are also considered in this chapter. The carcinogenic potential of the profi l ed substance is qualitativel y evaluated, when appropriat e , using existing toxic okinetic, genotoxic, and carcinogenic data. ATSDR does not currentl y assess cancer potenc y or perform cancer risk asse ss me nts. Minim a l Risk Levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. Lim itations to existing sci entific literature that preven t a satisfacto ry evaluati on of the relevance to public health are identified in th e Ch apter 3 Data Needs s ecti on. Interpr e tation of Minimal Risk Levels Where suffici ent toxicologic information is availabl e, ATSDR has derived MRLs for inhalatio n and oral routes of entry at each duration of expos ure (acute , interm ediat e , and chronic). These MRLs a r e notAMMONIA B-2 APPENDIX B meant to support regulator y action, but t o acquaint he alth professionals with e xposure levels at which adverse healt heffects ar e not expected to occur in humans. MRLs should help phy s icians and pu blic health officials determ ine the safety of a community l i ving near a che m i cal e m ission, given the concentration of a conta m inant in air or the estimated daily dose in water. MRLs are ba sed largely on toxicologic a l studies in animals and on reports of hu man occupational exposure. MRL users should be fam i liar with the toxicologic inf o rmation on which the num b er is based

. Chapter 2, "Relevance to Public Health," contains basic informa tion k nown a bout th e subst ance. Other sections such as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populati ons that are Unusually Susceptible" provide im por tant supplem ental inform ation. MRL users should also un derstand the MRL deri vation m e thodolo g y . MRLs are derived using a m odified version of th e risk assessment methodolog y that the Envir onm ental Pro t ection Agency (EPA) provides (Barnes and Dourson 1988) to determ ine ref e rence doses (RfDs) for lif eti m e exposure. To derive an MRL, ATSDR generally s e lects the m o st sensitive end point whic h, in its best judgem e nt, represents the m o st sensitive hum an heal th effect for a given exposure route and duration. ATSDR cannot m ake this judgem e nt or derive anMRL unless inform ation (quantitative or qualitative ) is available for all potenti al sy stem ic, neurological, and develo pm ental effect s. If this inform ation and reli able quantitative data on the chosen end point are availabl e, ATSDR deri ves an MRL using the m o st sensitive species (when inform ation from m u ltipl e species is availa ble) with the highest no-observed-adverse-effect level (NOAE L) that does not exceed any adverse eff e c t levels. When a NOAEL i s not available, a lowest-observed-adverse- effect level ( L OAEL) can be u sed to derive an MRL, and an uncertainty factor (UF) of 10 must be em ploy ed. Additi o n al uncerta inty factors of 1 0 m u st be used both for hum an variability to protect sensitive subpopulat ions (peopl e who are m o stsusceptible to the health e ffects caused by th e substance) and for i n terspecies vari ability (extrapolat ion from animals to humans). In deriving an MRL, these individual unc ertainty fact ors are m u ltipl i ed together. The product i s then divided i n to th e inhalation concentration or oral dosag e selected from the study . Uncertainty f actors used in developi ng a substance-specific MRL are provided i nthe footnote s of the levels of significant exposure (LSE) tables. Chapter 3 Health Effects Tables and Figures for Le vels of Significant Exposure (LSE) Tables and figures are used to summ arize health effe cts and illustrate graphica lly levels of exposure associat ed wi th those effects. These levels cover heal th effects observed at increasing dose concentrations and duratio ns, diffe rence s in response by species, MRLs to hum a n s for noncancer end points, and E P A's esti m ated range associated with an upper- bound indivi dual lif eti m e cancer risk of 1 i n 10,000 to 1 i n10,000, 000. Use the LSE tables and figures for a qui ck review of the health effects and to locate data for a specific ex posure scenar io. The LSE tables and figures should al way s be used in conjunction with the text. All entries in these tables a nd figures represent studies that provide reliable, quantitative esti m ates of NOAELs, LOAELs , or Cancer Effect L e vels (CELs). The legends presented below de m onstrate the appli cation of these tables and figures. Representative exam ples of LSE Table 3-1 and Figure 3-1 are shown. The num b ers in the left columnof the legends correspond to the num bers in the exam ple table and figure.AMMONIA B-3 APPENDIX B

LEGE ND See Sam p le LSE Table 3-1 (page B-6) (1) Route of Exposure

. One of the first considerations whenreviewing the toxicity of a substance using these tables and figur es should be th e relevant and appropriate route of exposure. T y pic a lly when sufficient data exist, three LSE tables and two LSE figures are presented in the docum en t. The three LSE tables present data on th e three princi pal routes of exposure, i.e., inhalation, oral, and dermal (LSE Tables 3-1, 3-2, and 3-3, respec tively )

. LSE figures are li mited to the i nhal a tion (LSE Figure 3-1) and oral (LSE Figure 3-2) rout es. Not all substances will have data on each route of exposure and will not, therefore , have all five of the tables and figures. (2) Exposure Period

. T h ree exposure period s—acute (less than 15 day s ), intermediate (15– 364 day s ), an d chronic (3 6 5 day s or m o re)—are prese nted within e ach relevant route of exp o sure. In this exam p l e, an inhalation study of i n term ediate exposure durati on is reported

. For q u ick reference to health effects occurring fro m a know n length of expos ure, locate the applicable exposure period within the LSE table and figure. (3) Health Effect

. The m a jor c a tegories of health effect s included in LSE tables and figures are death, sy stemic, immunological, neurolo g ical , developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects bu t cancer. Sy stem ic effects are further defined in th e "S y s tem " columnof the LSE table (see key num ber 18). (4) Key to Figure

. Each ke y num b er in the LSE table links study inf o r

m ation to one or m o re data points using th e same key num ber in the correspondi ng LSE figure. In this example, the study represented by ke y num b er 18 has been used to derive a NO AEL a nd a Less Ser i ous LOAEL (also see the t w o "18r" data points in sam pl e Figure 3-1). (5) Species

. The test specie s , whether ani m al or hum an, are identified in this column . Chapter 2, "Relevance t o Public Health," covers the rele vance o f animal data to hum an toxi city an d Section 3.4, " T oxicokinetic s," contains any availa ble inform ation on com p arative toxicokineti cs. Although NOAELs and LOAELs are species specifi c , the levels are extrapolated to equi valent hum an doses to derive an MRL. (6) Exposure Frequenc y / Duration

. T h e dur ation of the st udy an d the weekly and daily exposure regim e ns are provided in th is column . This perm its co m p arison of NOAELs and LOAELs from different studies. In this case (key num b er 18), rats were exposed to “Chem i cal x” via inhalation for 6 h ours/d ay , 5 day s /week, for 13 weeks. For a more co m p lete review of the dosing regim e n, refer to the appropriate sect ions of the te xt or th e original reference paper (i.e., Nitschke et al. 1981). (7) Sy stem
. This columnfurther defines the sy stem ic effe cts. These sy ste m s include respiratory , cardiovascula r, gastrointestinal, hematologi cal, m u s c uloskeletal, hepatic, renal, and derm al/ocular. "Other" refers to any s y s t em ic ef fect ( e .g., a decrea se in body weight) not cove red in these sy stems. In the exa m ple of key num be r 18, one sy stem ic e ffect (respirat ory ) was investigated. (8) NOAEL

. A NOAEL is th e highest exposure level at which no harmful effect s were s een in the organ s y stem studied. Ke y num ber 18 reports a NOAEL of 3 ppm for the respiratory s y stem ,AMMONIA B-4 APPENDIX B
which was used to derive an interm ediate exposure, inhalation MRL of 0.0 05 pp m (see footnote " b "). (9) LOAEL

. A LOAEL is the lowest dose used in the study that caused a harm ful health effect. LOAELs hav e been classif i ed into "Less Serious" an d "Serious" effects. These d i stinctions help readers identify the levels of exposure at whic h adverse health effects first appear and the gradation of e ffects with increasing dose

. A brie f description of the specific endpoint used to quantify the adverse effect acco m p anie s the LOAEL. The respiratory effect reported in ke y num ber 18 (hyperplasia) is a Less Serio u s LOAEL of 10 ppm

. MRLs are not derived from Serious LOAELs. (10) Referen c e . The com p let e r e ferenc e citat i on is gi ven i nChapter 9 o f the profile. (11) CEL

. A CEL is the lowest exposure level associ ated with the onset of carcinogenesis in experi m e ntal or epidem iologic studies. CELs are al way s considered serious effects. The LSE tables and figures do not c ontain NOAELs for cancer, but the text may report doses not causing mea s urable c ancer increa s es. (12) Footno tes
. Explanations of abbreviations or refere nce notes for dat ain the LSE t a bles are fou nd in the footnot es. Footnote "b" in dicates that the NOAEL of 3 ppm in ke y nu m b er 18 was used to derive an MRL of 0.0 05 pp m .
LEGE ND See Sam p le Figure 3-1 (p age B-7) LSE figures graphically ill ustrate the data presented in the corresponding LSE tabl es. Figures help the reader quickly com p are health effects according t o exposure concentrations for particular exposure periods. (13) Exposure Period

. T h e same exposure periods appear as in the LSE table. In this exam ple, health effects observ e d within the acute and interm ediate exp o sure periods are illustrated. (14) Health Effect

. These are t h e categories of health effects for which reliable quantitative data exists. The sam e health eff ects appear i nthe LSE table. (15) Levels of Exposure

. Conc entrations or doses for each health effect in the LSE tables are graphically di splay e d i nthe LSE figures. Exposur e concentration or dose is measured on th e log scale "y " axis. Inhalation e xposure is reported in m g /m 3 or ppm an d oral exposur e is reported in m g /kg/day

. (16) NOAEL

. In this exa m ple, the open circle designated 18r identifies a NOAEL cri tical end point in the rat upon which an interm ediate inhalati on exposure MRL is based. The ke y num ber 18 corresponds to the entr y i n the LSE table. The dashed descending arrow indicates the extrapolation from the exp o sure level of 3 ppm (see e n try 18 in the table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17) CEL

. Key num b e r 38m is one of three studies fo r whi c h CELs were derived. Th e diam ond sy m bol refers to a CEL for the test species-m ouse. The num ber 38 corresponds to the entr y i nthe LSE table.AMMONIA B-5 APPENDIX B (18) Estim a ted Up per-Bound H u man Cancer Risk Levels

. This is the range associate dwith the upperbound for life time cancer ri sk of 1 i n10,000 t o 1 i n10,000,000. These risk level s are derived from the EPA' s Hu m an Health Assessment Group' s upper-bound e s tim a tes of the slope of the cancer dose r esponse curve at low dose levels (q 1 *). (19) Key to LSE F i gure . The K e y explains the abbreviations and s y m bols used in the figure.AMMONIA B-6 APPENDIX BSAMPLE1→Table 3-1.Levels ofSignificant Exposure to [Chemical x] – InhalationExposureLOAEL (effect)Key tofrequency/NOAELLess seriousSerious (ppm)figureaSpeciesdurationSystem(ppm)(ppm)Reference10↓9↓8↓7↓6↓5↓INTERMEDIATE EXPOSURESystemic→→23418Rat13 wkResp3b10 (hyperplasia)→5 d/wkNitschke et al. 19816 hr/dCHRONIC EXPOSURECancer11↓38Rat18 mo20(CEL, multipleWonget al. 19825 d/wkorgans)7 hr/d39Rat89–104 wk10(CEL, lung tumors,NTP 19825 d/wknasal tumors)6 hr/d40Mouse79–103 wk10(CEL, lung tumors,NTP 19825 d/wkhemangiosarcomas)6 hr/d12→aThe number corresponds toentries inFigure 3-1.bUsed to derive an intermediate inhalationMinimal Risk Level (MRL)of5x10-3ppm; dose adjusted forintermittent exposure and dividedby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for humanvariability).AMMONIA B-7 APPENDIX BAMMONIA C-1



### APPENDI X C. ACRONYMS, AB BREVI ATIONS, AND SYMBOLS
ACGIH Am erican Co nference of Gove rnm e ntal Industrial H y g i enists ACOEM A m eri can Co llege of Occupational and Environm ental Medicine ADI acceptable da ily intake ADME absorption, di stribution, m e tabolism , andexcretion AED ato m ic emission detection AFID alkali flam e ionization det ector AFOSH Air Force Off i ce of Safety and Health ALT alanine a m in otransferas e AML acute my eloid leukem i a AOAC Association of Official An aly tical Chemists AOEC Association of Occupationa l and Environmental Clinics AP alkaline phos phatase APHA A m eri can Public Health A ssociation AST aspartate a m i notransferase at m at m o sphere ATSDR Agency for Toxic Substanc es and Disea s e Registry AWQC Am bient Wat e r Quality Cri t eria BAT best available technolog y BCF bioconcentration factor BEI Biological Exposure Index BMD benchmark dose BMR benchmark response BSC Board of Scientific Counselors C centigrade CAA Clean Air Act CAG Cancer Assessm ent Group of the U.S. E nvironm ental Protection Ag ency CAS Che m ic al Abstract Servic e s CDC Centers for D i seas e Control and Prevention CEL cancer eff ect level CELDS Co m puter-Environm ental Legislative D a ta Sy stem CERCLA Co m p rehensive Enviro nmental Res ponse, Co m p ensat ion, and Liability Act CFR Code of Federal Regulations Ci curie CI confidence interval CL ceiling lim it value CLP Contract Laborator y Progr am c mcenti m e t e r CML chronic my eloid leukem i a CPSC Consumer Products Safety Commission CWA Clean Water Act DHEW Department of Health, Education, and W e lfare DHHS Depart ment of Health and Hu m an Services DNA deox y r ib onuc leic acid DOD Depart ment of Defense DOE Department of Energ y DOL Department of Labor DOT Department of TransportationAMMONIA C-2 APPENDIX C
DOT/UN/ Department of Transportation/United Nations/ NA/IMCO North Am erica/Inte rnational Maritime Dangerous Goods Code DWEL drinkin g water exposure level ECD electron captu re detection ECG/EKG electrocardio g ra m EEG electroenceph a logra m EEGL Em ergency Exposure Guid ance Level EPA Environm ental Protection Agency F Fahrenheit F 1 first-filial generation FAO Food an d Agr i cultural Organization of th e United Nations FDA Food an d Dru g Adm i nistration FEMA Federal Em ergency Manag e m e nt Agency FIFRA Federal Insecticide, F ungic i de, and Rode nticide Act FPD flam e photometric detectio n fpm feet per m i nute FR Federal Register FSH follicle sti m ulating horm one g gram GC gas chro m a to graphy gd gestational day GLC gas liquid chr o matography GPC gel permeatio n chrom a tography HPLC high-perform ance liquid chrom a tograp hy HRGC high resolution gas chrom a tography HSDB Hazardous Su bstance Data Bank IARC International Agency for Resear ch on Cancer IDLH imm e diately dangerous to life and health ILO International Labor Organization IRIS Integrated Risk Inform atio n Sy stem Kd adsorption rat i o kg kilogram kkg metric ton K oc organic carbon partition coefficient K ow octanol-water partition coe fficient liter LC liquid chr o m a tography LC 50 lethal concentration, 50% kill LC Lo lethal concentration, low LD 50 lethal dose, 50% kill LD Lo lethal dose, low LDH lactic dehy drogenase LH luteinizing horm one LOAEL lowest-observed-adverse- effect level LSE Levels of Significant Exposure LT 50 lethal time, 50% kill m m e ter MA trans,trans -muconic acid MAL maxi m u m allowable level mCi millicurie MCL maxi m u m contam inant level LAMMONIA C-3 APPENDIX C
MCLG maxim u m contam inant level goal MF m odify ing fa ctor MFO mixed function oxidase m g milligram mL milliliter mm milli m e t e r mmHg milli m e t e rs of mercury mmol milli m o le m

ppcf millions of particles per cubic foot MRL Minimal Risk Level MS mas s spectro metry NAA QS National A mbient Air Quality Standard NAS National Aca d e my of Scie nce NATICH National Air Toxics Infor m ation Clearingho use NATO North Atlantic Treaty Organization NCE norm o chro matic ery throc ytes NCEH National Center for Enviro nmental Health NCI National Cancer Institute ND not detected NFPA National Fire Protection Association ng nanogram NHANES National Heal th and Nutriti on Exam inati on Sur v ey NIEHS National Institute of Environmental Heal th Sciences NIOSH National Institute for O ccupational Safety and Health NIOSHTIC NIOSH ' s Com puteri zed Information Retrieval Sy stem NLM National Library of Medicine nm nanom eter nm ol nanom ole NOAEL no-observed-adverse-eff e c t level NOES National Occupational Exp o sure Surve y NOHS National Occ upational Hazard Surve y NPD nitrogen phos phorus detection NPDES National Pollutant Discharge Elim inatio n S y stem NPL National Priorities List NR not reported NRC National Research Council NS not specified NSPS New Source Perform ance Standards NTIS National Technical Information Service NTP National Toxi colog y Pr ogr am ODW Office of Drinking Water, EPA OERR Office of Emergency and Remedial Response, EPA OHM/TADS Oil and Hazardous Materials/ Technical Assistance Data Sy stem OPP Office of Pest icide Programs, EPA OPPT Office of Pollution Prevent i on and T oxic s , EPA OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA OR odds ratio OSHA Occupational Safety and H ealth Ad m i nistration OSW Office of Solid Waste, EPA OTS Office of Toxic Substances OW Office of Wat e rAMMONIA C-4 APPENDIX C
OWRS Office of Wat e r Regula tions and Standards, EPA PAH pol y c y c lic aromatic hy dr o carbon PBPD phy s iologically based pharmacody nam i c PBPK phy s iologically based pharmacokinetic PCE pol y c hrom atic ery throc y t e s PEL perm issible exposure lim it pg picogram PHS Public Health Service PID photo ionizati on detector pm ol picom o le PMR proporti onate m o rtality ratio ppb parts per billion ppm parts per m illion ppt parts per trillion PSNS pretreat ment standards for new sources RBC red bloo d cell REL reco mmended exposure le vel/lim it RfC referenc e concentration RfD reference dose RNA ribonucleic acid RQ reportable qu antity RTECS Registry of Toxic Effects of Che m ical S ubstances SARA Superfund A m end m ents and Reauthori zation Act SCE sister chro ma tid exchange SGOT seru m gluta m ic oxaloacetic transa m i nas e SGPT seru m glutamic p y ruvic tran sam i nase SIC standard industrial clas sific a tion SIM select ed ion m onitoring SMCL secondary m a xim u m contaminant level SMR standardized m o rt ality rati o SNARL suggested no adverse respo n se level SPEGL Short-Term P ublic Em ergency Gui d ance Level STEL short term exposure lim it STORET Storage and Retrieval TD 50 toxic dose, 50% specifi c toxic effect TLV threshold limit value TOC total organic carbon TPQ threshold planning quantity TRI Toxics Release Inventor y TSCA Toxic Substances Control Act TWA time-w e ighted average UF uncertainty factor U.S. United States USDA United States Depart ment of Agriculture USGS United States Geological Surve y VOC volatile organic co m pound WBC white blood c e ll WHO World Health OrganizationAMMONIA C-5 APPENDIX C

> greater than ≥ greater than or equal to = equal to < less than ≤ less than or equal to % percent αalpha β beta γ ga mma δ delta μ mmicro m eter μg microgram

* q 1 cancer slope f actor

– negative + positive (+) weakly positi ve result (–) weakly negati ve resultAMMONIA D-1



### APPENDI X D. INDEX
abs o r b ed dose

.................................................................................................................. ............................................ 97 adenocar cinom a ................................................................................................................. .................................... 49, 57 adre nal gland

.................................................................................................................. ......................... 21, 54, 67, 105 ads o r p tion

..................................................................................................................... ....................... 14, 127, 135, 136 aerobic

........................................................................................................................ ............................................... 137 anaer obic......................................................................................................................

...................................... 126, 137 aspartate am inotrans fe rase (s ee AS T)

........................................................................................... ............................... 68 AST (see aspart ate am inotrans ferase )

........................................................................................... ............................... 68 bioacc um ulation

................................................................................................................ ........................................ 148 bioavaila bility

................................................................................................................ ............................................ 148 biom arker

...................................................................................................................... ... 9 6 , 9 7 , 9 8 , 1 08, 109 , 15 3, 1 60 blood cell count
............................................................................................................... ...................................... 53, 66 body weight ef fects

............................................................................................................ .............................. 54, 67, 71 breast m ilk

.................................................................................................................... ......................................... 7, 145 bur n s ............................. 4, 6, 7, 8, 15, 16, 25, 26, 48, 52, 55, 65 , 66, 70, 71, 73, 75, 80, 90, 92, 95, 101, 102, 104 , 1 07 cancer ......................................................................................................................... ................................ 6, 70, 94, 106 carcinoge n..................................................................................................................... ................................... 57, 70, 98 carcinoge nic

................................................................................................................... 6 , 23 , 24 , 69 , 98 , 10 6, 1 0 8 , 163 carcinoge nicity

................................................................................................................ .......................................... 106 carcinom a ...................................................................................................................... .................................. 49, 56, 75 cardiac arr h ythm ia

............................................................................................................. .......................................... 52 cardi ovasc ular

................................................................................................................. ....... 21, 52, 56, 57 , 58, 71, 104 cardi ovasc ular effects

......................................................................................................... ..................... 52, 58, 71, 104 chr o m o som a l aber rations

........................................................................................................ ............................. 76, 106 death

................................................................................................................ 6, 15, 17, 23 , 25 , 48 , 58 , 66 , 73 , 90 , 10 2 deoxyri b onucleic acid (s ee D N A )

................................................................................................ ................................ 77 derm al effects

................................................................................................................. ........................... 16, 17, 54, 73 DN A (see de oxyri bonucleic acid)

................................................................................................ .......... 3, 15, 77, 78, 96 dyspnea

........................................................................................................................ .............. 19, 47, 48, 49, 105, 163 endoc r ine

...................................................................................................................... ....................... 54, 67, 71, 92, 93 endoc r ine e ffe cts
.............................................................................................................. ...................................... 54, 67 erythem a ....................................................................................................................... ......................................... 65, 74 fertilizer

......................................... 2, 3, 4, 7, 13, 14, 46, 47, 76, 95, 105, 106, 108, 11 8, 122, 126, 127, 131, 132 , 13 3, 1 3 9 , 140 , 14 1, 1 4 3 , 144 , 14 5, 1 6 2 , 163 , 16 8 fetus

.......................................................................................................................... ................................. 7, 56, 93, 106 gastr o intestin al effects

....................................................................................................... .............................. 52, 65, 71 gene ral popula tion

..................................................................................................... 14, 18, 70 , 96 , 10 6, 1 2 7 , 1 4 3 , 14 6 genotoxic

...................................................................................................................... ......................................... 23, 76 genotoxi city

................................................................................................................... ............................................ 106 gr oundw a ter
.................................................................................................................... ..... 95, 128, 131, 136, 137, 142 half-life

...................................................................................................................... .................... 14, 96, 126, 127, 137 hem a tological effects

.......................................................................................................... ................................... 53, 66 hepatic e ffects

................................................................................................................ ........................................ 53, 66 hydrol ysis

..................................................................................................................... ............................................. 133 hydroxyl ra dical

............................................................................................................... .................................. 126, 137 hype ramm onem i a .............................................................................................................. 15, 17 , 68 , 90 , 93 , 95 , 98 , 99 imm une system
.................................................................................................................. ............................ 55, 75, 107 imm unological

.................................................................................................................. ......................... 23, 55, 67, 75 imm unological effects

.......................................................................................................... ................................. 67, 75 irritation

......................................................................... 6, 8, 16, 18, 19, 26, 46, 47, 79, 95, 97, 99 , 102 , 10 4, 1 0 5 , 163 K ow ............................................................................................................................... .............................................. 115 LD 50 ............................................................................................................................... .............................................. 55AMMONIA D-2 APPENDIX D
livestock

............................................................. 5, 8, 13, 16 , 46, 74, 105, 126, 131, 132, 133, 139, 140, 14 1, 1 4 7 , 151 m anure ........................................................................................... 2, 5, 13, 14, 131, 136, 140, 1 42 , 14 3, 1 4 4 , 145 , 15 1 m e tabolic acidosi s............................................................................................................. ................. 21, 57, 58 , 66, 104 m i cronuclei

.................................................................................................................... ...................................... 76, 106 m ilk

........................................................................................................................... ......................................... 150, 151 m

u scarinic rec e ptor
............................................................................................................ .......................................... 90 m

u sculoskelet a l effects

........................................................................................................ .................................. 53, 66 neopla stic

..................................................................................................................... .......................................... 49, 57 neur obe havior al

................................................................................................................ ........................................... 93 neur ochem i cal

.................................................................................................................. .......................................... 107 neur otrans m i tter
............................................................................................................... .................................... 95, 107 nitrate ..........................................................2, 14, 83, 113, 122, 126, 127, 136, 137, 138, 142, 159, 166, 1 67 , 168 , 16 9 nitrite

........................................................................................................................ ........................... 14, 126, 127, 159 nitroge n cycle

................................................................................................................. ........... 117, 123, 131, 137, 148 nitroge nfi xation

.............................................................................................................. .................. 117, 123, 126, 134 ocular ef fects

................................................................................................................. ...................... 17, 54, 58, 71, 74 pharm acodynam i c ................................................................................................................ ........................................ 87 pharm acokinet i c................................................................................................................ ................... 87, 88, 89, 90, 94 placenta

....................................................................................................................... ................................................... 7 poultry

............................................................................................................. 5, 14, 127, 1 31, 133 , 14 2, 1 44, 150 , 15 1 pulm onary function

................................................................................................ 16, 18, 19, 2 6 , 46 , 47 , 10 2, 1 0 5 , 1 63 rate constant
.................................................................................................................. ............................................. 137 renal e ffects

.................................................................................................................. ....... 15, 21, 53, 66 , 73, 104, 105 retention

...................................................................................................................... ........................................... 79, 81 solub ility

..................................................................................................................... ..................... 16, 73, 90, 101, 113 toxicoki netic

.................................................................................................................. ...................................... 23, 109 urea ............... 15, 17, 21, 57, 78 , 79, 80, 81, 82, 83, 86 , 87, 90, 91, 95, 97, 99 , 101, 109, 111, 122, 131, 133, 144, 155 vapor phase

.................................................................................................................... ............................................ 159 vola tility

..................................................................................................................... ................................................ 113 volatilization

...................................................................................... 126, 132 , 135, 136, 137, 13 8, 1 4 0 , 144 , 15 6, 1 5 9 weanling

....................................................................................................................... ............................. 58, 65, 66, 67