December 1990
WHITE PHOSPHORUS
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, DC 20460

-------
Health Advisory on White Phosphorus
Authors:
Loretta Gordon, M.S.
William R. Hartley, Sc.D.
Welford C. Roberts, Ph.D.
Project Officer:
Krishan Khanna, Ph.D.
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, DC 20460
December 1990

-------
PREFACE
This report was prepared tn accordance with the Memorandum of Understanding
between the Department of the Army, Deputy for Environment Safety and
Occupational Health (OASA(I&L)), and the U.S. Environmental Protection Agency
(EPA), Office of Drinking Water (ODW), Criteria and Standards Division, for
the purpose of developing drinking water Health Advisories (HAs) for selected
environmental contaminants, as requested by the Army.
Health Advisories provide specific advice on the levels of contaminants in
drinking water at which adverse health effects would not be anticipated and
which include a margin of safety so as to protect the most sensitive members
of the population at risk. A Health Advisory provides health effects
guidelines, analytical methods and recommends treatment techniques on a case-
by-case basis. These advisories are normally prepared for One-day, 10-day,
Longer-term and Lifetime exposure periods where available toxicological data
permit. These advisories do not condone the presence of contaminants in
drinking water; nor are they legally enforceable standards. They are not
issued as official regulations and they may or may not lead to the issuance of
national standards or Maximum Contaminant Levels (MCLs).
This report is the product of the foregoing process. Available toxicological
data, as provided by the Army, on the munitions chemical white phosphorus (WF)
have been reviewed and relevant findings are presented in this report in a
manner so as to allow for an evaluation of the data without continued
reference to the primary documents. This report has been submitted to
critical internal and external review by the EPA.
A companion document, "Data Deficiencies/Problem Areas and Recommendations for
Additional Data Base Development for White Phosphorus" is included in this
report.
1 would like to thank the authors, Ms. Loretta Gordon, Dr. William Hartley and
Dr. Welford Roberts who provided the extensive technica". skills required for
the preparation of this report. I am grateful to the members of the EPA Tox-
Review Panel who took time to review this report and to provide their
invaluable input, and I would like to thank Dr. Edward Ohanian, Chief, Health
Effects Branch, and Dr. Margaret Stasikowski, Director, Criteria and Standards
Division, for providing me with the opportunity and encouragement to be a part
of this project.
The preparation of this Advisory was funded in part by Interagency Agreement
(1AG) 85-PP5869 between the U.S. EPA and the U.S. Army Medical Research and
Development Command (USAMRDC). This IAG was conducted with the technical
support of the U.S. Army Biomedical Research and Development Laboratory
(USABRDL).
Krishan Khanna, Project Officer
Office of Drinking Water

-------
TABLE OF CONTENTS
ass
LIST OF TABLES 					Hi
LIST OF APPENDICES		Hi
EXECUTIVE SUMMARY 		ES-1
I. INTRODUCTION 			1-1
TI. GENERAL INFORMATION 				II-l
III. OCCURRENCE		IIM
IV.	ENVIRONMENTAL FATE
V.	PHARMACOKINETICS .
A.	Absorption . .
B.	Distribution
C.	Excretion . .
D.	Metabolism . .
IV-1
V-l
V-l
V-2
V-12
V-12
VI
VII.
B.
HEALTH EFFECTS 	
A. Health Effects in Humans 	
1.	Short-term Exposure 	
a,	Dermal/Ocular Effects 	
b.	Respiratory Effects . 	
2.	Longer-term Exposure 	
Health Effects in Animals				 .
1.	Short-term Exposure 	
a. Skin and Eye Irritation, Dermal Sensitization
2.	Longer-term Exposure 	
a.	Ninety-day to Eight-month Studies 	
b.	Lifetime Study		
Reproductive Effects 	
Developmental Effects 	
Carcinogenicity 	
Genotoxlcity 	 ,
3.
4.
5.
6.
HEALTH ADVISORY DEVELOPMENT 	
A.	Quantification of Toxicological Effects .
1.	One-day Health Advisory 	
2.	Ten-day Health Advisory 	
3.	Longer-term Health Advisory . , . .
4.	Lifetime Health Advisory 	
B.	Quantification of Carcinogenic Potential
VI-1
VI-1
VI-1
VI - 6
VI - 7
VI- 7
VI-10
VI-10
VI -13
VI -14
VI -15
VI -17
VI -17
VI -18
VI -18
VI	-18
VII-1
VII-5
VII	-6
VII -6
VII - 6
VII-6
VII-9
contlnued-
i

-------
Table of Contents - continued
Page
VIII.	OTHER CRITERIA, GUIDANCE AND STANDARDS 		VIII-1
IX.	ANALYTICAL METHODS			IX-1
X.	TREATMENT TECHNOLOGIES . 			X-l
XI.	CONCLUSIONS		XI-1
XII.	REFERENCES		XII-1
ii

-------
LIST OF TABLES
l&m
II-l General Chemical and Physical Properties of WP 		11 - 2
V-1 Percentage of Orally Administered ^P-WP
Recovered in Rats in 4 Hours and 1 and 5 Days		V-3
V-2 Average Radioactivity in Tissue Homogenates
of Mice, Rats and Rabbits		V-4
V-3 Radioactivity In Tissue Fractions 		V-5
V-4 Percent of Administered P Recovered from
Various Organs 2 Hours after Oral Administration of WP in Rats	V-7
V-5 Percent of Total Liver Activity of
In Hepatic Subcellular Fractions of WP-treated Rats 	 .	V-8
V-6 Percentage of Administered ^P-WP Recovered from
Various Tissues 4 Hours and 1 and 5 Days after Oral
Administration				V-9
V-7 Tissue-to-Blood Concentration Ratios at 4 Hours,
1 Day and 5 Days after Oral Administration of ^P-WP
to Rats , 		 V-10
V-8 Accumulation of Radioactivity in Rats
24 Hours after Receiving J
-------
EXECUTIVE SUMMARY
White phosphorus (WP) is a transparent waxy solid that is an allotropic form
of the element phosphorus. It is not a naturally occurring substance, but is
manufactured by reducing phosphate rock in the presence of sand and coke in an
electric furnace. White phosphorus exists in three basic forms: dissolved,
colloidal and large particulate.
White phosphorus is highly reactive and ignites spontaneously in air at 30C.
Storage and transport of WP must occur under water. The water used to store
and transport WP, and that used to manufacture and produce it are known as
"phossy water". The major transformation processes for WP are oxidation and
hydrolysis. Volatilization is a significant transport process between water
and air and soil and air. Photolysis, biodegradation and reduction are not
important fate processes of WP.
Military use of WP has been as a screening smoke and incendiary device. Non-
military uses have included WP in matches, fireworks and rat poison. These
uses have been discontinued because of toxicity concerns. White phosphorus is
still used in analytical chemistry, in the manufacture of phosphorus compounds
and as an additive to semiconductors and electroluminescent coatings.
Pharmacokinetics
White phosphorus may be absorbed by inhalation, oral intake or dermal contact.
Absorption following administration of -^P-labelled WP was moderate and
essentially complete in 24 hours. Most of the absorbed radioactivity was
excreted In the urine. In studies of the distribution of 3^P radioactivity In
various organs, the highest levels were in the liver. Blood and skeletal
muscle also contained significant levels of ^2p and accumulation was evident
in all examined tissues.
Health Effects in Humans
The principal adverse health effect associated with WP is its chronic effect
on bones, specifically the jaw. The occurrence of "phossy jaw", or phosphorus
necrosis of the jaw, is associated with inhalation of WP fumes over an
exposure period ranging from several months to over 18 years. Beginning as a
local mouth Irritation, "phossy jaw" progresses to a destructive bone disease,
affecting all of the upper and/or lower jaw. Although the exact cause of the
disease is not known, it is believed that it begins with a sore or extraction
site that will not heal. The symptoms are progressive in nature and include
inflammation and sclerosis of the bones and periosteum, swelling and
ulceration of the gums and mucous membranes of the buccal cavity, loose teeth
and eventually destruction of the jawbone, accompanied by a foul garlic-like
odor. A similar condition to "phossy jaw" was reported to result from
intermittent direct contact with a WP pellet placed in the mouth over a
15-year exposure period as part of a magic act.
ES-1

-------
Poisoning by ingestion of WP-containing substances has been reported with
fatal doses of 1 tng/kg in adults and 3 mg total in a child. Poisoning has
primarily been associated with ingestion of rat poisons or fireworks
containing WP, Acute poisoning with WP has resulted in electrocardiogrcphic
changes, accompanied by cardiac enlargement; effects on the central nervous
system, including lethargy, stupor, coma, delirium and convulsions; changes in
the metabolism of nitrogen, carbohydrates, fat and protein; hematological
changes including an increase in the red blood cells and hemoglobin, and
development of shock, hyperglycemia, hyponatremia, severe metabolic acidosis,
hypocalcemia, hyper- and hypophosphatemia and widespread edema.
White phosphorus burns resulting from its use as a munition chemical have
resulted In widespread tissue damage with necrosis and systemic effects. One
study determined that ocular exposure to WP particles resulted in minimal
signs of injury, while exposure to the fumes caused slight to severe symptoms
with conjunctivitis, blepharospasm, photophobia, lacrimation and discharge.
Inhalation of WP smoke has resulted in respiratory effects, including
restlessness, anxiety, distressed cough, shortness of breath and hoarseness.
Health Effects in Animals
Animal studies indicate an LD50 that averages approximately 3.5 mg/kg in rats
and 4.8 mg/kg in mice. Toxic oral doses are estimated to range from
8.78 mg/kg in rats to 25 mg/kg in mice and produce effects in the liver,
kidney and heart. Radiographic changes to the bone were evident at doses of
0.65 mg/kg/day for 16 days in rats and 0.3 mg/kg/day for 13-117 days in
rabbits. In other animal studies, white phosphorus solutions resulted in
burns which produced systemic toxicity. A 0.1% solution of WP did not cause
irritation to the skin or eye.
Studies of rats, rabbits and guinea pigs over periods varying from 90 days to
lifetime have shown that orally administered WP produces weight loss and
adverse liver and bone effects. Cirrhosis developed in rabbits and guinea
pigs given daily oral doses of 0.66 to 1 mg/kg over a 1-month period. Gross
liver lesions developed in guinea pigs after 9 weeks at a daily oral dose of
approximately 0.43 mg/kg/day. Rats exhibited marked and progressive growth
deficiency at a 0.072 mg/kg/day oral dose over a 4- to 6-month period. A
lower dose of 0.0027 mg/kg/day over 15 weeks produced a 13% late weight gain
with no growth depression. This dose was considered a No-Adverse-Effect-
Level (NOAEL) for effects of WP on growth.
A reproduction study of female rats given an administered dose of
0.075 mg/kg/day showed an increase in mortality of the offspring because of
difficulties during parturition. A (NOAEL) of 0.015 mg/kg/day was reported
for this study.
A concentration level of 0.015 mg/kg/day is identified as the NOAEL based on
the above described reproduction study in rats. Using this NOAEL, the
reference dose (RfD) is calculated to be 0.000015 mg/kg/day or 0.02 ug/kg/day.
ES-2

-------
The Drinking Water Equivalent Level (DWEL) is determined to be 0,5 ug/L and
the Lifetime Health Advisory (HA) is determined to be 0,1 ug/L. One-day, ten-
day s.nd longer-term health advisories are not recommended because of the
exf *ir.tr toxicity of WP following oral ingestion in humans and animals and the
lack of additional data.
Using the EPA criteria for cancer weight of evidence, WP has been classified
as Group D, Inadequate human and animal evidence of carcinogenicity.
ES-3

-------
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking Water
(ODW)t provides information on the health effects, analytical methodology and
treatment technology that would be useful in dealing with the contamination of
drinking water. Health Advisories describe nonregulatory concentrations of
drinking water contaminants at which adverse health effects would not be
anticipated to occur over specific exposure durations. Health Advisories
contain a margin of safety to protect sensitive members of the population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The Advisories are
subject to change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
For those substances that are known or probable human carcinogens, according
to the Agency classification scheme (Group A or B), Lifetime HAs are not
recommended. The chemical concentration values for Group A or B carcinogens
are correlated with carcinogenic risk estimates by employing a cancer potency
(unit risk) value together with assumptions for lifetime exposure and the
consumption of drinking water. The cancer unit risk is usually derived from
the linear multistage model with 95% upper confidence limits. This provides a
low-dose estimate of cancer risk to humans that is considered unlikely to pose
a carcinogenic risk in excess of the stated values. Excess cancer risk
estimates may also be calculated using the one-hit, Weibull, logit and probit
models. There is no current understanding of the biological mechanisms
involved in cancer to suggest that any one of these models is able to predict
risk more accurately than another. Because each model is based upon differing
assumptions, the estimates that are derived can differ by several orders of
magnitude.
1-1

-------
II. GENERAL INFORMATION
Pure white phosphorus (WP), a transparent waxy solid, is one of three
allotropic forms (white, red, black) of the element phosphorus (P).
Crystalline in nature, WP exists in two forms: alpha-white phosphorus, which
is the more common form and appears as cubic crystals at room temperature, or
beta-white phosphorus, which forms at -79. 6*C as hexagonal crystals (Uhrmacher
et al., 1985). The commercial product is 99.9% pure (0.02% arsenic; traces of
hydrocarbons) and has a slight yellow color, presumably due to traces of other
allotropic forms, primarily red phosphorus (Wasti et al., 1978). Yellow
phosphorus or elemental phosphorus are names synonymous with WP.
The general chemical and physical properties of WP are presented in Table
II-l. White phosphorus darkens upon exposure co light and is highly reactive,
igniting spontaneously in air at 30C and requiring its storage and transport
under water (Hawley, 1981). When heated between 400600C, red phosphorus is
produced. When melted or when its vapor is condensed, all allotropic forms
result in the same straw-colored liquid, which forms WP upon cooling. White
phosphorus reacts with atmospheric oxygen to form phosphorus pentoxide (F^^q)
which further reacts with the moisture in air to form phosphoric acid. With
aqueous alkali, WP reacts to form phosphine and with sulfur to form sulfides.
It combines with halogens to form tri- or penta-halides and with both metals
and nonraetals to form phosphides (Wasti et al., 1978).
When WP is combusted in air it produces a dense white smoke, a characteristic
which has contributed to its use, since World War II, as a screening smoke and
incendiary device. Chemical composition of the smoke has been reported by
Brown et al. (1981) as consisting of phosphorus pentoxide and lower oxides
which react rapidly with the moisture in air to form 0-phosphoric and
0-phosphorous acids. Manthei et al. (1980) reported that the residue
collected from WP/felt wedge (FU) spontaneous ignitions in chamber tests
contained 65% phosphoric acid. Original P4 content of the WP/FW device was
analyzed at 75.3% elemental phosphorus (Spanggord et al., 1985)
The nonmilitary use of WP in matches, fireworks and as a rat poison has been
largely discontinued due to its extreme toxicity (Spanggord et al., 1979).
White phosphorus is still used in analytical chemistry, in the manufacture of
phosphoric acid and other phosphorus compounds, phosphor bronzes and metallic
phosphides, as an additive to semiconductors and in electroluminescent
coatings (Hawley, 1981).
Elemental or white phosphorus does not exist as such in nature, but rather is
found as phosphate rock [impure Caj^O^^], its major commercial source, as
well as in apatite [035^04)3F] , in bones and teeth and in organic compounds
of living tissue (Hawley, 1981). It is mined from marine sediment deposits
(Halmann, 1972 as cited in Sullivan et al., 1979) and manufactured by reducing
the phosphate rock in the presence of sand and coke, in an electric furnace.
The gaseous product is condensed and collected to form the base for the
II-l

-------
Table II-1 General Chemical and Physical Properties of WP
CAS No,
Names
Molecular Weight
Empirical Formula
Structure
7723-14-0 (12185-10-3)
yellow phosphorus; elemental
phosphorus; WP
123.90
(tetrahedral)
Physical State
Specific Gravity
Melting Point
Boiling Point
Autoignition Temperature
Vapor Pressure
Solubility Characteristics
Water
Alcohol
Ether
Olive Oil
Chloroform
Benzene
Carbon Disulfide
Octanol/Water Partition Coefficient
(log Kow) (calculated)
colorless to yellow, waxy solid
1.82 (solid, 20*C)
1.745 (liquid, 44.5"C)
44.rc
280C
30'C (moist air; higher in dry air)
0.04 mmHg (25'C)
3mg/L (15C); 4.1 mg/L (25"C)
2.5 g/L
9.8 g/L
12.5 g/L
25 g/L
28.5 g/L
1,250 g/L
4.2-4.9 (15C)
References: Hawley, 1981; Spanggord et al. , 1983, 1985; Sullivan et al.,
1979; Uhroacher et al., 1985; Wasti et al., 1978; Windholz, 1983.
a CAS has assigned the first number to both red and white phosphorus;the
second applies to WP alone.
II-2

-------
refined commercial WP. Alternately, the phosphate rock may be reacted with
sulfuric acid. The product is filtered to remove the resulting calcium
sulfate (CaSO^) and the phosphoric acid is concentrated by evaporation (wet
method) (Hawley, 1981),
II-3

-------
III. OCCURRENCE
White phosphorus does not exist in nature in its free elemental form but
rather is found in phosphate rock from which it is reduced in the presence of
sand and coke in an electric furnace. Its use by the military as a screening
smoke, deployed by means of bursting devices such as shells and grenades, is
one source of its entry into the environment. Its use for nonmilitary
purposes is largely in the manufacture of other phosphorus salts and acids
while its usa in matches, rat poisons and fireworks has largely been
discontinued due to its high toxicity in the workplace environment.
White phosphorus, as used by the military, is purchased from commercial
sources and transported, under warm water, to their Pine Bluff, Arkansas
facility, where it is loaded, on an intermittent basis, into various
incendiary devices (Sullivan et al., 1979). The water generated during its
manufacture, production processes and transport remains as the single most
important source of WP introduction into the environment. This water, known
as "phossy water", includes any water that has come into direct contact with
the solid or liquid phosphorus. Included in this category is the water used
in its condensation, collection and transport and which contains significant
amounts of colloidal and larger WP particles as well as lesser amounts of
dissolved phosphorus. Also designated as "phossy water" are the effluents
from loading and packing operations to include dip-tank overflow, spray water
used to wet the dip-fill line conveyors, water used to flush WP from the pipes
and that used in the periodic cleanup of tanks and facilities. This source of
"phossy water" varies considerably both as to amount produced and phosphorus
concentration. It also contains both dissolved and particulate elemental
phosphorus.
In 1969, Idler (cited in Dacre and Rosenblatt, 1974) reported typical
wastewater "phossy water" P4 content from the Electric Reduction Company
(ERCO) of Canada to be 13 mg/L with a total phosphorus content of 18 mg/L. A
discharge rate of 1,250 and 1,630 lbs/day has been reported for the P^ and
total phosphorus, respectively. Ponds at the ERCO production facility
contained levels of P4 ranging from 0.0012 to 0.265 ppm (cited in Sullivan et
al., 1979). Ackman et al. (1970, as cited in Davidson et al., 1987) reported
that during the initial stages of operation, the ERCO plant discharged 68 to
91 kg/day (equivalent to 150 to 205 lbs/day) of colloidal yellow phosphorus
into the Long Harbor Inlet - Placentia Bay, Newfoundland. Concentrations in
the bottom sediment, where the particulate WP settles as sludge over time,
were measured at 5,000 ppm near the effluent pipe and at 1 ppm at a distance
of 2.4 km from the pipe. This facility was closed in 1969,
In 1971, during a single day's filling operations at the Pine Bluff facility,
Pearson et al. (1976) reported that WP discharge (as P4) ranged from
16-53.4 mg/L (mean of 33.19 mg/L for 15 samples) with a flow rate of
0.2120.286 million gallons/day (Mgd) with a mean of 0.243 Mgd. During
routine water quality monitoring procedures at the facility, during the period
III-l

-------
from April to December, 1971, F4 content was measured at 0.01 to 104.0 mg/L,
with a mean of 6.3 mg/L for 159 samples. Using these data, Pearson et al.
(1976) calculated a discharge rate of 6.47 kg P^/day from the filling plant
based on a mean P4 concentration of 6.3 mg/L and the average flow rate of
0.243 Mgd from one line, operating 8 hours per day.
Pine Bluff Arsenal wastewater "phossy water" content was measured in 1973
(Blumbergs et al. as cited in Sullivan et al., 1979) at 14 to 37 ppm for P4
and at 450 ppm for total phosphorus. The wastewater from the filling plant is
piped, underground, to a small settling pond which overflows into an open
ditch containing limestone to precipitate the orthophosphates as calcium
phosphate. This ditch joins White Creek and overflows into Yellow Lake, both
located on the Pine Bluff Facility, during periods of high stream flow, high
rainfall or inundation of the Lake by the Arkansas River. Between 1971 and
1972, P4 concentrations in Yellow Lake were measured at mean values between
0.140.22 mg/L. Concentrations that had settled in the lake mud were measured
at 0.13 mg/L (Rosenblatt et al., 1973). In 1975, the concentrations of
elemental phosphorus ranged from a low of 0.02 ug/L at a point in the lake
furthest from the load and pack facility to a high ranging between
8.81-40.41 ug/L at the nearest measurement point (Pearson et al., 1976).
Sediment concentrations during this same period ranged from a low of
0,02 ug P4/kg at various sample site to a high of 43.38 ug P4/kg (wet weight)
at the nearest point sampling site. In 1979(a), Lai measured the P4 levels in
various sites on and off the Pine Bluff facility and determined levels
averaging 0.008 ug/L in Yellow Lake, 7.3 ug/L in White Creek, 0.004 ug/L in
the Arkansas River and 0.006 ug/L at locations outside of the Pine Bluff
facility. The highest level measured in this study was 13.8 ug/L in one
sample from White Creek.
The Arkansas facility has three dip-fill lines and one dry-fill line. Under
conditions of maximum production, the three dip-fill lines combined can
produce approximately 10,000 lbs/hour. Rosenblatt et al. (1973) estimated a
total fill capacity of 5,000,000 lbs/month. In 1972, it was reported that a
one-shift operation per day processes 450,000 lbs per month of WP into shells.
The flow rate during such operations is 166,500 gallons/day (gpd). One dry-
fill line was installed at the facility in 1973 with the addition of three
more lines programmed between FY75 through FY77. The dry-fill operations
eliminate much of the "phossy water" produced by the dip-fill method but some
wastewater will remain from the transfer and cleaning operations. The
construction of a triple-effect evaporator at the Pine Bluff facility is
anticipated to treat the remaining "phossy water", recover the white
phosphorus from the evaporator slag and recycle the evaporator condensate
(Rosenblatt et al. (1973).
White phosphorus can also enter the environment through stack emissions at the
Pine Bluff facility. White phosphorus vapor is converted primarily to
phosphoric acids or phosphates in the ambient air. Under normal condition,
Berkowitz et al. (1981) as cited in Davidson et al. (1987) estimated that
III -2

-------
255 lbs/hr of phosphoric acid would be emitted and 5,100 lbs/hr in the event
of scrubber breakdowns. White phosphorus stack emissions of 1 part per
thousand have been reported (Davidson et al. (1987).
Combustion of UP devices is another potential source of environmental
contamination. Under field conditions, the WP is rapidly converted in moist
air to polyphosphoric acids, a number of organic compounds and several
permanent gases via phosphorus pentoxide (P^O^q). Spanggord et al. (1985)
determined that about 90% of the P4 was converted to the pentoxide. Of the
phosphoric acids, the ortho-, pyro- and triphosphoric acids comprised
approximately 35% of the total and the tetra- to octaphosphoric acids
comprised approximately 27%. The remaining 28% consisted of higher phosphoric
acids. Phosphinic, phosphorous and metaphosphoric acids were not detected.
At a smoke density of 0.1 g/m"*, carbon monoxide was calculated at a median
concentration of 520 ppb, hydrogen at 180 ppb, phosphorus at 21 ppb and
methane at 16 ppb. Other compounds were calculated to be at levels of 6 ppb
or less (Katz et al., 1981).
Shinn et al. (1985) estimated maximum environmental concentrations of smoke
from the various WP devices following detonation and determined a range of
5-25 mg/nr for WP/FW bursting devices such as howitzers and rockets, and a
range of 1,800-3,500 mg/nr* for WP bursting devices such as mortars, guns,
rockets and howitzers. The maximum area impacted for WP bursting devices was
also estimated by Shinn et al. (1985) to have a range of 100-800 w? (less than
one quarter acre maximum) for mortars, guns, rockets and howitzers and a range
of 9,500-12,000 m2 (3 acres maximum) for WP/FW rockets and howitzers.
III-3

-------
IV. ENVIRONMENTAL FATE
Oxidation and hydrolysis are the major transformation processes for VP in the
environment. Volatilization is a significant transport process between water
and air and soil and air. White phosphorus is not transformed by photolysis
and it is resistant to biodegradation by anaerobic organisms. Reduction is
not considered an important fate process.
White phosphorus is known to exist in water in three basic forms, as dissolved
phosphorus with a solubility level of 3 mg/L, as colloidal white phosphorus,
and as large particles suspended in the water. Burrows and Dacre (1973)
reported that at concentrations well below the solubility limit of 3 mg/L,
elemental phosphorus disappeared from water by a first-order process with a
half-life of 2 hours at a temperature of 10*C (Zitko et al., 1970) and
0.85 hours at 30*C (Addison, 1971). At concentrations between 50-100 mg/L the
half-life was 80 hours at 30*C and 240 hours at 0*C (Bullock and Newlands,
1969). This small temperature effect together with the concentration effect
was considered to be consistent with a diffusion-controlled process. In
kinetic studies, Lai and Rosenblatt (1977a) reported half-lives of 3.5-6 hours
with a rate constant suggestive of dependence upon the amount of dissolved
oxygen, the temperature and the pH of aqueous solutions. White phosphorus has
also been reported to react rapidly with chlorine in water to form phosphorous
acid by way of the intermediate phosphorus trichloride (Blumbergs et al.,
1973). In contrast, Spanggord et al. (1985) estimated a half-life for soluble
WP in water in the range of 42 hours and indicated that other mechanisms
besides oxidation may occur to include hydrolytic processes.
Studies conducted in 1979(b) by Lai indicated that elemental phosphorus is
highly reactive in aqueous solutions, undergoing rapid degradation through
oxidation processes. In the presence of strong oxidizing agents, the P4 is
almost instantaneously reduced to trace levels. Its reduction under
environmental conditions was considered to be rapid enough to result in levels
considered toxicologically safe to aquatic life.
When WP is present in turbulent waters, such as rapidly flowing streams, the
half-life was estimated at 42 hours via oxidation. Hydrolysis or
volatilization may also occur. A volatilization half-life of 48.5 minutes was
calculated for a stream 4 feet deep with an eddy diffusivity of 1 cnr/sec.
Under turbulent conditions volatilization is, therefore, considered the
dominant process (Spanggord et al., 1985).
Spanggord et al. (1985) reported a half-life of 2.43 years for a solid 1 cm**
chunk of WP in water. During the course of oxidation, the surface of the
chunk took on a white appearance apparently due to oxidative/hydrolytic
changes. This surface skin was felt to present a limiting factor to the
subsequent oxidation process by presenting a barrier, resulting in
transformation being limited to oxygen diffusion.
IV-1

-------
Lai (1981) also reported that elemental phosphorus from water Is taken up by
bottom sediments where it undergoes degradation but at a slower rate. The
degradation products consist of nontoxic phosphorus species such as
hypophosphorous acid, phosphorous acid, and phosphoric acid. At the same
time, amounts of the P4 in sediment are released back into the water, mostly
due to mixing processes, such as after rainfall, resulting in sudden increases
in the phosphorus concentration in the overlying water. This resuspended
phosphorus would then undergo degradation by the oxidation processes occurring
in the water.
In the soil, WP is anticipated to persist for longer periods of time due to
the low oxygen levels. Spanggord et al. (1985) calculated a half-life greater
than 2 years for WP under anaerobic conditions. For a solid chunk of WP, 1 cm
in diameter, buried 12 cm beneath the surface, 10 years would be required for
complete oxidation. A longer period would be required in the presence of an
oxide layer on the surface of the WP chunk, calculated to be in the range of
10,000 years.
Oxidation is also the main chemical transformation process for WP vapor and
solid WP particles in air where rapid oxidation to polyphosphoric acids occur.
At atmospheric pressure and 30C, combustion is expected to be slow. However,
as the temperature rises from the heat produced in the reaction process,
combustion results, with its rate diffusion-controlled (Spanggord et al.,
1983). It is, therefore, considered unlikely that elemental phosphorus from
smoke devices would deposit to any significant degree into terrestrial or
aquatic environments.
Hydrolysis is also a transformation process for white phosphorus but it is
competitive with the rate of oxidation and is reported to be strongly pH
dependent. The main hydrolysis product is phosphine (PH3) (Lai and
Rosenblatt, 1977a). In kinetic studies conducted by Spanggord et al. (1985),
the production of phosphine was inversely related to the oxygen concentration,
thus being favored at low oxygen pressures such as would occur in soils or in
storage in the presence of moisture.
The results of biotransformation studies conducted by Spanggord et al. (1985)
indicate that WP is not readily used by anaerobic aquatic bacteria.
Polyphosphates are hydrolyzed by both water and soil microorganisms under both
aerobic and anaerobic conditions. This indicates that the transformation
products of the smoke devices are susceptible to biotransformation and that
microorganisms will play a major role in their transformation to
orthophosphoric acid.
Dacre and Rosenblatt (1974) reported on a 16-hour exposure study in which cod
were shown to bioconcentrate phosphorus 1,000 times in the liver and 10 to
1,000 times in the muscle tissue from water containing levels of 20 to 80 ug/L
(Dyer et al., 1970). Herring and salmon were also shown to bioconcentrate
phosphorus to the 1 ppm level (Ackman et al., 1970). Pearson et al. (1976)
IV-2

-------
measured concentrations of P4 in the livers of channel catfish and freshwater
drum found in Yellow Lake at the Pine Bluff Arsenal, Before a rain, the
levels were reported to range from 3.13-4.5 ug/kg tissue with a significant
increase, to levels of 138.75 to 308.85 ug/kg tissue, after rainfall. In
contrast, Spanggord et al. (1985) reported that biosorption was not
significant for microorganisms and WP would not be toxic to aquatic bacteria.
IV-3

-------
v.	PHARMACOKINETICS
White phosphorus may be absorbed by inhalation, oral intake or dermal contact.
Absorption following oral administration was moderate and essentially complete
in 24 hours. The liver contained the largest amount of WP with other tissues
containing only small amounts, although accumulation was evident in all
tissues examined. Most of the absorbed radioactivity was excreted in the
urine and two metabolic components were indicated. One metabolite was
similar, upon thin layer chromatography (TLC) analysis, to inorganic phosphate
while the second metabolite was more nonpolar and suggestive of an organic
phosphate.
A, Absorption
In 1971, Ghoshal et al. studied the absorption of WP in male Wlstar rats (160
to 200 g). The animals were fasted overnight before being dosed by gavage.
They received a toxic dose of unlabeled WP (0.75 mg/lOOg bw) mixed with 10 uCi
of -^P in mineral oil. A number of animals were sacrificed under anesthesia
at 15 and 30 minutes after dosing and at 1, 1.5, 2, 2.5, 3, 4 and 10 hours
after dosing. Blood was collected in heparin, and liver, brain, pancreas,
kidneys and spleen were homogenized as 10% suspensions In water. In addition,
the nuclear, microsomal, mitochondrial and supernatant hepatic fractions,
total and microsomal hepatic lipid fractions, trichloroacetic acid (TCA)-
precipitable material of whole liver homogenates and the different hepatic
subcellular fractions were collected. All samples were analyzed for
radioactivity in a Nuclear-Chicago beta counter.
Less than 5% of the administered radioactivity was detected In blood and liver
in the first 15 minutes. Within 2 to 3 hours, liver radioactivity increased
to its maximum of 65 to 70% of the administered dose. While levels of
radioactivity in the blood were low, reaching a maximum of approximately 20%
at 10 hours after administration, they generally paralleled those of the liver
over the entire study period.
Lee et al. (1975) studied the absorption of WP in Charles River CD female rats
(175 to 250 g) that had been fasted overnight before receiving a single oral
dose. They were given approximately 0.3 mg WP/kg bw, which is approximately
one tenth of the oral LDcn of the test compound, spiked with 10 uCi of
TO
P-labelled compound. The test material was suspended in peanut oil and
administered via intragastric intubation at a volume of 1 mL/100 g body
weight. After dosing, each rat was placed in a "Roth-Delmar" metabolism cage
where feces and urine were collected separately. At termination of the
experiment, each rat was anesthetized, and aortic blood was collected in a
heparinized syringe. Liver, kidneys, brain, lung, spleen, thigh muscle,
gastrointestinal (GI) tract plus contents and the feces were homogenized in
water and assayed for radioactivity at 4 hours and 1 and 5 days after WP
administration.
V-l

-------
Approximately 60 to 65% of the administered dose was absorbed with absorption
essentially complete in 24 hours. Most of the absorbed radioactivity was
excreted in the urine, averaging 46.7% after 5 days, while feces contained
approximately 33% over the same time period. Table -1 compares the recovery
at the three indicated time periods.
B. Distribution
J O
Cameron and Patrick (1966) studied the distribution of radioactivity in
rats, mice and rabbits following the administration of a single sublethal oral
dose of WP in arachis oil. The doses were 0.5, 3.5, and 20 mg/animal in mice,
rats and rabbits, respectively. The animals were sacrificed 48 hours after
dosing and tissue blocks were prepared for autoradiographic analysis. When
the tissue blocks were fixed in formol alcohol and passed through paraffin,
all of the radioactive material was eluted from the tissues and could not be
measured. Alternately, additional blocks were frozen with carbon dioxide-
methanol, cut, flattened on a slide, fixed with formalin vapor and coated with
celloidin to conserve radioactive material.
Uptake was indicated to be intense in the liver, renal cortex, bowel mucosa,
epidermis, hair follicles, pancreas and adrenal cortex. In order to eliminate
the possibility that blood remaining in the tissues was responsible for the
indicated uptake, additional tissues were prepared from animals that were
perfused with isotonic saline Immediately after death. Similar findings were
indicated in these tissues. The authors indicated that phosphorus in the
liver had a zonal distribution with the greater distribution being to the
centrilobular areas. The cortex of the kidney and adrenal were more heavily
labelled than the medulla, while in the spleen the intensity was greatest in
the red pulp. Highest intensity in the lungs was associated with the presence
of small vessels and bronchi. Table V-2 compares the average radioactivity in
the various tissues, homogenized in isotonic saline, measured with an end-
window liquid counter and expressed as millimicrocuries (muCi) per milligram
of tissue in all three species.
Further separation of the liver, kidney, heart and brain fractions was carried
out with a series of successive extractions and ftitrations using acetone
(twice), chloroform-methanol (three times) followed by acetone (once) and
diethyl ether (three times). The author did not indicate whether the organs
were from mice, rats, rabbits, or all three species combined. The filtrates
were pooled, reduced in volume by evaporation and dissolved in equal parts of
diethyl ether and water. Chloroform was added to make an emulsion and acetone
was added to clear the solution and effect separation into water and fat-
soluble layers. These layers, as well as the dried and defatted filter
residues dissolved in boiling hydrochloric acid, were measured for
radioactivity. Table V-3 compares the radioactivity of the various fractions.
While most of the liver, kidney and heart radioactivity was associated with
V-2

-------
Table V-l Percentage of Orally Administered ^P-WP (0.3 rag/kg)
Recovered in Rats in 4 Hours and 1 and 5 Days
Total Recovery
Feces
GI Tract
Plus Contents
Urine
Other Tissues
4 Hours
98.6b
2.0
57.0
17.1
22.5
% of Administered Dose
1 Day
94.0
16.6
15.3
34.5
27.6
5 Days
96.0
33.0
1.7
46.7C
14.6
Reference: Lee et al. (1975)
a Standard deviations omitted,
k Mean of three rats.
c Pooled samples from three rats,
V-3

-------
Table V-2 Average Radioactivity in Tissue Homogenates
of Mice, Rats and Rabbits
millimicrocuries/milligrara (muCi/mg)
Tissue3
Mice
Rats
Rabbits
Dose (mg/kg)
0.5
3.5
20
Urine/mL

 -
250.0
Blood/mL
57.0
20.0
50.0
Feces
4.6
2.4
4.0
Bowel
0.5
0.24
0.3
Liver
0.2
0.16
0.1
Kidney
0.18
0.12
0.06
Spleen
0.18
0.1
0.06
Lung
0.16
0.06
0.05
Heart
0.05
0.06
0.02
Muscle
0.05
0.05
0.02
Pancreas
0.05
0.04
0.01
Adrenal
0.05
0.01
0.023
Brain
0.03
0.02
0.02
Thymus
0.03
0.01
0.02
Testes
0.025


Ovary

0.016
0.007
Uterus

0.016
0.007
Reference: Cameron and Patrick (1966)
a Levels in the thyroid, fat, bone, aorta, trachea and pituitary were measured
at <0.015.
V-4

-------
Table V-3 Radioactivity in Tissue Fractions


counts/minute x 10




Water
Fat



Dry
soluble
soluble

Whole
Tissue
residue
extract
extract
Total
tissue3
Liver
0.299
0.011
0.044
0.354
0.379
Kidney
0.181
0.019
0.033
0.233
0.243
Heart
0.020
0.002
0.080
0.102
0.085
Brain
0.006
0.010
0.016
0.032
0.031
Reference:
Cameron and
Patrick
(1966)


a Different tissue samples, as comparison.
V-5

-------
the dry residue, the radioactivity in the brain was primarily associated with
the extractable fractions.
Ghoshal et al, (1971) studied the distribution of the administered JtP-
radioactivity mixed with WP in the various organs of male Wistar rats over a
15-minute to 10-hour time period after the administration of a single oral
dose of 0,75 mg/100 g body weight of WP. Levels in the various tissues, as
well as in the hepatic fractions, were reported at 2 hours, the time of
maximum hepatic incorporation. Table V-4 compares these various tissue levels
while Table V-5 compares the levels in the hepatic subcellular fractions and
in the trichloroacetic acid (TCA)-precipitable material of the hepatic
subcellular fractions.
The level of radioactivity in the liver at 2 hours was 65% of the administered
^F while that in other tissues was significantly lower. At 3 hours post-
dosing, the percentage of radioactivity in the various tissues remained the
same while liver radioactivity levels Increased to approximately 70% of the
administered dose. Approximately 40% of the administered dose was recovered
in the liver at 10 hours after dosing.
Levels of radioactivity recovered from the total hepatic lipids increased with
time but were only 1.4 to 3% of the administered radioactivity at the time of
maximum hepatic incorporation (2 to 3 hours after dosing). At 4 and 10 hours
after dosing, the total radioactivity in the hepatic microsomal lipid fraction
was slightly greater than 2.5 and 4%, respectively, of the total liver
activity. When the 4-hour and 10-hour recoveries were compared as percentage
of administered ^2p, the differences were significant, with the 10-hour
recovery almost twice that of the 4-hour recovered dose.
Lee et al. (1975) reported that the liver contained the highest amount of
radioactivity, 16.9% of the administered dose, 24 hours after administration
of a single dose of approximately 0.3 mg/kg body weight of the ^P-labelled
WP. The blood and skeletal muscle also contained significant amounts.
Table V-6 compares the levels of recovered radioactivity In the various
tissues at 4-hours and at 1 and 5 days after dosing. Table V-7 compares the
tissue-to-blood concentration ratios (ug eq/g of tissue per ug eq/mL blood)
over the same time periods. The levels of radioactivity in the blood
decreased slowly with time while those of the other tissues remained
relatively constant or decreased only slightly, resulting in large increases
in the ratios of all tissues.
An additional group of rats were administered the same dose of ^P-labelled WP
for 5 consecutive days in order to compare the radioactivity levels 24 hours
after the last dose with those 24 hours after a single dose. The results of
this study are shown in Table V-8. All tissues from rats receiving the
multiple doses contained levels of radioactivity ranging from 4.1 to
10.5 times higher than levels from the single-dose group, indicating an
accumulation of radioactivity in all tissues. As in the single-dose study,
V-6

-------
Table V-4 Percent of Administered 32P Recovered from
Various Organs 2 Hours after Oral Administration of WP in Rats3
Tissue
%32p
Liver
65
Blood
12
Kidneys
4
Spleen
0.4
Pancreas
0.4
Brain
0.39
Reference: Ghoshal et al, (1971)
a A single oral dose of 0.75 mg WP/lOOg body weight.
V-7

-------
Table V-5 Percent of Total Liver Activity of 32P
in Hepatic Subcellular Fractions of WP- treated Rats8'*3
TCA-precipitable
Subcellular Fractions	Subcellular Fractions0
1	%
Supernatant
54
18
Microsomal
18
52
Nuclear
16
15
Mitochondrial
10
6
Reference: Ghoshal et al. (1971)
a The animals were given a single oral dose of 0.75 mg WF/100 g body weight,
k Measured at 2 hours after time of maximum hepatic incorporation.
c Trichloroacetic acid precipitable; % is approximate.
V-8

-------
Table V-6 Percentage of Administered -^P-WP (o,3 mg/kg) Recovered
from Various Tissues 4 Hours and 1 and 5 Days after Oral Administration
% of Administered Dosea'^

4 Hours
i Pay
5 Pays
Liver
16.1
16.9
6.3
Kidneys
0.7
0.8
0.4
Spleen
0.1
0.1
0.1
Lungs
0.4
0.3
0.2
Brain
0.1
0.1
0.1
Skeletal Muscle
(as 40% body weight)
4.0
5.5
6.0
Whole Blood
(as 7% body weight)
6.1
4.1
1.7
Reference: Lee et al. (1975)
a Standard deviations were omitted because of small values,
k Mean of three rats.
V-9

-------
Table V-7 Tissue-to-Blood Concentration Ratiosa,b at 4 Hours,
1 Day and 5 Days after Oral Administration of ^P-WP (0.3 mg/kg) to Rats

4 Hours
1 Dav
5 Davs
Liver
18. 7b
51.4
103.2
Kidneys
4.2
14.4
33.5
Spleen
1.8
6.4
18.6
Lungs
2.6
5.8
16.5
Brain
0.3
0.7
3.6
Skeletal Muscle
0.4
1.8
8.7
Bone
1.7
12.7
66.9
Blood
1.0(6.l)c
1.0(4.1)
1.0(1.7)
Reference: Lee et al. (1975)
a ug eq/g wet tissue per ug eq/mL blood.
b Mean of three rats; standard deviations were omitted because of small
values,
c The numbers in parentheses are percent of the administered dose in whole
blood based on the assumption that whole blood accounts for 7% of the body
weight.
V-10

-------
Table V-8 Accumulation of Radioactivity in Rats
24 Hours after Receiving "^P White Phosphorus (0.3 mg/kg)
as Single or 5 Daily Doses
dpm/gm x 10"
Single Dose	Five Doses	Ratio3
Blood
2.91b
28.42
9.8
Liver
19.30
79.44
4.1
Kidney
5.44
39.29
7.2
Spleen
2.38
17.70
7.4
Brain
0.25
2.63
10.5
Lungs
2.19
22.21
10.2
Skeletal Muscle
0.68
5.90
8.7
Bone
4.77
36.81
7.7
Reference: Lee et al. (1975)
a Radioactivity from five-dose rats/radioactivity from single-dose rats
k Average of three rats.
V-ll

-------
liver contained the highest level of radioactivity when compared to the other
tissues analyzed,
C,	Excretion
a n
Lee et al. (1975) measured the excretion of P-labelled phosphorus in Charles
River CD female rats. At 24 hours after dosing, an average of 34.5% of the
administered dose was excreted in the urine while approximately 15,3% was
found in the GI tract plus contents and 16.61 in the feces. Radioactivity was
also measured at 4 hours and 5 days post-dosing. A comparison of these time
periods can be found in Table V-l.
D.	Metabolism
In the study by Lee et al. (1975), (TLC) analysis of the radioactive compounds
in the 4- and 24-hour urine and liver extracts of rats treated with ^P-
labelled WF was carried out in a butanol:methanol:water solvent system. In
the urine, two major peaks of radioactivity were found with one peak having an
Rf value (ratio of movement from origin:solvent front) similar to that of
inorganic phosphate (0.25). The second peak, with an Rf of 0.45, while less
polar, was unidentified. Liver extract analysis by TLC in the same solvent
system produced similar results. The first peak had an Rf value of 0.19, in
the region for inorganic phosphate, and the second peak had an Rf of 0.48 and
was unidentified. Results in urine were similar at both the 4- and 24-hour
analysis while those in the liver extract showed a shift toward the inorganic
phosphate peak at the 24-hour analysis.
V-12

-------
VI. HEALTH EFFECTS
a. Malth Effects in Humeri?
The toxic effects of WP in man have long been known, with reports on the
occurrence of "phossy jaw" appearing as early as 1839, In 1906, upon
ratification of the Berne Convention by all major European countries, it
became the first industrial poison to be internationally banned from
manufacture and import in the form of white phosphorus-containing matches
(Lucifers). Its later use in fireworks and rodent poisons resulted in a
resurgence of WP toxicity with conflicting reports as to Its acutely toxic
signs. Its chronic effects on the bone remain most widely known. Numerous
case reports in the literature indicate that while WP is a known liver toxin,
death due to its effects on the myocardium are not uncommon,
1. Short-term Exposure
Poisoning by ingestion of WP-containing substances has been frequently
reported. McNally (1937) as cited in Heiman (1946) reported an average fatal
dose by oral ingestion to be 1.5 grains (equivalent to 97.2 mg) although
death has occurred after Ingestion of as little as one-eighth of a grain
(~8 mg). Brewer (1958) reported a minimum lethal dose of 1 mg/kg while
Christensen (1972 as cited in Dacre and Rosenblatt, 1974) reported a lethal
dose of 1.4 mg/kg. In a child, death has occurred after the consumption of as
little as 3 mg (Brewer, 1958). Reports of WP poisoning have been largely
associated with ingestion of rat poisons with suicidal intent or by the
accidental ingestion by children of WP-containing wafers used as fireworks.
In 1926, the U.S. Bureau of Labor Statistics included, in a report on
phosphorus-induced necrosis in Industrial settings, an accounting of 26 deaths
in children, between the years 1922-1925, following the ingestion of
fireworks. The children, ages 1-11 years, all had ingested a thin, v.afer-
like, phosphorus-containing fireworks device resembling a candy lozenge. The
initial symptoms generally involved the gastrointestinal (GI) tract and most
deaths occurred within the first 24 hours to 3 days (Ward, 1926).
In 1949, Rubltsky and Myerson reviewed 16 earlier cases of acute phosphorus
poisoning, largely due to the ingestion of rat poison, and described what
became known as the classic three-stage clinical picture. The initial acute
signs usually involve the GI tract and include abdominal pain, nausea,
vomiting and shock. An unmistakable garlic odor of the breath, vomitus and
feces is classic, and luminescence of the vomitus and feces may also appear.
Simon and Pickering (1976) later described this characteristic as the "smoking
stool syndrome". Survival following this first stage, which usually lasts
from 6 to 8 hours, results in a relatively symptom-free period (Stage 2) of
1 to 3 days but occasionally as long as 10 days. The patient regains
consciousness and appears to be recovering. The third stage is also
manifested by GI symptoms and is accompanied by signs of systemic poisoning In
the liver, kidneys and hematopoietic system.
VI-1

-------
Electrocardiographic changes have been reported by Dathe and Nathan (1946 as
cited in Rubitsky and Myerson, 1949). Involvement of the central nervous
system results in coma, delirium and convulsions. Of the nine deaths reported
in this study, four occurred during Stage 1 and five during Stage 3. Recovery
is more likely to occur during the first stages of toxicity.
Pathological changes include extreme fatty degeneration of hepatic cells, with
accumulation of fat globules in the liver, kidney, stomach, intestine, small
arteries and skeletal muscles also reported (Rabinowitch, 1943; Oliver, 1938;
as cited in Rubitsky and Myerson, 1949). The brain is also susceptible to
fatty degeneration (Wertham, 1932 as cited in Rubitsky and Myerson, 1949).
Metabolic changes have been reported to include interference with glycogen
deposition as well as disturbances in the metabolism of nitrogen,
carbohydrate, fat and protein.
In a comprehensive review of 56 cases of acute poisoning with.suicidal intent
by ingestion of rodent poisons containing 2,5% yellow phosphorus, Diaz-Rivera
et al. (1950) calculated a mortality rate of 48.2% with an average ingestion
of 1.13 g of phosphorus (equivalent to ~16 mg/kg, assuming an average weight
of 70 kg). A 100% mortality was associated with ingestion of >4 g while the
mortality rate for ingestion of 1.57 g (equivalent to ~22,5 mg/kg for a 70 kg
man) was 90%. Only 15.6% died after ingestion of 0,39 to 0,78 g (~5.6 to
11.1 mg/kg) of phosphorus. In contrast, death occurred in one female 8 days
after the ingestion of only 0.19 g. Average age among the 56 cases was
25.1 years. Ingestion with alcohol as the vehicle appeared to increase the
rate of absorption and, therefore, increase the risk of mortality.
Additional findings in this review included the development of vomiting in all
cases, hepatomegaly in 71% of the patients, jaundice in 36%, severe
restlessness in 54%, and azotemia in 54%. The development of severe
hypoglycemia (35-50 mg%) in seven of the affected individuals resulted in
death, suggestive of hypoglycemic shock due to extensive liver damage.
Hematological findings included a constant increase in the number of red blood
cells (RBCs), >5million/mnr, and a corresponding increase in hemoglobin (Hgb).
Significant changes in the electrocardiogram (ECG) were seen in 12/16 patients
so evaluated, and included progressive changes in the T waves, ST segments,
QRS waves and QT interval. These changes were encountered early in the course
of the intoxication and were reversible in the majority of cases.
Diaz-Rivera et al, (1950) also reported that the development of shock as
measured by low blood pressure (BP), and other clinical signs, along with
hypoglycemia, severe restlessness, delirium or coma, were Indicative of
impending death. Prognosis was considered to be poor with early onset of
hepatomegaly, jaundice or azotemia. Death within the first 12 hours was
always due to peripheral vascular collapse while death within 24 to 48 hours
might be similarly ccused but was usually accompanied by signs of lower
VI-2

-------
nephron nephrosis. Signs of renal damage were always present among those
individuals dying 48 to 72 hours after ingestion of phosphorus. Survival over
3 days was indicative of a favorable prognosis but death could still result
from a combination of hepatic, renal and cardiac failure.
Electrocardiographic changes due to ingestion of WP were reported as early as
1948 by Newburger et al. in the case of a 21-year-old male who had ingested
60 g of rat paste containing 2.5% WP (1.5 g, equivalent to approximately
20 mg/kg for a 70 kg man) mixed into a glass of beer. Two to three hours
after ingestion, vital signs were normal but the skin was grayish in color and
the breath was garlic-like in odor. Some vomiting had occurred and the
patient showed evidence of tenderness in the epigastric region. Laboratory
findings included a definite leukopenia and neutropenia with a normal red
blood count and hemoglobin values. Electrocardiographic changes seen 2 days
after the incident were confined to moderate T wave abnormalities which took
fully 1 month to return to normal. Significant liver toxicity was evidenced
by an increase in the blood non-protein nitrogen (NPN) and a decrease in the
blood urea nitrogen (BUN), resulting in an abnormal ratio which subsequently
returned to normal. An abnormal cephalin-cholesterol flocculation test
remained abnormal for several months.
In a further study of the electrocardiographic (EGG) changes associated with
acute phosphorus poisoning, Diaz-Rivera et al. (1961) studied the ECGs from
55 individuals that had ingested between 0.22 and 1.5 g of phosphorus in the
form of rat poison during suicide attempts. Mortality rate in this study was
16%. Abnormal results were found in 33 cases while three cases were
borderline. The type of abnormality in the EGG varied considerably with
approximately 50% of the abnormal readings showing changes in the T wave.
Other changes included prolongation of the QT interval, ST wave changes,
abnormalities in rhythm and low voltage of QRS complexes. An apparent
correlation was seen between the development of abnormalities and the amount
of phosphorus ingested, with irregularities apparent in approximately 73% of
those ingesting 1.5 g (21 mg/kg for a 70 kg man). A definite correlation was
seen between the ECG and the icteric index. No correlation was evident
between the ECG and the age, sex, blood pressure, hemoglobin, vomiting,
diarrhea or vehicle utilized for the ingestion. While the described ECG
changes may result from direct action of the poison on the myocardium, the
authors indicated that severe myocardial ischemia due to decreased coronary
blood flow, resulting from poor venous return with decreased cardiac output,
may be the underlying cause of death.
In 1968, Pietras et al. reported on the development of ECG changes suggestive
of acute myocardial infarction in a 30-year-old male who had attempted suicide
by ingestion of an amount of rat poison containing approximately 1.2 g of
phosphorus (equivalent to 17 mg/kg for a 70 kg man). The abnormal ECG, which
occurred 48 hours after the time of ingestion, was accompanied by cardiac
enlargement and an infiltration of the right middle lobe of the lung. The
patient's condition deteriorated over the next 24 hours while the ECG remained
unchanged. Improvement in the ECG pattern was evident within 6 days of the
VI -3

-------
initial abnormality and pathological Q waves were no longer evident 2 days
later, A vectorcardiogram, administered within 2 weeks of the initial acute
attack, failed to demonstrate any evidence diagnostic of previous myocardial
infarction. While ischemic myocardial necrosis was possible, the authors
postulated that the phosphorus acted, either directly or indirectly, in some
biochemical manner to simulate myocardial infarction. The presence of
pericarditis also could not, by itself, account for the observed alterations
in the QRS complex seen in this patient.
Further evidence of cardiovascular toxicity was reported by Talley et al.
(1972) after evaluation of the cardiovascular function of a 16-year-old female
that had ingested 1,100 mg of elemental phosphorus during a suicide attempt.
Hemodynamic data were suggestive of a direct toxic effect on the myocardium
and the peripheral vessels. This effect was postulated to be related to an
inhibition of amino acid incorporation into myocardial proteins. The patient,
who succumbed approximately 22 hours after ingestion of the poison, had an ECG
that revealed atrial fibrillation with a wide, slurred QRS complex. Chest
X-ray revealed a diffuse cardiac enlargement with clear lungs. Vascular
damage was demonstrated by an extremely low systemic resistance and a failure
to respond to Alpha-adrenergic agents. The cardiotoxic effect was further
evidenced by elevated ventricular end-diastolic pressures, abnormal pressure
tracing in both ventricles, extremely poor contractions upon angiography, and
a generalized cardiac dilatation resulting in opening of the foramen ovale
with bidirectional shunting at the atrium level. Upon postmortem examination,
the heart was found to be pale and dilated with diffuse changes throughout the
myocardium. Myocardial cells were separated by interstitial edema without
cellular infiltrate; cytoplasm was vacuolated with pale linear areas.
Fletcher and Galambos (1963) reported on the results of liver biopsies in two
female patients following the development of acute toxicity resulting from the
intake of rat poison containing between 350 and 715 mg of phosphorus. The
needle biopsy revealed that initial liver damage was more severe in the case
of the higher phosphorus intake. Findings included prominent periportal
necrosis and edema with degenerative changes in the liver cells in the
midzonal and central areas. These changes included mild central phlebitis and
scattered inflammatory exudate with vacuolization and intracellular and
intracanalicular cholestasis. A follow-up liver biopsy of the female
ingesting 715 mg of phosphorus, performed at 116 weeks after discharge from
the hospital, indicated normal hepatic architecture with no signs of fibrosis.
The follow-up biopsy of the second patient, 14 weeks after the phosphorus
ingestion, revealed moderate periportal fibrosis with minimal inflammatory
exudate in the area of the collagenous septi and small, focal areas of acute
inflammatory cell accumulation scattered throughout the lobule. There was no
longer evidence of vacuolization, necrosis nor fatty infiltration.
Death due to cardio-respiratory arrest was reported in a 13-month-old female
within 48 hours of ingestion of rat poison containing 3% yellow phosphorus
(Rao and Brown, 1974). Clinical findings included abnormal ECG, enlarged
liver, edema of the eyelids, oliguria, elevated blood urea nitrogen (BUN) and
VI-4

-------
marked hyperglycemia, hyponatremia, and severe metabolic acidosis. Autopsy
revealed flabby, markedly dilated cardiac chambers with diffuse congestion and
edema of the lungs. The liver was yellow in color with extensive central
necrosis. Generalized cerebral edema was also Indicated.
Winek et al. (1973) reported tissue phosphorus levels ranging from 9.5 to
0,78 mg% in three patients that died after ingestion of unspecified amounts of
rat poisons containing 3% yellow phosphorus. Phosphorus content was measured
in the liver and/or kidney tissue. In all three cases, nonspecific methods of
treatment were administered.
In 1981, HcCarron et al. undertook a study of 41 individual reports of
phosphorus poisoning, along with a group of 50 additional cases, In an attempt
to determine the continued significance of the classic three-stage diagnostic
picture. In all cases, initial symptoms involved either the GI tract, the
central nervous system (CNS) or both. Initial GI symptoms, with character-
istic vomiting and/or abdominal pain were seen in 48 individuals (53%).
Mortality rate among this group was 23% (11/48) with five deaths attributed to
cardiac arrest and most occurring 5 to 8 days after onset of symptoms.
Central nervous system effects included restlessness, irritability,
drowsiness, lethargy, stupor or coma. In this study, 26 cases (28%) Initially
presented CNS effects and the mortality rate among this group was 73% (19/26).
Only two deaths were specifically reported due to cardiac arrest. Deaths
among this group occurred earlier than for the group with initial GI symptoms,
often within the first 24 hours.
When patients presented a combination of GI and CNS symptoms, all had vomiting
and/or epigastric pain accompanied by irritability, lethargy, stupor or coma.
Seventeen of the studied cases (19%) were in this group with a mortality rate
of 47% (8/17) and only one was attributed to cardiac arrest. Time of death
varied from 5 hours to 5 days.
Of the 41 cases examined in individual detail, McCarron et al. (1981) reported
that 71% vomited, most on the first day, 54% displayed abnormal liver function
tests and 49% developed abdominal pain. Approximately one-half (46%) of the
patients exhibited shock, characterized by low blood pressure (BP). Shock
occurred on the first day in half these cases. Between 27 and 44% of the
cases presented the following symptoms listed in order of decreasing
frequency; jaundice, abnormal renal tests, lethargy/stupor, restlessness/
irritability, GI bleeding, hepatomegaly, diarrhea and coma. Other symptoms
present in 5 to 20% of the patients were: leukopenia, cardiac arrest and
abnormal ECG (20%), garlic odor and hypopro-thrombinemia (17%), hypoglycemia
(15%), hypocalcemia (12%), mucosal burns, hypo- or hyperphos-phatemia (10%),
renal failure, phosphorescent vomitus or feces ("smoking stool") (7%) and low
platelets (5%). Furthermore, 73% of the cases did not have an identifiable
asymptomatic period (Stage 2) after initial onset. Some patients recovered
without developing the later symptoms (Stage 3). This study found no clear
relationship between the amount of phosphorus ingested and the onset of
VI-5

-------
vomiting or the final outcome. These authors proposed a new classification
for diagnosis of phosphorus poisoning, stressing the lag period between
ingestion and onset of symptoms. Type of initial symptoms was considered a
key factor.
a. pec^l/QcuUt Effect?
The use of white phosphorus in munitions has been reported to result in burns
when .flaming droplets of the phosphorus embed in the skin and spread beneath
the dermis due to the solubility of WP in lipid (Oberraer, 1943 as cited in
Summerlin et al., 1967). Damage to the tissue results from the heat of the
combusted phosphorus, the corrosive action of the resulting phosphoric acid
and the hygroscopic action of the chemical intermediate in the reaction
(phosphorus pentoxide). The burn area becomes necrotic, is yellowish in color
and may have the typical garlic odor and phosphorescence encountered in
phosphorus poisoning (Ben-Hur and Appelbaum, 1973), These signs may be
accompanied by emission of a white vapor characteristic of burning WP
(Konjoyan, 1983). Pain is severe and death has been reported when only 12 to
151 of the body surface is affected (Ben-Hur and Appelbaum, 1973). Wounds are
slow to heal and damage to other organs, particularly the liver and kidneys,
may result from systemic effects. The primary site of toxicity from white
phosphorus burns is reportedly the kidney; however, systemic effects due to WP
burns and those due to treatment with solutions of copper sulfate must be
distinguished. Summerlin et al. (1967) reported on the development of massive
hemolysis in WP-burn patients treated with solutions of 2% copper sulfate.
Bowen et al, (1971) reported on sudden deaths among WP-burn patients, one of
whom demonstrated a reverse calcium-phosphorus ratio with no ECG abnormalities
and two who died with ventricular arrhythmias. Other patients have reportedly
survived more extensive burns with little or no systemic toxicity. These
authors suggested that a metabolic derangement associated with Ca-P shifts and
cardiac dysfunction may occur prior to morphological changes, providing an
additional mechanism of phosphorus toxicity.
In a composite report based on four separate WP explosions at the Edgewood
Arsenal between May and July, 1945, Walker et al. (1947) described the effects
of exposure to WP, via burns or vapor inhalation, among a total of 31 affected
individuals. In the most serious accident on an assembly line for WP-filled
grenade bodies, nine females died within minutes with third-degree burns over
approximately 90% of their bodies. Two additional patients died within the
next 11 hours, both with burns over 35% of their bodies. Ten additional
persons were admitted with various degrees of WP burns and all survived. In a
similar accident, three individuals were burned with one dying 19 hours after
the injury when she became comatose and went into respiratory arrest. There
was no evidence of cardiac involvement and the exact cause of the delayed
death was unknown. A second critically burned individual survived while the
third victim received only minor burns. Two additional explosions, one
involving a rifle grenade and the other a WP rocket, caused severe burns to
three individuals, all of whom survived.
VI-6

-------
Of the 18 patients admitted for burn treatment, all were treated with a
5% solution of copper sulfate, both at the site and at the hospital, until
they underwent debridement after which the burns were dressed with petrolatum
gauze and thick roll bandage. Two of these individuals developed a massive
hemolysis within the next 21 hours. While both patients showed a sickling
trait, this was not felt to have influenced the hemolysis and the cause was
unexplained. Evidence from more recent reports (Summerlin et al., 1967) would
indicate that the hemolysis was the result of absorption of the copper sulfate
used in the treatment of the burns. None of the victims showed any evidence
of systemic injury due to absorption of unburned WP and the clinical course
was similar to that in most third-degree thermal burn cases.
Scherling and Blondis (1945) reported on the ocular effects in humans due to
exposure to WP particles and fumes. Exposure to particles of WP resulted in
minimal signs and symptoms that lasted for only 1 day with a return to normal
after treatment with copper sulfate solution. In contrast, WP fumes caused
slight to severe symptoms, with a duration of 1 to 4 days (average -
2.25 days) in duration. In the case of particulate WP, the conjunctival sacs
were found to be emitting a white smoke. Upon removal of the WP particles, a
slight blepharospasm developed, but it disappeared spontaneously within
one-half hour. Vision was 20/20, no lacrimation nor edema were evident and
only a moderate congestion was detectable at the burn site. White phosphorus
fumes produced signs of pure chemical conjunctivitis with blepharospasm,
photophobia, lacrimation and an absence of discharge. There was a constant
congestion of the tarsal and bulbar conjunctiva.
b Respiratory Effects
In an incident described by Walker et al. (1947), four females were exposed to
dense white, grey and black smoke for a period of 15 to 20 minutes and all
developed severe respiratory symptoms. These symptoms included restlessness,
anxiety, distressed cough, and a nonfrothy expectoration. Two females also
developed shortness of breath and hoarseness. There was no cyanosis;
respirations were regular, although moderately rapid, but not shallow. Rales
were heard throughout the lung field. While other chemicals were present in
the area, it was felt that inhalation of WP smoke, comprised largely of
phosphorus pentoxide which reacts in moist air to form phosphoric acid and
pyrophosphoric acids, was the predominant factor in the respiratory injury.
There was no evidence of irritation to the eyes, nose or throat. Injury was
limited to the trachea and bronchial tree and recovery was generally complete,
except for a residual hoarseness in the two most seriously-injured patients,
both of whom showed a persistent hoarseness which was still evident 8 months
after the incident.
2. Longer-term Exposure
The occurrence of "phossy jaw", reported as early as the Victorian rimes, is a
well-known manifestation of chronic phosphorus exposure (Hughes et al., 1962),
Its occurrence among workers involved in the production of phosphorus matches
VI-7

-------
was essentially eliminated by the Berne Convention which outlawed the use of
WP for this purpose. The first recorded case was in Vienna in 1839 and was
described, in 1862, by John Simon, Medical Officer for the Privy Council, as
"a peculiar disease of the jawbones" beginning as a local irritation like a
toothache or a gumboil and progressing to a destructive bone disease,
affecting all of the upper or lower jaw. It was thought to occur from the
reaction of the phosphorus with the saliva, although the exact nature of the
phosphorus compound responsible for the disease was not known. It was
theorized that the phosphorus gained access to the jaw through decayed teeth
or another break in the integrity of the affected part.
Current knowledge remains similarly uncertain with the most widely held theory
being that the phosphorus enters the jaw directly and reacts with the mouth
flora, giving rise to an infection and subsequent development of the condition
(Hughes et al., 1962). Differences have been noted in the tartar on the teeth
among workers in a phosphorus-making factory and those in an unrelated
industry. A predominant theory is that "phossy jaw" arises following a break
in the gingival margin, due either to dental caries, direct trauma,
inflammation, tooth extraction or other similar conditions. The bone slowly
becomes denuded of mucoperiosteum until an area of bone is exposed. Others
feel that "phossy jaw" may be part of a systemic disease and is evidenced by
reports of multiple spontaneous fractures among phosphorus workers (Dearden,
1899 as cited in Hughes et al., 1962). Hunter (1957 as cited in Hughef et
al., 1962) has reported the development of symptoms up to 2 years after
removal from exposure to phosphorus fumes.
In one of the earliest reported occupational health studies, conducted by the
Bureau of Labor Statistics, Ward (1926) reported on the incidence of "phossy
jaw" among workers involved primarily in the manufacture of white phosphorus -
containing fireworks and including workers involved in uhe preparation of the
WP itself. Fourteen cases of phosphorus necrosis were tied to exposure in the
production of firecrackers, thirteen of which, all females, were exposed
during the molding and wrapping of the devices and one, a male, exposed during
the mixing process. Exposure duration was from 3 months to 6 years. Average
age was 21.6 years with a range of 18 to 28 years, a mortality rate of 141
(2/14) was reported; the two women were exposed for 2 and 6 years,
respectively. Among the nonfatal cases, symptoms ranged from slight to very
severe. Additional cases were reported among a group of four men, ranging in
age from 34 to 64 years (average age - 43.25 years) who were exposed while
processing (dipping, weighing, grinding or mixing) WP. Exposure duration was
from 3-12 years and symptoms ranged from moderate to very severe. Exposure
levels were not estimated.
In all cases, the initially affected area was the jaw, with 56% of the cases
involving the lower jaw, 33% the upper jaw and 111 involving both jaws.
Symptoms began with inflammation and sclerosis of the facial bones and
periosteum, and, by extension of the suppurative process, developed into a
necrotic condition. Swelling and ulceration of the gums and mucous membranes
of the buccal cavity were accompanied by severe pain. Teeth would loosen and
VI-8

-------
fall out and the soft tissue surrounding the jaw was often infiltrated with a
board-like hardness. Suppuration and destruction of the jawbone followed with
fistulae that, in some cases, burrowed through to the external cheek. This
condition was usually accompanied by a characteristic foul, garlic-like odor.
Extension of the inflammatory process sometimes involved the palatal and
orbital bones, meninges and cerebral abscesses and was usually fatal.
Severely affected individuals often developed brittle bones, loss of appetite,
pallor, diarrhea, emaciation, degeneration of the abdominal organs and,
eventually, death by sepsis.
Development of the "phossy jaw" process was extremely slow, often taking
years. It usually began as a sore or an extraction site that did not heal,
followed a separation of the periosteum, necrosis of the affected tissue and
exfoliation, accompanied by a continuous flow of pus. In the latter stages,
pieces of bone, 1.5-3 inches in length, would be "thrown off". Characteristic
of this condition, the destruction of one area of tissue was often accompanied
by the formation of new bone in another area. Treatment was limited to
supportive measures, extraction of the affected teeth and surgical removal of
the sequestrum.
In 1944, Kennon and Hallam reported that the first sign of more recent chronic
phosphorus poisoning, evident before or in the absence of sequestra, was the
appearance of a dull red spot in the mucosa, usually without pain, and
possibly associated with a slow healing socket or an unexpected sinus
formation. Hughes et al. (1962) reported that the entire mucosa might have a
dull, red, unhealthy appearance. Pain varied in intensity and duration. Rate
of development also varied among individuals, being acute with abscess or
almost unnoticeable. Exposure duration among the ten cases reported by Hughes
et al. (1962) varied from as little as 10 months to 18 years. In almost all
cases, removal of the sequestrum resulted in eventual recovery, with areas of
bone regeneration evident in some but not all of the affected individuals. No
estimation of phosphorus i-n the atmosphere was indicated.
Other individuals have been Identified among phosphorus workers in whom
necrosis did not develop, little or no bone loss was seen, and the only sign
of phosphorus-related effects was a delayed healing following normal dental
extractions. During these periods, the workers were removed from exposure and
were not returned to the workplace until they were clinically healed (Hughes
et al., 1962). Exposure among these individuals ranged from 4 months to
23 years. These authors reported that exposure to phosphorus had an adverse
effect on all naturally occurring dental conditions except for dental caries.
In a study among 48 apparently healthy workers in a phosphorus plant, matched
with 28 unexposed controls, Hughes et al. (1962) found no evidence of effects
on the Hgb, leucocyte counts, mean plasma levels of phosphorus, alkaline
phosphatase, calcium or magnesium nor on urinary creatinine. Radiographs of
both hands along with standard bone and ivory discs, revealed no difference in
the density of the bone.
VI-9

-------
In an overall analysis of the foregoing studies, Hughes et al. (1962)
concluded that the diagnosis was distinguishable from other forms of
osteomyelitis, and that the radiographic picture also differed in these
individuals. The sequestra were typically light in weight, yellow to brown in
color, worm-eaten in appearance, not unlike a pumice stone. They were usually
osteoporotic and decalcified, unlike sequestra from acute staphylococcal
osteomyelitis which were sharp, white, dense and well calcified. Furthermore,
necrosis occurred in the absence of any visible pathology upon radiographic
examination. It was suspected that the mechanism of "phossy jaw" was related
to a lower resistance of the individual to the normal flora of the mouth and
this theory was supported by the delayed healing that is often seen following
routine dental extractions. Susceptibility to the condition is rare with less
than 10% of those exposed to phosphorus in the workplace developing symptoms,
necrotic or non-necrotic, which could be related to phosphorus exposure.
In 1983, Jakhi et al. described a case in which exposure was not due to
inhalation of WP fumes but rather involved a 30-year old male exposed by
direct contact with a WP pellet held within the buccal cavity during the
performance of magic shows. Exposure duration was more than 15 years and
resulted in the development of resorption of the maxilla on the affected side.
A perforation in the molar region opened into the maxillary sinus and nasal
cavity. The premaxillary bone was devoid of soft tissue, and sequestration
was extensive and characterized by the brown pumice stone appearance of
phosphorus necrosis. On the opposite side, discharge and swelling were
absent, but considerable gingival recession was present. Radiographic
examination revealed a normal mandible, but destruction of the maxilla was
extensive. The premaxillary bone was abnormally porous and mobile. No
formation of new solid periosteal bone was indicated. No abnormalities were
detected in the chest or long bones. The concentration of the WP pellet was
not indicated,
B. Health Effects in Animals
White phosphorus is highly toxic when administered at acute doses. Primary
effects from oral exposure are to the liver and kidney with effects on the
bone also evident. It does not cause eye or skin irritation when applied as a
weak solution but burns have resulted in systemic toxicity evidenced by
effects on the liver and kidney. Serum electrolyte changes were also measured
and electrocardiographic changes were seen. Effects due to other exposure
routes, e.g., parenteral and inhalation, are reviewed by Davidson et al.
(1987).
1- Short-term Exposure
Lee et al. (1975) determined the acute oral toxicity of WP in Charles River
CD rats and albino Swiss mice. Rats and mice were fasted for at least
16 hours prior to dosing by intragastric intubation with a 0.1% solution of WP
in peanut oil. After treatment, the survivors were observed daily for 14 days
VI-10

-------
for delayed mortality or toxic signs. The LD50 was calculated by a computer
program based on the method of maximum likelihood of Finney (1971).
The acute oral LD50 values in male and female rats were 3.76 and 3.03 mg/kg,
respectively; in male and female mice they were 4.85 and 4.82 mg/kg,
respectively. No specific toxic signs were reported in this study. Death
occurred over a period of several days. Gross pathological examination of the
animals that died revealed the presence of large yellow nutmeg livers.
In comparison, the acute inhalation LD50 for the liquid condensate of burning
military grade WP-felt, consisting of 65% phosphoric acid, was reported to be
2,184.5 mg/kg in male and female Sprague-Dawley rats (Brown et al., 1980).
Toxic signs included lethargy and gastric distress. At higher doses,
prostration occurred and progressed to death, usually within the first
24 hours.
In a preliminary study to determine the toxic oral dose for WP in mice, rats
and rabbits, Cameron and Patrick (1966) dissolved small portions of WP In
arachis oil at 50'C until a 1% solution in oil was obtained. The solution was
administered by esophageal tube and the toxic doses were calculated at 0.5,
3.5 and 20 me for mice, rats and rabbits, respectively. Using standard
weights for adult animals (Lehman, 1959), these doses would correspond to
approximately 25, 8.75 and 10 mg/kg in mice, rats and rabbits, respectively,
assuming body weights of 0.02, 0.4 and 2.0 kg, respectively. While these
doses could not be accurately converted to mg/kg due to lack of data on the
size or age of the animals involved, the toxic effects in these animals were
worthy of note. Fatty degeneration of the liver, kidneys and heart was
histologically similar to that found in humans poisoned with WP. Hemorrhagic
tendencies were not as marked in the animals but some livers showed zones of
centrilobular necrosis as well as the more commonly known periportal
distribution of fat.
Seakins and Robinson (1964) studied the effects of a single oral dose of WP on
the lipid content of the liver and plasma in rats. Female Wistar rats
(5/group) weighing between 180-200 g were fasted for 16 hours prior to
receiving a single oral dose of 1.5 mg of WP dissolved in olive oil
(equivalent to 7.5 to 8.3 mg/kg). Twenty-four hours later the animals were
sacrificed and the total esterified fatty acids, phospholipids and cholesterol
of the plasma and liver were measured. Esterified fatty acids as well as
cholesterol were markedly increased in the livers and the livers were visibly
fatty in appearance. While total phospholipid was also significantly
increased, its concentration relative to the enlarged liver was decreased when
compared to the olive oil-treated controls. The concentrations of all plasma
lipids were markedly decreased when compared to controls.
The same authors treated two additional groups of animals in order to measure
the uptake of DL- [l-^Cjleucine and [**?]orthophosphate into the proteins and
phospholipids of rat liver and plasma. The labelled compounds were injected
VI-11

-------
into the rat tail veins at two hours after the oral administration of the WP
and the rats were sacrificed from two to three hours later. Incorporation of
the ^C-leucine was significantly less in the liver and plasma proteins in the
1 O
WP-treated rats while there was no significant difference in the P-ortho-
phosphate incorporation when compared to controls. Treatment with WP also had
no significant effect on the plasraa-free amino acid concentration. The
results of this study suggested to the authors that the development of fatty
liver as a result of poisoning with WP results from a decrease in the
formation of the low-density lipoproteins resulting in an accumulation of
triglyceride in the liver along with a fall in the lipid components of the
plasma lipoproteins.
Ghoshal et al. (1972) reported the occurrence of fatty livers in male Wistar
rats within 4 to 6 hours after the administration of a single oral dose of
1.5 mg/100 g body weight (15 mg/kg) of WP in mineral oil. No significant
depression of glucose-6-phosphatase activity was seen up to 24 hours.
Microsomal lipoperoxidation was not detectable at 2 hours post-dosing but
conjugated dienes were present at 4 hours.
Pani et al. (1972) demonstrated that triglycerides accumulated in the liver of
female Sprague-Dawley rats within 4 hours of treatment with a single oral dose
of a 0.1% solution of WP in mineral oil administered at a level of 10 mg/kg.
While the levels were increased by 2 to 3 hours after dosing, the increases
were not significant when compared to the mineral oil-treated controls.
Maximum levels of fat infiltration were measured at 12 hours with no
additional increase indicated at 24 hours. Pretreatraent with either
phenobarbital or N,N'-diphenyl-p-phenylenediaraine (DPPD) had no effect on
liver triglycerides of WP-treated rats indicating to the authors that lipid
peroxidation is a necessary step in WP poisoning. In contrast, pretreatment
with glutathione or propyl gallate exerted a protective effect on the
triglyceride infiltration in the liver of WP-treated rats, as well as on the
polysomal damage induced by WP. A study of the polyribosomal patterns in rat
livers after treatment with WP indicated that WP induced a disaggregation of
the polyribosomes, which suggested to the authors that the WP acts to inhibit
protein synthesis.
Whalen et al. (1973) treated 23-day-old female Wistar rats (4/group) with WP
suspended in soy bean oil and incorporated into the diet at a level of
0.065 mg/animal/day (equivalent to approximately 0.65 mg/kg/day for a 0.1 kg
rat) for 8 days with a 16-day recovery period or for 16 days with no recovery
period. Radiographic examination of the tibia and fibula from the animals
exposed for 16 days indicated a widening of the metaphyseal trabeculae while
the marrow space appeared obscured. The metaphysis appeared broadened and the
lateral contour was slightly convex when compared to control animals.
Additional changes included a reduction or absence of osteocytic osteolysis
and chondrolysis with areas of diffuse matrix metachromasia or basophilia
often merging into sharply defined bands. Normal internal resorption of
metaphyseal trabeculae was altered and, combined with other changes, resulted
VI-12

-------
in bone mass being added to the surfaces with subsequent widening of the
trabeculae. When treated rats were removed from the WP diet after 8 days of
treatment and placed on a recovery regimen for 16 days, a return to a normal
metaphyseal density and tapering was seen. No other pathological parameters
were examined.
a. SHin Eye IrrUatjop, Pe^nel sepsttjseUpn
The primary skin and eye irritation tests in rabbits, using the modified
Draize method (Federal Register, 1974 as cited in Lee et al., 1975), indicated
that a 0.1% solution of WP was negative for irritation to both the skin and
eye. The possibility of systemic toxicity precluded the use of higher doses
in this test procedure. No dermal sensitization tests were performed.
Bowen et al. (1971) developed a method of producing a standard white
phosphorus burn (SWPB) in New Zealand White rabbits in an attempt to determine
the cause of the sudden deaths encountered in WP burn patients. The burn
area, estimated to represent 10 to 20% of the body surface area, was produced
by applying a WP wafer to the flank of the animal and igniting it with hot air
for a one minute burn time. Preliminary studies on serum chemistry indicted a
depression of serum calcium and an elevation of serum phosphorus with no
changes in sodium, potassium, chloride, bicarbonate, lactic dehydrogenase,
glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase nor bilirubin.
A mortality rate of 65 to 85% was noted, with the higher rate occurring in
rabbits anesthetized for electrocardiographic determinations. Most deaths
occurred within the first 18 to 24 hours. Toxic signs prior to death included
depression, poor response to stimuli, twitching and failure to eat or drink.
Excision of the burn area at one hour post-burn had no effect on survival or
toxic signs. Serum calcium was depressed in 80% of the animals with a greater
degree of depression in those animals that died. A significant elevation in
serum phosphorus was seen in all animals that died. Several of the control
animals received "branding burns" but none of these controls died nor
exhibited any toxic signs.
Among the WP-burned rabbits that were anesthetized for measurement of
electrocardiographic abnormalities, depression of serum calcium and elevation
of serum phosphorus levels were seen as early as 1 hour post-burn.
Abnormalities of the ECG were noted in 70% of these animals and consisted of
prolongation of the Q-T interval, ST segment depression, T-wave changes,
bradycardia and low voltage of the QRS complex. In the survivors, the
calcium/phosphorus values and the ECG changes were minor. No morphological
changes were seen in the heart, liver, kidney or lungs of any of the animals
that died due to WP burns, indicating that the calcium/phosphorus shifts and
ECG changes may precede any of the tissue damage previously seen in
individuals ingesting WP.
A similar study was undertaken in Hadassah-bred adult male rats (10/group) in
which the phosphorus was introduced into a longitudinal incision in the
VI-13

-------
inguinal area at concentrations of 10 or 50 rag/animal (equivalent to 25-
125 mg/k for a 0,4 kg animal) (Ben-Hur et al., 1972). The phosphorus was
ignited and allowed to burn to cessation of active combustion, a period of
about 4 minutes. One group of treated rats received the phosphorus insertion
and the incision was closed without active burning. The mortality rate in the
burned rats was 50%, with death occurring within 3 to 4 days. Blood and urine
chemistry indicated an increase in serum phosphorus, urea, potassium, serum
glutamic pyruvic transaminase (SGPT) and osmolality and a slight decrease in
serum sodium at 72 hours after the phosphorus burn. The urinary output was
increased as was the water intake. Both the urine osmolality and the creatine
clearance were decreased. The rise in serum phosphorus was seen within
2 hours of the burn, reaching a maximum at about 24 hours and persisting at
this level through at least 72 hours.
Both the liver and the kidney showed evidence of damage, with the liver being
swollen, yellow-brown in color and containing patchy areas of hemorrhage
scattered over the surface. Histological examination revealed diffuse areas
of necrosis, periportal infiltration with inflammatory cells, areas of
ballooning degeneration and microthrombi of the portal veins. The kidneys
were slightly swollen and pale. Microscopic examination showed evidence of
cellular swelling, desquamation and perinuclear vacuolization and necrosis as
well as vacuolar degeneration of the proximal convoluted tubules. Surviving
rats, followed for up to 6 months, showed recovery, normal growth and
reproduction. Ben-Hur et al. (1972) postulated that death resulted from renal
failure.
2 Longer-term Exposure
Studies have been conducted in rats, rabbits and guinea pigs over periods
ranging from approximately 90 days to lifetime. Oral administration of WP
produced significant weight loss as well as effects on the liver and bone in
various species.
In a study designed to compare the effects of prolonged administration of UP
on growing bones and growing teeth, Adams and Sarnat (1940) administered the
minimal effective dose to approximately 15-17 rabbits (27-87 days old) and 14
rats (28-56 days old) for periods ranging from 13-117 days and 22-57 days,
respectively. The rabbits received the WP in tablet form at a concentration
of 0.6 mg/rabbit/day (equivalent to 0.3 mg/kg/day for a 2 kg rabbit) while
the rats received phosphorized cod liver oil containing 0.01% WP (equivalent
dose could not be estimated from available data). Equal numbers of litter
mates were included as controls. Doses were increased in some of the animals
to a maximum of 6.0 mg/rabbit while rat doses were increased four-fold.
Effects on the growing bone were followed by roentgenograms taken at the
start, at intervals during the experiment and just before termination.
The rabbits receiving the phosphorus gained less weight than the controls.
Average daily growth of the tibial diaphysis was 0.27 mm in the WP-treated
rabbits and 0.36 in the controls (significance not specified). When WP was
VI-14

-------
administered for 4 weeks or more, a definite retardation was seen in the
normal tubulation process. The phosphorus bands were consistent with the
periods of WP administration. Histological examination revealed a narrowing
of the epiphysial cartilage plate, a reduction in the number of cartilage
cells in each column, increased density in the metaphyseal zone accompanied by
an increase in the number of trabeculae which contained an increased amount of
calcified cartilage and, in some cases, a replacement of the hemopoietic
marrow of the bone with loose fibrous tissue. The changes were related to the
duration of exposure. The teeth of the treated animals were not similarly
affected although zones of disturbed calcification of the dentin was evident.
These changes corresponded to changes in the dose level.
a- Nlnetv-dav to Eight-month Studies
Mallory (1933) undertook a study to determine the dose and duration of
exposure to WP that would produce cirrhotic changes in the liver of rabbits
and guinea pigs, A daily oral dose of 0,66 to 1 mg/kg of WP dissolved in oil
of sweet almonds was sufficient to produce a definite cirrhosis in both
rabbits and guinea pigs in a period of 3 months or more. These changes
included destruction of the fibroblasts of the stroma, followed by
regeneration, as well as fibrosis of the liver cells throughout the lobule.
With larger doses (1 mg/kg), destruction of liver cells was more marked and
regeneration was active with numerous mitotic figures. At smaller dose levels
(0.33 mg/kg) for longer periods, liver cell degeneration was very slow and,
instead of necrosis, a series of retrograde changes similar to those found in
alcoholic cirrhosis developed.
In 1925, Sollmann fed WP in the diet to young female albino rats (6-10/group)
at median doses 0,0032, 0,018 or 0.072 mg/kg/day for 22 weeks and to 10 older
male rats at a median dose of 0,0027 mg/kg/day for 25 weeks. Half of the
animals from each female rat group were removed from the test diet during the
later part of the experiment and they were observed in the same manner as the
animals that continued to receive the test diet. A zero dose concurrent
control group was not included in the experiment; however, the results from
this study were compared to "normal growth curves" determined by the author
and others in 13 previous investigations using a total of 72 rats.
The 0,072 mg/kg/day group exhibited 30% (3/10) mortality and a marked and
progressive weight loss. Upon termination of the experiment the final weight
of the animals was 41% below normal. No recovery was evident when the test
diet was removed from a part of the test group after 10 weeks, but the
progressive weight loss was checked. There was 50% (3/6) mortality for the
0.018 aig/kg/day group and growth was below normal resulting in a final weight
15% less than normal. When the test diet was removed from several animals in
this dose group their growth returned to normal. There was a check in growth
at 15 weeks and an overall mortality of 33% (2/6) for the 0.0032 mg/kg/day
animals. There was no definite growth effect prior to 15 weeks. When animals
from this group were removed from the diet their weights increased to levels
beyond normal.
VI-15

-------
The male rats who received 0.0027 mg/kg/day demonstrated weight gain to a
level greater than normal growth while remaining on the test diet. They had a
10% (1/10) mortality; however, no other treatment related effects or toxicity
signs were reported. The median dose of 0.0027 was considered the NOAEL from
this study based upon body weight gain.
The effects of oral administration of WP on the liver of guinea pigs was
studied by Ashburn et al. (1948). The animals, weighing between 300 and 500 g
and divided into two groups of approximately 25 each, received doses of WP as
a 0.1% solution in olive oil at levels of 0.75 mg/kg for 4 days/week or
1.5 mg/kg for 2 days/week by oral intubation (equivalent to approximately
0.43 mg/kg/day when adjusted for a 7-day week). Dosing was continued for up
to 35 weeks with 1-2 animals sacrificed at various Intervals in order to
follow any progressive effects. Occasionally doses were adjusted or omitted
to compensate for the overall toxic effects of WP.
As no differences were seen between the lesions of either group when examined
at necropsy, the results from both groups were combined. At 9 weeks after the
start of the experiment, gross liver lesions were detected. The lesions
appeared as dark brown areas at the hilar portion of most lobes and were
characterized by a sharp margination and depression suggestive of the loss of
parenchymal substance. The lesions were progressive with time and varied
considerably in size and shape. Atrophy and shrinkage of one or more lobes
was sometimes extreme, resulting in displacement of the gall bladder.
Hypertrophy was generally present in the uninvolved lobes. Nodular
hyperplasia was not detected.
Microscopic examination revealed a variation in appearance which was
attributed to the age of the lesion. Early lesions were characterized by a
decrease in the number of hepatic cells with sinusoids which were collapsed or
open and blood-filled. Hydropic, fatty or other degenerative changes were
evident in the remaining cells. No hyperplasia was seen and connective tissue
fibers were not numerous. A slight to moderate proliferation of the bile
ducts was reported. Fibrous tissue increased with age, and cellularity
decreased, as did the numbers of bile ducts and liver cells. After the
twenty-third week of treatment, fibrosis was moderate to marked. Extensive
necrosis was seen in only one animal while liver lobules were considerably
reduced in size.
Fine droplet fat deposits, moderate in degree but diffusely distributed, were
seen in the early stages but were not always evident in the latter stages.
Portal cellular infiltrate was seen In most animals while proliferation of the
bile ducts was irregular in degree and occurrence. Collagen deposition,
usually slight, was seen regularly after the first 16 weeks of treatment.
While cirrhosis was not evident, many changes in the liver were considered
precirrhotic.
VI -16

-------
b. Lifetime Study
In a study to determine the effects of WP on the bone, Fleming et al. (1942)
fed domestic male and female rats (6/group) stock diets containing WP mixed in
peanut oil at levels of 0, 0.2, 0.4, 0.8 or 1.6 mg/kg/day over the lifetime of
the animals. In general, mortality of the treated animals decreased with a
decrease in the concentration of WP but did not differ significantly from the
control animals where background mortality rate exceeded that of the treatment
groups (33 deaths/100 animal-days in controls versus an average of 25/100 for
treated groups). Feeding of WP resulted in a retardation of growth and was
accompanied by a decrease in the food Intake. All WP treated animals showed
bone changes consisting of a thickening of the epiphyseal line and an
extension of the trabeculae into the shaft of the femur. No indication of a
dose-response effect was given. Except for acute lung changes, which included
pneumonitis, bronchial pneumonia, congestion and edema, that might have been
due to a general debility of the rats, no other organs showed changes that
could be related to the feeding of WP. A Lowest-Observed-Adverse-Effect-Level
(LOAEL) or NOAEL could not be determined for this study.
3 Reproductive Effects
In a two-litter, one-generation reproduction study, the Monsanto Company
tested the effects of orally administered phosphorus In three groups of
15 male and 30 female Sprague-Dawley rats (Condray, 1985). The elemental
yellow phosphorus was administered in corn oil by gavage at doses of 0, 0.005,
0.015, or 0.075 mg/kg/day beginning at 80 days prior to mating and continuing
throughout two complete reproductive cycles and weaning. The adult and
weanling rats were observed for signs of toxicity and detailed examinations
were performed weekly. Body weights were recorded weekly and females were
also weighed on Days 0, 6, 13 and 20 of gestation and on Days 0, 4, 14 and 21
of lactation. Pups were sacrificed at weaning and the parental animals after
weaning of the F^ litter. Postmortem examinations were carried out on ten
males/group, all of the females, and ten and five F^a pups/sex/group.
Microscopic examinations were performed on selected tissues from ten Fg
parental and ten F^, pups/sex/group.
Mortality was comparable to control in all groups except the high-dose female
rats where a rate of 53% (16/30) was seen. These deaths were attributed to
difficulty during parturition because 13 of these deaths occurred on Day 21 or
22 of gestation. No specific cause of death was determined. The only toxic
sign among these animals was hair loss on the forellrabs of the high-dose
(0.075 mg/kg/day) group. The fertility index was low for all groups,
including the controls, during the F|a mating and were comparable to controls
during the F^ mating. Mean number of viable pups in the F^a litter of the
high dose groups was slightly ^ower than controls but not significantly so,
nor was the concomitant increase in the mean number of dead pups. Similar
findings were seen in the second litter. All other groups were comparable to
controls. There were no changes in pup survival, mean pup weights from birth
VI-17

-------
through lactation, appearance or behavior. No compound-related changes were
seen upon gross and microscopic examination of the tissues. A NOAEL of
0,015 mg/kg/day was reported for this study.
Developmental Effects
No information was found in the available literature regarding possible
developmental effects of WP in animals.
5.	Carcinogenicity
No specific information was found in the available literature regarding the
possible carcinogenic effects of WP in animals. In lifetime studies conducted
in rats fed WP at doses up to 1.6 mg/kg/day (Fleming et al., 1942), no
evidence of lesions related to WP feeding was indicated.
6.	Genotoxicitv
Ellis et al. (1978) conducted the Ames mutagenicity test exposing Salmonella
tvphimurlum (tester strains TA1535, TA1537, TA1538, TA98 and TA100) to 100 uL
of various concentrations of WP for 48 hours at 37C. The test concentrations
included a saturated solution of WP in distilled water and serial dilutions of
1/2, 1/10, 1/33 and 1/100. No statistically significant increase in the
number of revertant colonies was observed when compared to levels of
spontaneous revertants either with or without S9 metabolic activation (added
rodent liver homogenate).
VI-18

-------
VII. HEALTH ADVISORY DEVELOPMENT
Available data on both the acute and longer-term effects of exposure to WP in
humans and animals have been reviewed. The effects of dermal and ocular
exposure in both humans and animals are also included. By way of contrast,
inhalation toxicity is reviewed. Oral LD5q's in animals and short-term to
lifetime exposure, as well as reproductive effects and genotoxicity studies
are included. No studies were located concerning developmental effects and no
bioassay for carcinogenicity was reported.
Ingestion of WP formulations, usually rat poisons taken in suicide attempts,
but also WP-containing fireworks accidentally ingested by children, has
resulted in death when doses were as low as 1 mg/kg in adults or 3 mg total
for a child (Brewer, 1958). While initial symptoms usually involved the GI
tract, other systemic signs of toxicity have been reported. These include
toxic effects on the liver, kidney, heart, CNS, hematopoietic system and
bones. Mortality rates ranged between 15%, after the ingestion of
approximately 5-11 mg/kg in adults (0.4 to 0,8 g) and 100% with amounts >4 g
(Diaz-Rivera et al., 1950).
Exposure to WP fumes in the workplace has resulted in the now well-known
"phossy jaw" syndrome (Ward, 1926; Kennon and Hallam, 1944; Hughes et al.,
1962). A similar condition was described when exposure was by direct contact
with a WP pellet placed in the buccal cavity (Jakhi et al., 1983). Exposure
in all cases of human "phossy jaw" were longer-term in nature, ranging from
several months to more than 18 years. Effects on the bone were described as a
gross necrosis of the jaw beginning as a local inflammation or irritation.
Symptoms were progressive, resulting in swelling, ulceration and suppuration
and finally causing a frank destruction of the jawbone with perforation to the
sinus or nasal cavities and externally to the cheek. Death sometimes
resulted, usually due to a general debilitation of the individual, although
the development of meningeal inflammation and cerebral abscesses have also
resulted in death (Ward, 1926). While multiple spontaneous fractures and
brittle bones were reported in some cases (Dearden, 1899 as cited in Hughes et
al., 1962; Ward, 1926), radiographic examination of the hands of a group of
apparently healthy workers exposed to WP in the workplace revealed no
difference in bone density as compared to unexposed controls (Hughes et al..
1962). Other exposed workers displayed no significant bone necrosis or bone
loss but exhibited a delayed healing following normal dental extractions. In
most human exposure studies, the levels of WP could not be determined.
In contrast, Whalen et al. (1973) reported changes in the bones of young
female rats following exposure to WP in the diet after only 16 days at a level
of approximately 0.65 mg/kg/day. The changes were described as a widening of
the metaphyseal trabeculae and an obscuring of the marrow spaces. There was
also a reduction in or an absence of osteocytic osteolysis and chondrolysis
with these changes resulting in the addition of bone mass to the surface. A
VII-1

-------
return to normal was reported when the animals were removed from the 8-day
test regimen and allowed to recover for 16 days,
Adams and Sarnat (1940) reported a decrease in the average daily growth of the
tibial diaphysis with a retardation of the normal tubulation process after 4
weeks or more of oral exposure of rabbits by means of a tablet containing WF
at a level equivalent to approximately 0.3 mg/kg/day for a 2 kg rabbit.
Histological examination revealed other changes to the bone including a
narrowing of the epiphyseal cartilage plate, a decrease in the number of
cartilage cells, an increase in density of the metaphyseal zone and in the
number of trabeculae, and the replacement of marrow with loose fibrous tissue.
Severity of the changes was related to the dose and duration of exposure.
White phosphorus in the diet of male and female rats at doses ranging between
0.0027 and 0.072 mg/kg/day over a 4- to 6-month period resulted in a marked
growth retardation at the highest level and an apparently dose-related
reduction at lower doses with recovery after removal of the test substance
(Sollmann, 1925). At the low dose of 0.0027 mg/kg/day, a 13% increase in
growth rate was seen in older male rats and this level was considered a NOAEL
for effects of WP on growth retardation. In a lifetime study in male and
female rats, bone changes were characterized by a thickening of the epiphyseal
line and an extension of the trabeculae into the shaft of the femur at doses
between 0.2 and 1.6 rag/kg/day in the diet (Fleming et al., 1942).
Fatty degeneration of the liver has also been reported as an effect of
exposure to WP in humans and animals. In a comprehensive review of 56 cases
of WP poisoning by ingestion of rat poison, Diaz-Rivera et al. (1950) reported
the development of hepatomegaly in 71% of the patients with jaundice present
in 36%. Liver biopsy of two females who consumed 350 or 715 mg of phosphorus
as rat poison revealed prominent periportal necrosis and edema with
degenerative changes of the midzonal and central area liver cells and
including mild central phlebitis, scattered inflammatory exudate with
vacuolization and intracellular and intracanalicular cholestasis (Fletcher and
Galambos. 1963). Enlarged liver was reported in a 13-month-old child within
48 hours after ingestion of rat poison containing 3% yellow phosphorus (Rao
and Brown, 1974). McCarron et al. (1981) reported abnormal liver function in
54% of 41 cases poisoned with WP. Other findings included hepatomegaly and
j aundice.
Fatty degeneration of the liver was reported in mice, rats and rabbits
following a single toxic oral dose of 0.5, 3.5 and 20 mg, respectively
(equivalent to approximately 25, 8.75 and 10 mg/kg based on standard body
weights of 0.02, 0.4 and 2.0 kg, respectively) of WP in arachis oil. Zones of
centrilobular necrosis and periportal fat distribution were also reported
(Cameron and Patrick, 1966). Seakins and Robinson (1964) reported a marked
increase in esterlfied fatty acids and cholesterol in the liver of female rats
following a single oral dose of approximately 8 mg/kg. The liver was enlarged
and the total phospholipid content was decreased relative to the liver size.
VII -2

-------
Triglyceride accumulation was measured in the livers of female rats within
4 hours of a single oral dose of 10 mg/kg (Pani et al., 1972) while maximum
levels of fat infiltration were measured at 12 hours. A dose of 15 mg/kg
resulted in fatty livers in male rats within 4 hours of a single oral dose
(Ghoshal et al., 1972).
When exposure was by means of a phosphorus burn to the body surface,, rat
livers were reported to be swollen and discolored with patchy areas of
hemorrhage. Histological examination revealed diffuse necrosis, periportal
infiltration with Inflammatory cells, areas of ballooning degeneration and
microthrombi of the portal veins (Ben-Hur et al., 1972).
Oral doses of 0.66 to 1 mg/kg/day resulted in a definite cirrhosis in rabbits
and guinea pigs after 3 months of exposure. Fibrosis of the cells was evident
throughout the liver and was accompanied by a destruction of fibroblasts of
the stroma followed by regeneration. A dose response was evident. At a lower
dose of 0.33 mg/kg/day, degeneration was slower to develop and necrosis di''
not occur, but liver changes were described as similar to those found in
alcoholic cirrhosis (Mallory, 1933). Gross liver lesions were also seen in
guinea pigs after 9 weeks of oral intubation, two to four times per week, at
doses equivalent to approximately 0.43 mg/kg/day (adjusted for a 7-day
treatment schedule; Ashburn et al., 1948). The liver lesions were dark brown
and characterized by sharp margination and depression suggestive of loss of
parenchymal substance. The lesions were progressive with time and in some
cases, extreme atrophy of the lobes was seen. Hydropic, fatty or degenerative
changes were seen but no hyperplasia was evident. After 23 weeks of exposure,
fibrosis was moderate to marked. Extensive necrosis was seen in only one
animal where liver lobules were considerably smaller. Fine-droplet fat
deposits, moderate in degree, were evident in the early stages of tissue
degeneration, while collagen deposition was evident after 16 weeks of
exposure. Changes were considered to be pre-cirrhotic in nature. No liver
pathology was seen in rats fed diets containing WP at levels of 0.2 to
1.6 mg/kg/day over their lifetime (Fleming et al., 1942).
White phosphorus has also been reported to cause adverse effects on the
kidney, but to a lesser degree than its effects in the liver. Toxic effects
include accumulation of fat globules in humans acutely exposed (cited in
Rubitsky and Myerson, 1949), Azotemia was reported in 54% of a group of 56
individuals that had ingested phosphorus as rat poison. Signs of renal damage
were present in all individuals dying between 48 and 72 hours after ingestion
(Diaz-Rivera, 1950). In another comprehensive study of poisoning patients,
McCarron et al. (1981) reported abnormal renal function tests in >25% of the
patients and renal failure in 7%,
Cameron and Patrick (1966) reported fatty degeneration of the kidneys after a
single oral dose of approximately 25, 8.75 and 10 mg/kg in mice, rats and
rabbits, respectively. Exposure by WP burn resulted in a slight swelling of
the kidneys (Ben-Hur et al,, 1972). Histological examination revealed
cellular swelling, desquamation, perinuclear vacuolization and necrosis as
VII-3

-------
well as vacuolar degeneration of the proximal convoluted tubules. No effects
on the kidney were reported in rats exposed over their lifetime to levels of
0.2 to 1.6 mg/kg/day in the diet (Fleming et al., 1942).
Electrocardiographic changes have been reported in humans and animals, Diaz-
Rivera et al. (1950) reported ECG changes in 75% of acutely poisoned
individuals so evaluated. The findings, detected early in the course of
intoxication, were reversible and included progressive changes in T waves,
ST segments, QRS waves and Q-T interval. Two days after the ingestion of
approximately 20 mg/kg of WP in rat poison, Newburger et al, (1948) reported
that a 21-year-old male developed ECG changes characterized by moderate T wave
abnormalities which took fully 1 month to return to normal. Diaz-Rivera et
al. (1961) studied the ECG changes of 55 individuals who had ingested between
0.22 and 1.5 g of WP. Abnormalities were found in 601 but the type of
abnormality varied considerably with approximately 50% being abnormal T waves.
Other changes included prolongation of the Q-T interval, ST wave changes,
abnormal rhythm and low voltage of the QRS complex. A correlation was
reported between development of the abnormalities and the amount of WP
ingested. Irregularities were seen in 73% of individuals ingesting 1.5 g
(~21 mg/kg). A definite correlation was reported between the ECG changes and
the icteric index.
Electrocardiographic changes suggestive of myocardial infarction were reported
48 hours after ingestion of approximately 1.2 g of WP and were accompanied by
cardiac enlargement (Pietras et al., 1968). Improvement was evident in 6 days
and a subsequent vectorcardiogram, 2 weeks after the WP ingestion, failed to
demonstrate any evidence of myocardial involvement. Talley et al. (1972)
reported similar findings of cardiac enlargement in a 16-year-old female who
had ingested 1,100 mg of WP. Evidence of atrial fibrillation and a wide,
slurred QRS complex was also seen. Postmortem examination revealed a pale,
dilated heart with diffuse myocardial changes. The cells were separated by
interstitial edema without cellular infiltrate and cytoplasm was vacuolated.
A 13-month-old female succumbed to cardio-respiratory arrest after ingestion
of rat poison containing WP (Rao and Brown, 1974), In addition to an abnormal
ECG, the postmortem examination revealed a flabby, markedly dilated cardiac
chamber with diffuse congestion.
In animals exposed to WP by means of a standard WP burn, Bowen et al. (1971)
reported that 70% developed changes in their ECG. These changes included
prolongation of the Q-T interval, depression of the ST segment, T-wave
changes, bradycardia and low voltage of the QRS complex. Similar changes seen
in animals that survived the burn procedure were considered minor.
Other findings following acute poisoning with WP in humans include CNS effects
with coma, delirium and convulsions, changes in the metabolism of nitrogen,
carbohydrates, fat and protein, and hematological changes including an
increase in the red blood cells and hemoglobin. Symptoms of WP poisoning have
also been accompanied by the development of shock, hypoglycemia, hyponatremia,
VII-4

-------
severe metabolic acidosis, hypocalcemia, hyper- and hypophosphatemia and
widespread edema (McCarron et al., 1981).
White phosphorus burns resulted in widespread tissue damage with necrosis and
systemic effects (Ben-Hur and Appelbaum, 1973). Ocular exposure to WP
particles resulted in minimal signs of injury, while exposure to the fumes
caused slight to severe symptoms with conjunctivitis, blepharospasm,
photophobia, lacrimation and discharge (Scherling and Blondis, 1945).
In animal studies, a 0.1% solution of WP did not irritate the skin or eye (Lee
et al. , 1975), while burns produced systemic effects. Serum calcium levels
were significantly decreased while phosphorus levels wiire increased. Both
changes were correlated with mortality (Bowen et al., 1971).
When exposure to WP was by inhalation, respiratory symptoms were evident and
included cough, hoarseness and shortness of breath. Respiration was usually
regular although moderately rapid and somewhat shallow. Mucosal injury was
limited to the trachea and bronchial tree. Hoarseness was the only persistent
symptom after an otherwise complete recovery (Walker et al., 1947).
In reproduction studies in rats, Condray (1985) reported an increase in
mortality due to difficulties during parturition in the females receiving a
high dose of 0.075 mg/kg/day by gavage. Hair loss on the forelimbs was the
only other toxic sign in this group of animals. Fertility index was low in
all groups, including the control, during the first mating and was comparable
to controls for both generations. Mean number of pups was slightly lower in
the high-dose group but the changes were not statistically significant, nor
was there an increase in the number of dead pups. No other effects on the
reproductive parameters were reported, nor was there any other significant
maternal toxicity. A NOAEL of 0.015 mg/kg/day was indicated for this study.
No specific studies were undertaken to evaluate the potential for
carcinogenicity due to WP exposure, although the lifetime study of Fleming et
al. (1942) produced no significant lesions. Ellis et al. (1978) reported that
WP was negative for mutagenicity.
A. Quantification of Toxicological Effects
Health Advisories are generally determined for one-day, ten-day, longer-term
(approximately 7 years) and lifetime exposures if adequate dat^ are available
that identify a sensitive noncarcinogenic end point of toxicity. The HAs for
noncarcinogenic toxicants are derived using the following formula:
HA - (NOAEL or LOAEL) x (BW) - 	 mg/L (	ug/L)
(UF(s)) (_ L/day)
VII-5

-------
where:
NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect Level
in mg/kg bw/day.
BW - assumed body weight of a child (10 kg) or
an adult (70 kg).
UF - uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
_L/day - assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
1 One-dav Health Advisory
White phosphorus is extremely toxic following ingestion by the oral route. A
minimum lethal dose of 1 mg/kg has been reported and death has occurred
following the ingestion of as little as 8 mg in an adult (0.1 mg/kg for a 70
kg man) and at 3 mg in a child (~0.3 mg/kg for a 10 kg child). Due to the
lack of additional data, a One-day HA is, therefore, not recommended.
2.	Ten-dav Health Advisory
Due to the extreme toxicity of WP following oral ingestion and the lack of
additional data, as indicated for the One-day HA, a Ten-day HA is not
recommended.
3.	Longer-term Health Advisory
Due to the extreme toxicity of WP following oral ingestion and the lack of
additional data, as indicated for the One-day HA, a Longer-term HA is not
recommended.
4.	Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure that
is attributed to drinking water and Is considered protective against
noncarcinogenic adverse health effects over a lifetime exposure. The Lifetime
HA is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Dally Intake (ADI). The RfD is an
estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects over a lifetime, and is
derived from the NOAEL (or LOAEL), identified from a chronic (or subchronic)
study, divided by an uncertainty factor(s). From the RfD, a Drinking Water
Equivalent Level (DWEL) can be determined (Step 2). A DWEL is a medium-
specific (i.e., drinking water) lifetime exposure level, assuming 100%
exposure from that medium, at which adverse, noncarcinogenic health effects
would not be expected to occur. The DWEL is derived from the multiplication
VII-6

-------
of the RfD by the assumed body weight of an adult divided by the assumed daily
water consumption of an adult. The Lifetime HA is determined in Step 3 by
factoring in other sources of exposure, the relative source contribution
(RSC). The RSC from drinking water is based on actual exposure data or, if
data are not available, a value of 20% is assumed. If the contaminant is
classified as a Group A or B carcinogen, according to the Agency's classifi-
cation scheme of carcinogenic potential (U.S. EPA, 1986), then caution should
be exercised in assessing the risks associated with lifetime exposure to this
chemical.
The studies of Sollmann (1925) and Condray (1985) may be considered for use in
determination of a Lifetime HA. In the Sollmann study, male and female rats
were given doses of WP in the diet at levels of 0, 0.0027, 0.0032, 0.018 or
0.072 mg/kg/day for 4 to 6 months. Approximately one-third of the animals
receiving the highest dose died during this study. Toxicity was also
evidenced by a significant retardation of growth from the start of the
treatment at the two highest dose levels and after 15 weeks of treatment at
the next highest level. The animals receiving the low dose of
0.0027 mg/kg/day exhibited a 13% late increase in growth and this level may be
considered a NOAEL for the negative effects of WP on growth.
In a one-generation, two-litter reproduction study, Condray (1985) reported a
significant increase in mortality during parturition among the parental
females receiving the high dose level of 0.075 mg/kg/day. Difficulty during
parturition is not common in rat reproduction studies and this was considered
to be a toxic effect due to WP ingestion, although the specific cause of these
deaths could not be determined. Other doses in this study were 0,015 and
0.005 mg/kg/day. A slight inhibition of weight gain was seen in males at the
two highest dose levels but this change was not statistically significant. The
author reported a NOAEL of 0.015 mg/kg/day.
Due to the extreme toxicity of WP following oral ingestion in humans and
animals and the histological changes in the bone at doses as low as
0.2 mg/kg/day over a lifetime and 0.65 mg/kg/day over a 16-day exposure
period, the more conservative NOAEL of 0.015 mg/kg/day from the study by
Condray (1985) has been selected for use in the development of the Lifetime
Health Advisory. Though this NOAEL is based on excessive mortality in female
rats during parturition, the exact cause of death was not determined.
However, since parturition difficulty is not common in rats, the mortality was
considered to be related to the WP,
Other studies indicate significant WP related body weight and/or bone changes
at doses lower than those tested by Condray (1985), but the studies have
design deficiencies that weaken the validity of the reported observations.
The investigation by Sollmann (1925) did not use concurrent controls,
treatment groups differed by sex, and, judging from the initial weight at the
beginning of the study, the test animals appeared to be from different age
groups. The studies by Adams and Sarnat (1940) and Fleming et al. (1942) both
suggest WP-induced bone growth retardation; however, the numbers of animals in
VII-7

-------
the dose groups were snail and in some cases, the exact dose of the test
compound administered could not be determined. The experimental design in the
Condray study had an adequate number of animals, concurrent controls, the
doses administered were clearly evident, and a variety of gross and
histological endpoints were evaluated. Therefore, using the NOAEL of 0.015
mg/kg/day from the study of Condray (1985), the Lifetime HA may be calculated
as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD - (0.015 nig/kg/day's - 0.000015 mg/kg/day
(1,000)	(rounded to 0.02 ug/kg/day)
where:
0.015 mg/kg/day - NOAEL based on the absence of parturition mortality in
rats.
1,000 - uncertainty factor; this uncertainty factor was chosen
in accordance with NAS/0DW guidelines in which a NOAEL
from an animal study was employed, and includes a factor
of 10 for interspecies diversity, and 10 for incomplete
reproductive/developmental data and a less-than-adequate
lifetime study.
Step 2: Determination of a Drinking Water Equivalent Level (DWEL)
DWEL - (0.015 ug/ke/dav') (70 kg) - 0.525 ug/L
2 L/day	(rounded to 0.5 ug/L)
where:
0.015 ug/kg/day - RfD
70 kg - assumed body weight of an adult.
2 L/day - assumed daily water consumption of an adult.
Step 3: Determination of a Lifetime Health Advisory (HA)
HA - (0.525 ug/L) (20%) - 0.105 ug/L
(rounded to 0.1 ug/L)
where:
0.525 ug/L - DWEL
20% - assumed percentage of daily exposure contributed by
ingestion of drinking water.
Vll-8

-------
B. Qygntiflmi9Tl 9f C^rglnoRentc potential
Applying the criteria described in EPA's guidelines for the assessment of
carcinogenic risk (U.S. EPA, 1986), WP is classified in Group D: not
classifiable as to human carcinogenicity. This category is for agents with
inadequate animal evidence of carcinogenicity.
VII-9

-------
VIII. OTHER CRITERIA. GUIDANCE AND STANDARDS
The ACGIH (1986) 8-hour, time-weighted, average threshold limit value (TWA-
TLV) for exposure to WP is 0.1 mg/m^ for acute poisoning. It was indicated
that this level may not provide sufficient protection from undesirable
effects. Regular dental examinations along with scrupulous hygiene should be
maintained to prevent the development of WP effects on the jaw ("phossy jaw").
The Short-Term Exposure Limit (STEL) was deleted until additional
toxicological data and industrial hygiene experience is sufficient to provide
a better evaluation. The previous STEL was set at 0.3 mg/m^.
In 1978, the National Institute for Occupational Safety and Health (NIOSH),
along with the Occupational Safety and Health Administration (OSHA), reported
a permissible exposure limit (PEL) of 0.1 mg/m^. A complete medical
surveillance program was recommended which includes a complete initial medical
examination with a history and physical examination, dental examination, liver
function tests and a complete blood count, A further recommendation was made
that examinations be conducted on a semiannual basis.
An ambient water quality criterion for elemental phosphorus in water of
0.04 ug/L was recommended for the protection of freshwater aquatic life
(Bentley et al. (1978).
In 1979, Sullivan et al. recommended that an environmentally safe
concentration should be <0.01 ug/L, based on an evaluation of available
aquatic environmental data. Insufficient Information was available for
recommendation of a final criterion for WP in aquatic species. Lai (1979a)
reports a recommended discharge standard of 0.01 ug/L.
VIII-1

-------
IX. ANALYTICAL METHODS
White phosphorus can be present In water, both in solution and in a colloidal
form. The dissolved WP is quickly oxidized to various oxides but mainly Per-
oxidation of the colloidal form by dissolved air can give rise to lower
phosphorus oxides, including P^O which is insoluble in water. At neutral pH,
oxidation products consist of a complex mixture of phosphorus-containing
products to include phosphorous acid and hypophosphoric acid (Rosenblatt et
al., 1973).
Analysis of water for elemental phosphorus and oxidized phosphorus species
usually begins with an extraction in an organic solvent such as benzene.
Quantification can then proceed via several methods to include colorimetric
detection by the molybdenum blue procedure, gas-liquid chromatography (with a
flame photometric and flame ionization detector) or neutron activation
analysis.
The neutron activation method, as developed by Lai and Rosenblatt (1977b) and
further evaluated by Lai (1979a), involves an initial extraction with benzene
at a water:benzene ratio of 10 or less. The benzene extract is then oxidized
with 8 M nitric acid (10:1) for 2 hours by agitation, with a recovery of >99%
as P04*^. The volume is reduced to less than 0.5 mL in an evaporation chamber
at low temperature and activation analysis proceeds. The solution,
transferred to polyethylene tubing, is irradiated in the National Bureau of
Standards (NBS) reactor for 1 hour at a neutron flux of 5x10^ n/cm^-sec. The
radioactive phosphorus is separated by precipitation as yellow ammonium
phosphomolybdate after the addition of nitric acid, phosphorus carrier and
molybdic acid reagent in the presence of heat with stirring. The precipitate
is purified by washing with nitric acid and dissolved in ammonium hydroxide,
followed by further precipitation as MgNH^PO^.6H2O by the addition of magnesia
mixture and ammonium hydroxide. Further washing with ammonium hydroxide and
95% alcohol is followed by filtration on Whatman's No. 42 filter paper where
it is dried with air for 10 minutes, weighed, and measured for bet
radioactivity as ^P with a low-background proportional counter. Corrections
for decay and chemical yield are applied before determination of elemental
phosphorus.
The authors reported a detection sensitivity of 0.001 ug for P^. Sensitivity
is limited by the actual background -^P radioactivity (equivalent to 0.01 
0.005 ug) of the environmental samples and the cost of the procedure.
Practical lower limits for detection of P4 were set at 0.01 ug/L (Lai, 1979a).
Interference by other inorganic and organic phosphorus species were considered
essentially insignificant.
A less expensive method of analysis for phosphorus is by gas liquid
chromatography of the benzene-water extract. Isooctane may also be used for
extraction. The extracts are analyzed with a flame photometric phosphorus
IX-1

-------
detector using 3* SE-30 on Chromosorb W arid a 526 run filter (Addison and
Acknan, 1970 as cited in Rosenblatt et al., 1973). The limits of detection
are lower, in the range of 0.001 mg/L. A concentration step could increase
the sensitivity of this method.
IX-2

-------
x.	TREATMENT TECHNOLOGIES
Studies on the natural degradation of P4 in environmental waters indicates
that both suspended and dissolved elemental phosphorus are highly reactive and
are rapidly oxidized to lower states of phosphorus in aerated waters. These
degradation products are further converted to hypophosphorous acid,
phosphorous acid and phosphoric acid. In addition, some of the P4 is also
reduced to phosphine gas, released from the solution and dispersed in the
atmosphere (Lai and Rosenblatt, 1977a).
Initial studies (Lai and Rosenblatt, 1977a) indicated that residual P4
concentrations leveled off with time and remained at a concentration of
<0.1 ug/L for a period of at least 10 days. Since this level was considered
to be near the minimum incipient lethal level for aquatic organisms, further
studies to determine the exact nature of this apparent flattening of the decay
curve were recommended.
Under natural conditions and with better detection techniques, Lai (1979b)
determined that P4 deteriorated rapidly to a level considered toxicologically
safe for aquatic life, with levels below the detection limit of 0.01 ug/L
after 28 days of exposure under environmental conditions. A change in the
rate of degradation was detected after 10 days, when levels were measured at
approximately 0.1 ug/L, but degradation continued with time to levels
considered environmentally safe.
Lai (1979b) also studied the effects of further oxidation of water with
various agents on the removal of elemental phosphorus from environmental
waters. While all tested substances were effective in degrading test
solutions of P4, ozone and sodium hypochlorite were judged most effective,
reducing concentrations below the detection limits for the test period.
Furthermore, sodium hypochlorite was extremely rapid and inexpensive for use
in the removal of elemental phosphorus from environmental waters when natural
degradation with time was not possible.
When tested with samples of environmental "phossy water", P4 could be
instantly reduced to trace levels in the presence of oxidizing agents.
X-l

-------
XI. CONCLUSIONS
Based on the available human and animal toxicity data, and considering the
extreme toxicity of WP following oral exposure, HAs for One-day, Ten-day and
Longer-term exposures are not recommended. A Lifetime HA of 0.1 ug/L has been
determined. This value is considered protective against toxic effects for the
most sensitive members of the population. There are no currently available
data adequate to assess the carcinogenic risk for WP. Using the EPA criteria
for classification of carcinogenic risk, WP meets the criteria for category D
(not classifiable as to human carcinogenicity). This category is for agents
with inadequate human and animal evidence of carcinogenicity or for which no
data are available,
A companion report, "Data Deficiencies/Problem Areas and Recommendations for
Additional Database Development for White Phosphorus" (Appendix 1), summarizes
the scope of existing data reviewed for this HA. In view of the effects of WP
on bone, recommendations are made for additional studies to assess
developmental effects in animals exposed to WP.
XI-1

-------
XII. REFMCSS
Ackman RG, Addison RF, Hingley J. 1970. An assessment of the assimilation of
elemental phosphorus by Newfoundland marine organisms in the 1969 pollution
problem and in the 1970 monitoring operation. Fish. Res. Board Can. Tech.
Rep. 208. as cited in Davidson et al. (1987) and Dacre and Rosenblatt (ln74).
Adams CO, Sarnat BG. 1940. Effects of yellow phosphorus and arsenic trioxide
on growing bones and growing teeth. Arch. Pathol. 30:1192-1201.
Addison RF, 1971. Analysis of elemental phosphorus and some of its compounds
by gas chromatography. Proc. Int. Symp. Identification Measurement
Environmental Pollutants, Ottawa, Ont. June 14-17, pp. 386-390 as cited in
Burrows and Dacre (1973).
Addison RF, Ackman RG. 1970. Direct determination of elemental phosphorus by
gas-liquid chromatography, J. Chromatog. 47:421-426 as cited in Rosenblatt
et al. (1973).
American Conference of Governmental and Industrial Hygienists (ACGIH). 1986.
Documentation of the threshold limit values and biological exposure indices.
5th ed. American Conference of Governmental and Industrial Hygienists, Inc.
p.484.
Ashburn LL, McQueeney AJ, Faulkner RR. 1948. Scarring and precirrhosis of
the liver in chronic phosphorus poisoning of guinea pigs. Proc. Soc. Exp.
Biol. Med. 67:351-358.
Ben-Hur N, Appelbaum J. 1973, Biochemistry, histopathology and treatment of
phosphorus burns. Israel J. Med, Sci. 9(l):40-48.
Ben-Hur N, Giladi A, Neuman Z, Shugerman B, Appelbaum J. 1972. Phosphorus
burns - a pathophysiological study. Br. J. Plastic Surgery 25:238-244.
Bentley RE, Deam JW, Hollister TA, Leblanc GA, Sauter A, Sleight BH, III.,
Wilson WG. 1978, Laboratory evaluation of the toxicity of elemental
phosphorus (P4) to aquatic organisms. Final Report. E G & G, Bionomics,
Wareham, MA. Contract No. DAMD-17-74-C-4101. AD-A061 785.
Berkowitz JB, Young RC, Anderson AJ, Colella AJ, Lyman WJ, Preston AL, Steber
WD, Thomas RG, Vranka RG. 1981. Research and development for health and
environmental hazard assessment task order 5. Occupational and environmental
hazards associated with the formulation and use of white phosphorus-felt and
red phosphorus-butyl rubber screening smokes. AD-A116 956. Arthur D. Little,
Inc. Cambridge, MA. DAMD17-79-C-9139 as cited in Davidson et al. (1987).
XII-1

-------
Blumbergs P, Gilmann RC. Gault R, Hatto DL, Ash AB, Stevens CL. 1973.
Chemical process studies for commercially unavailable materials. Edgewood
Arsenal Technical Report EACR-1510-Z. Detroit, MI. 36 pp. as cited in
Sullivan et al. (1979) and Burrows and Dacre (1973).
Bowen TE, Whelan TJ, Nilson TG. 1971. Sudden deaths after phosphorus burns;
experimental observations of hypocalcemia, hyperphosphatemia, and
electrocardiographic abnormalities following production of a standardized
white phosphorus burn. Ann. Surg. 174:779-784.
Brewer E, Haggerty RJ. 1958. Toxic Hazards - Rat poisons. II - phosphorus.
Mass. Med. Soc. 258(3);147-148.
Brown BJ, Affleck GE, Cummings EG, Farrand RL, Starke WC, Weimer JT, Ghumman
MS, Pellerin RJ. 1981. The subchronic effects of repeated exposure to white
phosphorus/felt screening smokes in rats. Technical Report No. ARCSL-TR-
80068. Chemical Systems Laboratory, Aberdeen Proving Ground, MD. AD-B058
048L.
Brown BJ, Affleck GE, Farrand RL, Heitkamp DH, Lee FK, Weimer JT. 1980. The
acute effects of single exposures to white phosphorus smoke in rats and guinea
pigs. Technical Report No,. ARCSL-TR-80013. Chemical Systems Laboratory,
Aberdeen Proving Ground, MD. AD-B051 836L.
Bullock E, Newlands MJ. 1969. Decomposition of phosphorus in water. Proc.
Conf. Poll. Che. Inst. Can., Halifax, NS, August 24-26, pp. 23-24 as cited in
Burrows and Dacre (1973)
Burrows D, Dacre JC. 1973. Mammalian toxicology and toxicity to aquatic
organisms of white phosphorus and "phossy water". a waterborne munitions
manufacturing waste pollutant - a literature evaluation. Final Comprehensive
Report. Associated Water and Air Resources Engineers, Inc. Nashville, TN.
Contract No. DAMD-17-73-C-3170.
Cameron JM, Patrick RS. 1966. Acute phosphorus poisoning-the distribution of
toxic doses of yellow phosphorus in the tissues of experimental animals. Med.
Sci. Law 6(4) :2C9-214.
Christensen HE, ed. 1972. Toxic substances list. 1972 ed. UASHEW/NIOSH.
p. 422 as cited in Dacre and Rosenblatt (1974).
Condray JR. 1985, Elemental yellow phosphorus one generation reproduction
study in rats. IR-82-215; IRD No, 401-189. Monsanto Company, St. Louis, MO.
Dacre JC, Rosenblatt DH, 1974. Mammalian toxicology and toxicity to aquatic
organisms of four important types of waterborne pollutants - an extensive
literature review. Technical Report No. 7403. U. S. Army Medical
Bioengineering Research and Development Laboratory, Aberdeen Proving Ground,
MD.
XII-2

-------
Dathe RA, Nathan DA. 1946. Electrocardiographic changes resulting from
phosphorus poisoning. Am. Heart J. 31:98 as cited in Rubitsky and Myerson,
1949.
Davidson KA,	Hovatter PS, Sigmon CF.
phosphorus.	Final Report ORNL-6336.
613.
Dearden VF.	1899. British Med. J.
1987. Water quality criteria for white
Oak Ridge National Laboratory. AD-A186
2:270 as ited in Hughes et al. (1962).
Diaz-Rivera RS, Collazo PJ, Pons ER, Torregroj- v. FV. 1950. Acute phosphorus
poisoning in man: a study of 56 cases. Medicine ^1:269-298.
Diaz-Rivera RS, Ramos-Morales F, Garcia-Palmieri MR. 1961. The
electrocardiographic changes in acute phosphorus poisoning in man. Am. J.
Med. Sci. 241:758-765.
Dyer WJ, Hiltz DF, Ackman RG, Hingley J, Fletcher GL. 1970. In vivo
assimilation by cod muscle and liver tissue of elemental phosphorus from
polluted sea water. J. Fish. Res. Bd. Canada, 27:1131-1139 as cited in Dacre
and Rosenblatt (1974).
Ellis III HV, Hodgson JR, Hwang SW, Halfpap LM, Helton DO, Anderson BS, Van
Goethem DL, Lee C-C. 1978. Mammalian toxicity of munitions compounds, Phase
I: Acute oral toxicity, primary skin and eye irritation, dermal
sensitization, disposition and metabolism, and Ames tests of additional
compounds. Progress Report No. 6. Midwest Research Institute, Project No.
3900-B, Kansas City, MO. DAMD-17-74-C-4073. AD-A069 333.
Federal Register, 1974. Title 21 - Food and Drugs, Part 191.11, Method of
testing primary irritant substances, Part 191.12; Test for eye irritants as
cited in Lee et al. (1975).
Finney DJ. 1971, Probit Analysis, Cambridge University Press, as cited in
Lee et al., 1975,
Fleming RBL, Miller JW, Swayne Jr. VR. 1942. Some recent observations on
phosphorus toxicology. J. Ind. Hyg. Toxicol. 24(6):154-158.
Fletcher GF, Galambos JT. 1963. Phosphorus poisoning in humans. Arch. Int.
Med. 112:846-852.
Ghoshal AK, Porta EA, Hartroft WS. 1972. Comparative studies on the
hepatotoxicity of CCI4 and white phosphorus in rats. Gastroenterology 62:193
XII-3

-------
Ghoshal AK, Porta EA, Hartroft WS. 1971, Isotopic studies 011 the absorption
and tissue distribution of white phosphorus in rats, Exper, Molec, Pathol.
14:212-219.
Halmann M, 1972 The role of phosphorus in the world. In: Analytical
chemistry of phosphorus compounds. H. Halmann, ed. Wiley Interscience. pp.
1-8 as cited in Sullivan et al. (1979).
Hawley GG, ed. 1981. The condensed chemical dictionary, 10th ed. New York:
Van Nostrand Reinhold Co. p. 810.
Heiman H. 1946, Chronic phosphorus poisoning. J, Indust. Hyg. Toxicol.
28:142-150.
Hughes JPW, Baron R, Buckland DH, Cooke MA, Craig JD, Durfield DP, Grosart
AW, Parkes PWJ, Porter A, Frazer AC, Hallam JW, Snawdon JWE,Tavenner RWH.
1962. Phosphorus necrosis of the jaw: a present-day study with clinical and
biochemical studies, Brit. J. Industr, Med. 19:83-99.
Hunter D. 1957, The Diseases of Occupations. 2nd ed. London: English
University Press as cited in Hughes et al. (1962).
Idler DR. 1969. Coexistence of a fishery and a major industry in Placentia
Bay. In: Effects of elemental phosphorus on marine life. P.M. Jangaard, ed.
Fisheries Research Board of Canada Circular No. 2. 1972. pp. 1-6 as cited in
Dacre and Rosenblatt (1974) and Sullivan et al. (1979).
Jakhi SA, Parekh BK, Gupta S. 1983. Phosphorus necrosis of the maxilla. J.
Oral Med. 38(4):174-176.
Katz S, Snelson A, Butler R, Bock W, Rajendran N, Relwani S. 1981. Physical
and chemical characterization of military smokes. Part III-White phosphorus -
felt smokes. Final Report. ITT Research Institute, Chicago, IL. Contract
No. DAMD-17-78-C-8085. AD-A115 657.
Kennon R, Hallam JW. 1944. Modern phosphorus caries and necrosis. Br.
Dental J. 76(12):32330.
Konjoyan TR. 1983, White phosphorus burns: case report and literature
review. Milit. Med. 148:881-885.
Lai MG. 1981. Characterization of white phosphorus in water: III, Behavior
of white phosphorus in the water-sediment interface. Final Report No.
NSWC/TR-81-87. Naval Surface Weapons Center, Silver Spring, MD. AD-B059
442L.
XII-4

-------
Lai MG. 1979a. Characterization of white phosphorus in water; I.
Determination of white phosphorus in environmental waters at the nanogram
level. Final Report No. NSWC/TR-79-3. Naval Surface Weapons Center, Silver
Spring, MD, AD-B042 884.
Lai MG. 1979b. Characterization of white phosphorus in water: II.
Degradation of white phosphorus in aqueous system. Final Report No. NSWC/TR-
79-5. Naval Surface Weapons Center, Silver Spring, MD. AD-B098 687L.
Lai MG, Rosenblatt DH. 1977a, Identification of transformation products of
white phosphorus in water. Final Report. NSWC/WOL/TR-76-103. Naval Surface
Weapons Center, Silver Spring, MD. AD-A041 068.
Lai MG, Rosenblatt DH. 1977b. Determination of ultramicro quantities of
elemental phosphorus in water by neutron activation analysis. Final Report.
NSWC/WOL/TR-77-49. Naval Surface Weapons Center, Silver Spring, MD. AD-A091
773.
Lee C-C, Dilley JV, Hodgson JR, Helton DO, Weigand WJ, Roberts DN, Anderson
BS, Halfpap LM, Kurtz LD, West N. 1975. Mammalian toxicity of munitions
compounds: Phase I. Acute oral toxicity, primary skin and eye irritation,
dermal sensitization, and disposition and metabolism. Report No. 1, Midwest
Research Institute, Project No. 3900-B, Kansas City, MO. DAMD 17-74-C-4073.
AD-3011 150.
Lehman AJ. 1959. Appraisal of the safety of chemicals in foods, drugs and
cosmetics. Association of Food and Drug Officials of the United States.
Mallory FB, 1933. Phosphorus and alcoholic cirrhosis. Am. J. Pathol.
9:557-567.
Manthei JH, Donnelly M, Lee FK, Jr., Weimer JT. 1980. Preliminary toxicity
screening studies of 11 smoke candidate compounds (U). Report No. ARCSL-TR-
79056. Chemical Systems Laboratory, Aberdeen Proving Ground, MD.
McCarron MM, Gaddis GP, Trotter AT. 1981. Acute yellow phosphorus poisoning
from pesticide pastes. Clin. Toxicol. 18(6):693-711.
McNally WD. 1937. Toxicology. Chicago: Industrial Medicine Publishing Co.,
as cited in Heimann (1946).
National Institute of Occupational Safety and Health (NIOSH)/Occupational
Safety and Health Administration (0SHA). 1978. Occupational health
guidelines for phosphorus (yellow), pp. 1-5.
Newburger RA, Beaser SB, Shwachman H. 1948. Phosphorus poisoning with
recovery accompanied by electrocardiographic changes. Am. J. Med. 4:927-930.
XII-5

-------
Obermer E. 1943. Phosphorus burns. Lancet 1:202 as cited In Summerlin et
al. (1967).
Oliver T. 1938. Conquest of an occupational disease: phosphorus poisoning in
Lucifer match making. J. Roy. Inst, Pub. Health & Hyg. 1:660 as cited in
Rubitsky and Myerson, 1949.
Pani P, Gravela E, Mazzarino C, Burdino E. 1972. On the mechanism of fatty
liver in white phosphorus poisoned rats. Exp. Mol. Pathol. 16:201-209.
Pearson JG, Bender ES, Taormina DH, Manuel KL, Robinson PF, Asaki AE, 1976.
Effects of elemental phosphorus on the biota of Yellow Lake, Pine Bluff
Arsenal, Arkansas. March 1974 - January 1975. Technical Report EO-TR-76077.
Edgewood Arsenal, Aberdeen Proving Ground, MD. AD-A035 925.
Pietras RJ, Stavrakos C, Gunnar RM, Tobin JR. 1968, Phosphorus poisoning
simulating acute myocardial infarction. Arch. Intern. Med. 122:430-434.
Rabinowitch IM. 1943. Treatment of phosphorus burns. Canad. M. A. J. 48:291
as cited in Rubitsky and Myerson, 1949.
Rao S, Brown RH. 1974. Acute yellow phosphorus rat poisoning. 111. Med. J.
145(2):128-130.
Rosenblatt DH, Small MJ, Barkley JJ. 1973. Munitions production products of
potential concern as waterborne pollutants - Phase I. USAMEERU Report No, 73-
07. U.S. Army Medical Environmental Engineering Research Unit. Edgewood
Arsenal, MD.
Rubitsky HJ, Myerson RM. 1949. Acute phosphorus poisoning. Arch. Ind. Med.
83:164-178.
Scherling SS, Blondis RR. 1945. The effect of chemical warfare agents on the
human eye. Military Surgeon 96:70-78.
Seaklns A, Robinson DS. 1964. Changes associated with the production of
fatty livers by white phosphorus and by ethanol in the rat. Biochem. J.
92:308-312.
Shinn JH, Martins SA, Cederwall PL, Gratt LB. 1985. Smokes and obscurants:
a health and environmental effects data base assessment. A first-order,
environmental screening and ranking of Army smokes and obscurants. Phase I
Report, Lawrence Livermore National Library, Livermore, CA. AD-A185 377.
Simon FA, Pickering LK. 1976, Acute yellow phosphorus poisoning "smoking
stool syndrome". JAMA 235(13):1343-1344.
XII -6

-------
Sollmann T, 1925, Studies of chronic intoxications on albino rats. VIII.
Yellow phosphorus. J. Pharmacol. Exp. Therap, 24:119-122.
Spanggord RJ, Podoll RT, Rewick RT, Chou T-W, Wilson RB, Bsckovsky J, Roberts
DL. 1983. Environmental fate of white phosphorus/felt and red
phosphorus/butyl rubber military screening smokes: Phase I - Literature
review, Final Report. SRI International, Menlo Park, CA. Contract No. DAMD
17-82-C-2320. AD-A150 754.
Spanggord RJ, Rewick R, Chou T-W, Wilson R, Podoll RT, Hill T, Parnas R, Platz
R, Roberts D. 1985. Environmental fate of white phosphorus/felt and red
phosphorus/butyl rubber military screening smokes. Final Report. SRI
International, Menlo PArk, CA. Contract No. DAMD 17-82-C-2320. AD-A176 922.
Sullivan JH, Putnam HD, Keirn MA, Pruitt Jr. BC, Nichols JC, McClave JT.
1979. A summary and evaluation of aquatic environmental data in relation to
establishing water quality criteria for munitions-unique compounds. Part 3:
White phosphorus. Final Report, Water and Air Research, Inc., Gainesville,
FL. Contract No. DAMD-17-77-C-7027. AD A083 625.
Summerlin WT, Walder AI, Moncrief JA. 1967. White phosphorus burns and
massive hemolysis. J. of Trauma 7(3):476-484.
Talley RC, Linhart JW, Trevino AJ, Moore L, Seller BM. 1972. Acute elemental
phosphorus poisoning in man: cardiovascular toxicity. Am. Heart J. 84(1):139-
140.
Uhrmacher JC, Werschulz PP, Schultz DO, Weber DO. 1985. A health and
environmental effects data base assessment of U.S. Army waste material. Final
Report, Phase II Report, Carltech Associates, Inc., Columbia, MD, Contract No.
DAMD-17-84-C-4133.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
Walker J, Jr., Galdston M, Wexler J, Hill ML, Modgely G. 1947. Medical
Division Report No. 103. WP casualties at Edgewood Arsenal, Maryland, 1945.
CMLEM-52, War Department, Office of the Chief, Chemical Corps, Washington 25,
D.C.
Ward EF. 1926, Phosphorus necrosis in the manufacture of fireworks and in
the preparation of phosphorus. Bull. U.S. Bur. Labor Stat. No. 405.
Wasti K, Abaidoo KJR, Villaume JE. 1978. A literature review - problem
definition studies on selected toxic chemicals. Volume 2 of 8. Occupational
health and safety aspects of phosphorus smoke compounds. Final Report, The
Franklin Institute Research Laboratories, Philadelphia, PA. Contract No.
DAMD-17-77-C-7020. AD A056 019.
XII - 7

-------
Wertham F. 1932, Central nervous system in acute phosphorus poisoning.
Arch. Nerol. & Psychiat 28:320 as cited in Rubitsky and Myerson, 1949.
Whalen JP, O'Donohue N, Krook L, Nunez EA. 1973. Pathogenesis of abnormal
remodeling of bones: effects of yellow phosphorus in the growing rat. Anat.
Rec. 177:15-22.
Windholz M, ed. 1983. The Merck Index, 10th ed. Rahway, N.J,: Merck & Co.,
Inc. pp. 1059-1060.
Winek CL, Collom WD, Fusia EP, 1973. Yellow phosphorus ingestion - three
fatal poisonings. Clin. Toxicol. 6(4):541-545.
Zitko V, Aiken DE, Tibbo SN, Besch KWT, Anderson JM. 1970. Toxicity of
Yellow phosphorus to herring (Clupea hareneus^, Atlantic salmon (Salmo Salar),
lobster (Horoarus americanus). and beach flea fGammarus oceanicus). J. Fish.
Res. Bd. Canada 27:21-29 as cited in Burrows and Dac're (1973).
XII -8

-------
APPENDIX 1
Data Deficiencies/Problem Areas and Recommendations for
Additional Database Development for White Phosphorus
Al-1

-------
INTRODUCTION
The Office of Drinking Water (ODW), Environmental Protection Agency (EPA), in
conjunction with the Department of the Army, has reviewed the available data
on white phosphorus (WP) for the purpose of developing a Health Advisory (HA)
useful in dealing with contamination of drinking water. The Health Advisory
also includes "state-of-the-art" information on environmental fate, health
effects and analytical methodology,
OBJECTIVES
The objective of this appendix is to provide an evaluation of the data
deficiencies and/or problem areas encountered in the review process for WP and
to make recommendations, as appropriate, for additional database development.
This document is presented as an independent analysis of the current status of
WP technology, as related to its possible presence in drinking water, and
includes a summary of the background information used in the development of
the HA. For greater detail on the toxicology of WP the Health Advisory on
White Phosphorus should be consulted.
BAqKGRQUNp
White phosphorus, a transparent, waxy solid, is the highly reactive allotropic
form of elemental phosphorus. When combusted in air, it gives rise to a dense
white smoke, and is used by the military as a screening smoke and incendiary
device. Its previous use in matches, rat poisons and fireworks has been
eliminated due to its high toxicity. It is still used commercially as a
chemical precursor, an analytical reagent, and in semiconductors and
electroluminescent coatings.
White phosphorus does not exist in its elemental form in nature but can be
found in phosphate rock, apatite, bones, teeth and organic compounds. In
water, it is present in three forms: dissolved (soluble to 3 mg/L), colloidal
and particulate (Hawley, 1981). In 1971, Pearson et al. (1976) reported that
"phossy water", as the wastewater that has come into direct contact with solid
or liquid phosphorus is known, had a P4 content that was measured in the range
of 0.01 to 104 mg/L. By the late 1970's, typical levels had been reduced to
the range of 0.004 to 13.8 ug/L (Lai, 1979a). In addition, WP is highly
reactive in aqueous solutions, undergoing rapid degradation by oxidation
processes. In the presence of strong oxidizing agent, WP has been reported to
be almost instantly reduced to trace levels (Lai, 1979b).
The pharmacokinetic properties of WP have been studied in various animal
species. Lee et al. (1975) determined that approximately 60 to 65% of an oral
dose of the P-labelled WP was absorbed, with absorption being essentially
complete in the first 24 hours. Most of the absorbed radioactivity was
detected in the liver although distribution to other tissues was seen.
Excretion over the first 24 hours was mainly via the urine (34%), although
Al-2

-------
significant amounts were also excreted in the feces (15%). Analysis by thin
layer chromatography (TLC) indicated the presence of two major peaks, one of
which was similar to inorganic phosphate, while the other less polar peaK was
unidentified.
Studies on human exposure to WP indicate that it is highly toxic upon oral
Ingestion, resulting in death at low dose levels with a minimum lethal dose
reported to be 1 mg/kg (Brewer, 1958). Deaths have also been reported after
the ingestion of <10 mg by adults and 3 mg by a child. Nonlethal doses
produce symptoms ranging from effects on the gastrointestinal (GI) tract to
effects on the central nervous system (CNS). Pathological changes include
fatty infiltration of various tissues (Rubitsky and Myerson, 1949), especially
the liver. Hepatic changes also include hepatomegaly with jaundice (Diaz-
Rivera et al., 1950) and necrosis with edema (Fletcher and Galambos, 1963).
Various electrocardiographic (ECG) changes have been reported in 60% of the
patients in a study by Diaz-Rivera et al. (1961). Fifty percent of the cases
showed changes In the T-wave. A suggestion of acute myocardial infarction was
seen after ingestion of approximately 17 mg/kg by an adult (Pietras et al.,
1968) , Rao and Brown (1974) reported that a 13-month-old child died of
cardio-pulmonary arrest due to white phosphorus exposure.
Other changes following acute oral exposure include abnormal kidney function,
metabolic changes, hyperglycemia, shock and hematological changes. Mucosal
burns were characteristic of exposure by the dermal route and systemic
involvement was also reported (Ben-Hur and Appelbaum, 1973). The primary site
of toxicity following WP burns is the kidney. Suggestions that metabolic
derangement precedes morphological changes were indicted by a shift in the
calcium-phosphorus ratio in rabbits (Bowen et al., 1971) with no ECG
abnormalities. Ocular burns in humans from contact with particulate WP have
resulted in reversible effects with moderate congestion, while exposure to WP
fumes has resulted in more severe effects with signs of pure chemical
conjunctivitis (Scherling and Blondis, 1945).
Inhalation exposure has resulted In respiratory symptoms with residual
hoarseness but no permanent tissue damage (Walker et al., 1947). Longer-term
exposure to WP in the workplace has resulted in bone necrosis characterized by
the now-classic picture known as "phossy jaw". Development of this sign of
toxicity was usually slow, often beginning with a sore or an extraction site
that would not heal. Destruction of the tissue sometimes progressed to the
point of penetration of the sinus or nasal cavities (Jakhi et al., 1983).
Death, when it occurred, was usually due to a general debilitation of the
affected Individual or to the development of a deep infection secondary to the
necrotic condition.
Animal studies indicate an LD50 that averages approximately 3.5 mg/kg in rats
and 4.8 mg/kg in mice (Lee et al., 1975). Liver Involvement was indicated by
enlargement and discoloration of the lobes. Toxic oral doses were estimated
Al-3

-------
to range from 8.75 mg/kg in rats to 25 mg/kg in mice (Cameron and Patrick,
1966). Fatty degeneration of the liver, kidneys and heart were evident after
these single-dose exposures. Fatty livers were shown to develop in 4 to
6	hours after administration of a single oral dose of 15 mg/kg in rats
(Ghoshal et al., 1972) while Pani et al. (1972) demonstrated triglyceride
accumulation in livers within 4 hours of a single oral dose of 10 mg/kg in
rats.
The development of radiographic changes to the bones of young rats was evident
following 16 days of dietary exposure to approximately 0.65 mg/kg/day (Whalen
et al., 1973). Similar effects were seen in rabbits at a dose of
approximately 0.3 mg/kg/day for 13-117 days (Adams and Sarnat, 1940), Changes
included a decrease in the average daily growth of the tibial diaphysis with a
retardation of the normal tubulation process. Development of phosphorus bands
was consistent with the periods of WP administration. Histological changes
included a narrowing of the epiphyseal cartilage plate, reduction in the
number of cartilage cells and an increased density of the metaphyseal zone
with an increase in the number of trabeculae. In some cases, hematopoietic
marrow was replaced by loose fibrous tissue.
A 0.1% solution of WP was negative for both skin and eye irritation (Lee et
al., 1975), while WP burns resulted in a depression of serum calcium with a
significant increase in serum phosphorus, which was seen in all animals that
succumbed from the WP burn (Bowen et al., 1971). Abnormalities of the EGG
were seen in 70% of the animals so evaluated. Changes consisted of a
prolongation of the Q-T interval, depression of the ST segment, T-wave
changes, bradycardia and low voltage of the QRS complex. These changes, as
well as the calcium-phosphorus shifts, were minor in the surviving animals.
In a similar study, adult males rats exposed to WP at doses of 25-125 mg/kg,
with exposure via insertion into an inguinal incision with a subsequent
4-minute burn, resulted in a 50% mortality rate (Ben-Hur et al., 1972). Serum
phosphorus was increased as was urea, potassium, SGPT and osmolality with a
slight decrease in serum sodium at 72 hours after burn. The increase in serum
phosphorus was seen within 2 hours. Evidence of liver and kidney damage was
seen, but there was no evidence of necrosis.
In 90-day studies in rabbits and guinea pigs, Mallory (1933) reported the
development of cirrhosis following daily oral doses of 0.66-1 mg/kg. At the
larger doses, destruction of liver cells was marked, and regeneration was
active. At lower doses (0.33 lag/kg) for longer periods, degeneration was
slower and necrosis did not develop, but changes were retrograde and similar
to those of alcoholic cirrhosis.
Ashburn et al. (1948) reported the development of gross liver lesions in
guinea pigs after 9 weeks of oral intubation with WP, two to four times a
week, at doses equivalent to approximately 0.43 mg/kg/day (adjusted for
7	days). The lesions were progressive in nature with signs of atrophy,
sometimes extreme. Histological changes included a decrease in the number of
hepatic cells with sinusoidal collapse and were accompanied by hydropic, fatty
Al-4

-------
or other degenerative changes. In later stages, fibrosis was moderate to
marked, but extensive necrosis was seen ir. only one animal. Collagen
deposition was seen after the first 16 weeks of treatment. Changes were
considered pre-cirrhotic in nature.
Sollmann (1925) demonstrated marked and progressive growth deficiency in rats
fed WP in the diet at 0.072 mg/kg/day over a period of 4 to 6 months. At
lower doses, to 0.0032 mg/kg/day, weight depression was evidenced after
15 weeks of exposure while a dose of 0.0027 mg/kg/day produced a 13% late
weight gain with no growth depression. This dose was considered a NOAEL for
negative effects of WP on growth.
Fleming et al. (1942) reported growth retardation following dietary
administration of WP to rats at doses ranging from 0.2 to 1.6 mg/kg/day over
the lifetime of the animals. Changes of the bone were also seen and consisted
of a thickening of the epiphyseal line and extension of trabeculae into the
shaft of the femur. No other organs were affected except for a congestion and
edema of the lung with pneumonitis and bronchial pneumonia.
Effects of WP on reproduction were studied by Condray (1985) in rats
administered oral doses of WP by gavage at levels of 0.005 to 0.075 mg/kg/day
for 80 days prior to mating and through production and weaning of two
generations. The only significant effect was an increase in the mortality
among the parental females receiving the high dose. Deaths occurred due to an
apparent difficulty during parturition, an effect that is not normally seen in
rats. A slight growth depression at the two highest doses was not
statistically significant. A NOAEL of 0.015 mg/kg/day was indicated.
No studies were available on the developmental effects of WP exposure, nor was
a bioassay for carcinogenicity found in the available literature. A lifetime
study in rats at doses up to 1.6 mg/kg/day was negative for WP-related
lesions. Ellis et al. (1978) reported that WP was negative for mutagenicity.
Several methods have been reported for the analysis of WP following its
extraction from water with benzene. The neutron activation method of Lai and
Rosenblatt (1977) and Lai (1979a) reported a lower limit of detection of
0.01 ug/L. A gas-liquid chromatographic method reported a detection limit of
0.001 mg/L (Rosenblatt et al., 1973).
Due to the high reactivity of WP in water, treatment technologies are
generally not required. The rate of oxidation can be significantly increased
by the addition of oxidizing agents such as ozone or sodium hypochlorite (Lai,
1979b).
Based on the studies discussed above, HA values for One-day, Ten-days and
Longer-term exposures were not recommended due to the extreme toxicity of WP
following oral exposure to low doses in both humans ant! animals. A Lifetime
HA value of 0.1 ug/L has been determined. In the absence of carcinogenic risk
Al-5

-------
studies and based on EPA's criteria for carcinogenic risk assessment (U.S.
EPA, 1986), WP is classed in Group D, not classified.
DISCUSSION
Available data on the pharmacokinetics, health effects, analysis and treatment
technologies for WP have been reviewed.
The pharmacokinetic properties of WP have been studied in several species and
the results indicated that it readily absorbed and distributed mainly to the
liver although distribution to other tissues is indicated. Excretion is
mainly via the urine although significant quantities are also excreted in the
feces. Chromatographic analysis indicates the presence of two main
metabolites, one similar to inorganic phosphate and the other, less polar, and
possibly organic in nature. Although positive identification of the
metabolites would be of interest, further studies are not required for
development of an HA.
Available studies on the toxicity of WP, in humans and animals, indicate that
it is extremely toxic by oral ingestion with a minimum lethal dose in the
range of 1 mg/kg in humans and LX^q's ranging between 3.5 and 4.8 mg/kg in
rats and mice, respectively. Short-term studies in humans and animals
indicate that the liver and kidney are targets of toxicity, but ECG changes
have been repeatedly reported in humans after oral ingestion of WP. In
animals, ECG effects were seen in rats following exposure by means of a WP
burn. Longer-term exposure of humans in an occupational setting has resulted
in the development of the now classical "phossy jaw" syndrome. Effects on the
bone have been reported in rabbits after exposure to doses of approximately
0.65 mg/kg/day for 16 days as well as in rats exposed to doses as low as
0.2 mg/kg/day in the diet over their lifetime. Growth depression has been
associated wich histopathological changes to the bone and may be an early sign
of this toxic effect. While HAs have not been recommended for one-day,
ten-day and longer-term exposures, additional studies on the acute toxicity of
WP are unlikely to provide more precise data for the establishment of these
numbers. The high toxicity of WP, with mortality being unpredictable at low
levels, precludes their establishment. Additional studies are, therefore, not
recommended at this time.
A one-generation, two litter reproductive study in rats indicates that WP does
not have any adverse effects on the normal reproductive parameters. Maternal
toxicity was indicated by a high mortality rate among the high-dose females
during the time of parturition. This effect is uncommon in rat reproduction
studies, and the precise cause of these deaths could not be determined. While
additional studies would be of interest in establishing the reason for the
difficulties encountered during parturition, this information is unlikely to
impact on the development of the Longer-term HA.
Al-6

-------
No information was found in the available literature on the developmental
effects of WP in animals. In view of the histological effects of WP on the
bones of animals, particularly at low doses over short periods of exposure, it
is recommended that additional studies be undertaken to evaluate the
possibility of developmental effects, particularly skeletal anomalies.
No carcinogenicity studies were located in the available literature, A
lifetime study in rats on the effects of dietary exposure to WP did not
indicate any lesions related to its intake, except for the effects of WP on
the bone. In addition, mutagenicity studies indicate that WP is not mutagenic
in the Ames assay. Additional studies on the carcinogenic potential of WP are
not recommended at this time.
Several methods for analysis of WP are available and appear to be adequate for
detection of WP at the low levels recommended for safety in drinking water.
Treatment technologies do not appear to be necessary to achieve these low
levels, although methods are available to increase the rate of degradation of
WP in drinking water.
CONCLUSIONS/RECOMMENDATIONS
Based on the above discussion, the following conclusions/recommendations can
be made:
1.	The available studies on the toxicity of WP are generally considered
adequate for the development of a Lifetime HA. Health Advisories for
shorter exposure durations are not recommended due to the extreme
acute toxicity of this compound.
2.	No data are available on the developmental effects of WP. In view of
the toxic effects of WP exposure on the bone, it is recommended that
screening studies be undertaken to assess the teratogenic potential of
WP.
3.	Aside from the aforementioned data gaps, no other studies of adverse
health effects from WP as related to its presence in drinking water,
are considered necessary at this time.
Al-7

-------
REFERENCES
Adams CO, Sarnat BG. 1940. Effects of yellow phosphorus and arsenic trioxide
on growing bones and growing teeth. Arch. Pathol. 30:1192-1201.
Ashburn LL, McQueeney AJ, Faulkner RR. 1948. Scarring and precirrhosis of
the liver in chronic phosphorus poisoning of guinea pigs. Proc. Soc. Exp.
Biol. Med. 67:351-358.
Ben-Hur N, Appelbaum J. 1973. Biochemistry, histopathology and treatment of
phosphorus burns. Israel J. Med. Sci. 9(l):40-48.
Ben-Hur N, Giladi A, Neuman Z, Shugerman B, Appelbaum J. 1972. Phosphorus
burns - a pathophysiological study. Br. J. Plastic Surgery 25:238-244.
Bowen TE, Whelan TJ, Nilson TG. 1971. Sudden deaths after phosphorus burns:
experimental observations of hypocalcemia, hyperphosphatemia, and
electrocardiographic abnormalities following production of a standardized
white phosphorus burn, Ann, Surg. 174(5):779-784.
Brewer E, Haggerty RJ. 1958. Toxic Hazards - Rat poisons. II - phosphorus.
Mass. Med. Soc. 258(3):147-148.
Cameron JM, Patrick RS. 1966. Acute phosphorus poisoning-the distribution of
toxic doses of yellow phosphorus in the tissues of experimental animals. Med.
Sci. Law 6(4);209-214.
Condray JR. 1985. Elemental yellow phosphorus one generation reproduction
study in rats. IR-82-215; IRD No. 401-189. Monsanto Company, St. Louis, MO.
Diaz-Rivera RS, Collazo PJ, Pons ER, Torregrosa MV. 1950. Acute phosphorus
poisoning in man: a study of 56 cases. Medicine 50:269-298.
Diaz-Rivera RS, Ramos-Morales F, Garcia-Palmieri MR. 1961. The
electrocardiographic changes in acute phosphorus poisoning in man. Am. J.
Med. Sci. 241:758-765.
Ellis III HV, Hodgson JR, Hwang SW, Halfpap LM, Helton DO, Anderson BS, Van
Goethem DL, Lee C-C. 1978. Mammalian toxicity of munitions compounds, Phase
I: Acute oral toxicity, primary skin and eye irritation, dermal
sensitization, disposition and metabolism, and Ames tests of additional
compounds. Progress Report No. 6. Midwest Research Institute, Project No.
3900-B, Kansas City, MO. DAMD-17-74-C-4073. AD-A069 333.
Fleming RBL, Miller JW, Swayne Jr. VR. 1942. Some recent observations on
phosphorus toxicology. J. Ind. Hyg. Toxicol. 24(6):154-158.
Fletcher GF, Galambos JT. 1963. Phosphorus poisoning in humans. Arch. Int.
Med. 112:846-85?..
Al-8

-------
Ghoshal AK, Porta EA, Hartroft WS. 1972. Comparative studies on the
hepatotoxlclty of CCl^ and white phosphorus in rats. Gastroenterology 62:193.
Hawley GG, ed. 1981. The condensed chemical dictionary, 10th ed. New York:
Van Nostrand Reinhold Co. p. 810.
Jakhi SA, Parekh BK, Gupta S. 1983. Phosphorus necrosis of the maxilla. J.
Oral Med. 38(4):174-176.
Lai MG. 1979a. Characterization of white phosphorus in water: I.
Determination of white phosphorus in environmental waters at the nanogram
level. Final Report No. NSWC/TR-79-3. Naval Surface Weapons Center, Silver
Spring, MD. AD-B042 884.
Lai MG. 1979b. Characterization of white phosphorus in water: II.
Degradation of white phosphorus in aqueous system. Final Report No. NSWC/TR-
79-5. Naval Surface Weapons Center, Silver Spring, MD. AD-B098 687L.
Lai MG, Rosenblatt DH. 1977. Determination of ultramicro quantities of
elemental phosphorus in water by neutron activation analysis. Final Report.
NSWC/WOL/TR-77-49. Naval Surface Weapons Center, Silver Spring, MD. AD-A091
773.
Lee C-C, Dilley JV, Hodgson JR, Helton DO, Weigand WJ, Roberts DN, Anderson
BS, Halfpap LM, Kurtz LD, West N. 1975. Mammalian toxicity of munition
compounds: Phase I. Acute oral toxicity, primary skin and eye irritation,
dermal sensitization, and disposition and metabolism. Report No, 1, Midwest
Research Institute, Project No. 3900-B, Kansas City, MO. DAMD 17-74-C-4073.
AD-B011 150.
Mallory FB. 1933. Phosphorus and alcoholic cirrhosis. Am. J. Pathol.
9:557-567.
Pani P, Gravela E, Mazzarino C, Burdino E. 1972. On the mechanism of fatty
liver in white phosphorus poisoned rats. Exp. Mol. Pathol. 16:201-209.
Pearson JG, Bender ES, Taormina DH, Manuel KL, Robinson PF, Asaki AE. 1976.
Effects of elemental phosphorus on the biota of Yellow Lake, Pine Bluff
Arsenal, Arkansas. March 1974 - January 1975. Technical Report EO-TR-76077.
Edgewood Arsenal, Aberdeen Proving Ground, MD. AD-A035 925.
Pietras RJ, Stavrakos C, Gunnar RM, Tobin JR. 1968. Phosphorus poisoning
simulating acute myocardial infarction. Arch. Intern. Med. 122:430-434.
Rao S, Brown RH. 1974. Acute yellow phosphorus rat poisoning. 111. Med. J.
145(2):128-130.
Al-9

-------
Rosenblatt DH, Small MJ, Barkley JJ. 1973. Munitions production products of
potential concern as waterborne pollutants - Phase I. USAMEERU Report No. 73-
07. U.S. Army Medical Environmental Engineering Research Unit. Edgewood
Arsenal, MD.
Rubitsky HJ, Myerson RM. 1949. Acute phosphorus poisoning. Arch. Ind. Med.
83:164-178.
Scherling SS, Blondis RR. 1945. The effect of chemical warfare agents on the
human eye. Military Surgeon 96:70-78.
Sollmann T. 1925. Studies of chronic intoxications on albino rats. VIII.
Yellow phosphorus. J. Pharmacol. Exp. Therap. 24:119-122.
U.S. EPA. 1986. U.S. Environmental Protection Agency. Guidelines for
carcinogen risk assessment. Federal Register. 51(185):33992-34003.
Walker J, Jr., Galdston M, Wexler J, Hill ML, Modgely G. 1947. Medical
Division Report No. 103. WP casualties at Edgewood Arsenal, Maryland, 1945.
CMLEM-52, War Department, Office of the Chief, Chemical Corps, Washington 25,
D.C.
Whalen JP, O'Donohue N, Krook L, Nunez EA. 1973. Pathogenesis of abnormal
remodeling of bones: effects of yellow phosphorus in the growing rat. Anat.
Rec. 177:15-22.
Al-10

-------
TECHNICAL REPORT DATA
/Please reed Instruction! on the reverse before compleir
1. REPORT NO. 2.
3,
* TITUS AND SUBTITLE
VlVvVe- ^V\os dVotoS
ne.cAW
5. REPORT DATE
6. PERFORMING ORGANIZATION COOS
?. AUTHORtSI
Lor Cro.-c\cA Vj.^lia.n 9x. Vl C .
J 1 1
a, performing organisation report no.
9. PERFORMING ORGANIZATION NAME ANC AOORESS
O^icc cS" D^inV. .1'?
IjS ^C-nOvcct\ fw i_o\cW \' C?\ /\j.nc.j
Vi ^ iVi \} C 4
10. PROGRAM ELEMENT no.
11. CONTRACT,GRANT NC.
i:. SPONSORING AGMCV NAME AND ACORESS
Kr.^-1 . ^ \
rwd;cc\ icjic.'cV ^
*>c\ V~--V- .
P v '_i ' k. mn i.-a 1
13. TYPE OP REPORT AND PERIOD COVERED
FincA
14 SPONSORING AGcNC CODE
15. SUPPLEMENTARY NOTES
?ftL$are_A \r\ C Cc 0<_.- A ' o.\ W-\'A Vn<_ U -S c ^
16. ABSTRACT I 1 " 1
This'"Health Advisory (HA) provides information on the health effects,
analytical methodology and treatment technology that would be useful in
dealing with White Phosphorus contamination of drinking water. Due to
the extreme toxicity of White Phosphorus following oral ingestion, One-
day, Ten-day, and Longer-term (child and adult) HAs are not
recommended. The Lifetime HA is 0.0001 mg/L. White Phosphorus is is
not classifiable as to human carcinogenicity. Health Advisories
describe nonregulatory concentrations of drinking water contaminants at
which adverse health effects would not be anticipated to occur over
specific exposure durations. The HAs, developed by the US
Environmental Protection Agency, Office of Drinking Water (ODW), are
not legally enforceable Federal standards and are subject to change as
new information becomes available. Health Advisories are developed for
One-day, Ten-day, Longer-term and Lifetime exposures based on data
describing noncarcinogenic end points of toxicity. For those
substances that are known or probable human carcinogens, according to
the EPA classification scheme, Lifetime HAs are not recommended. The
chemical concentration values for carcinogens are correlated with
carcinogenic risk estimates by employing a cancer potency (uni t risk)
value.
... KEY WORCS AND DOCUMENT ANALYSIS
a. OESCatPTCRS
b.IDENTIFIERS,OPEN ENCEO TERMS
c. COSATi Fieid/Croup
?V>c&nV%c'f ^
E\L^st,vV\ c i 5W-f (
Qr\r\V^ \\e.-.nV\ ^d : S >
^\yjpivic^o? V-i ncT-t-Sj "Ar^V) i  i } \


18. DISTRIBUTION STATEMENT
Ur\\i.v> A
-------