Document ID: EPA-HQ-OPP-2008-0407-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-07T04:00Z

June 8, 2009

MEMORANDUM

SUBJECT:	Decision Document for Petition Number 8E7329; 

	Ammonium Chloride (CAS Reg. No. 12125-02-9)

		

FROM:	Deirdre Sunderland, Industrial Hygienist

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

TO:		PV Shah, Chief

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

EXCUTIVE SUMMARY

A petition requesting that ammonium chloride (CAS Reg. No. 12125-02-9)
be granted an exemption from the requirement of tolerance under 40 CFR
180.920, when used as an inert ingredient in pesticidal formulations
applied pre-harvest to all raw agricultural commodities was submitted to
the Environmental Protection Agency (herein referred to as the Agency or
EPA) on May 8, 2008.  Ammonium chloride will be used in biopesticide
products and will be applied to targeted vegetables, fruit trees,
spices, bulb crops, and ornamentals via irrigation or drenching.

Ammonium chloride is a naturally occurring chemical found in a wide
variety of goods such as cleaning products, fertilizers, and other
industrially manufactured goods. In addition to its commercial value,
ammonium chloride is used in food manufacturing (human and agricultural)
and in pharmaceuticals.  

Therapeutically it is used in the United States to correct electrolyte
imbalances (hypochloremia) and to correct metabolic alkalosis in humans.

Ammonium chloride has been ingested by humans for decades. Ammonium and
chloride are integral components of normal human metabolic processes. In
some countries ammonium chloride has been approved for use in food with
no limitations. In the US it is regulated by both the EPA and Food and
Drug Administration (FDA). The FDA has given ammonium chloride the
designated of “generally recognized as safe” (GRAS).  Existing EPA
regulations include 40 CFR 180.910 and 40 CFR 180.940(a).

It appears that the primary effect of ammonium chloride is related to
the subsequent metabolic acidosis that occurs as a result of ingesting
high concentrations of the chemical. Fortunately, the body has
compensatory mechanisms used to return it to homeostasis. Ammonium
chloride is rapidly absorbed in the body and is readily detoxified by
the liver so it is unlikely that toxic levels will be reached.  Many of
the studies noted that the effects were reversible. Medical literature
gives the signs and symptoms of an ammonium chloride overdose ranging
from mild gastrointestinal symptoms to profound neuromuscular effect,
most likely a result of metabolic acidosis. 

Acute oral studies on mice and rats given ammonium chloride showed LD50
values ranging from 1220 mg/kg to 1630 mg/kg.  No acute dermal or
inhalation studies are available, however, skin irritation and eye
irritation studies revealed moderate transient irritation effects. Skin
sensitization studies showed that ammonium chloride has no sensitizing
potential. 

An 8 day dog study administered 200 mg/kg/day of ammonium chloride.
Metabolic acidosis occurred in the blood and the plasma, however, there
were no changes in the acid-base system in erythrocytes. Renal effects
were also observed at high doses in some of the studies. One study
administered 0 or 1.28 g/kg/day of ammonium chloride via drinking water
or gavage to Sprague- Dawley rats for 5 days. Renal hypertrophy was
observed; however, no increase in uptake of radioactive thymidine was
seen, implying that no increase in DNA synthesis or cell division
occurred.  

No clinical signs of toxicity or histopathological changes were
attributed to the treatment of ammonium chloride in rats given 580
mg/kg/day for 56 days. In another study male rats administered 684
mg/kg/day of ammonium chloride for 70 days showed a reduction in urinary
pH and an increase in urinary calcium, however, no crystals were found
in the urine. No histopathological changes were noted in the stomach,
bladder, or kidneys.

A 330 days study which administered 0 or 1.5 % ammonium chloride in
drinking water to rats showed the development of osteoporosis in test
animals due to loss of organic bone substance and bone minerals. The
effect was reversible with the supplement of bicarbonate. The release of
bone mineral by resorption is thought to provide additional buffering
capacity, sparing bicarbonate.  Various studies are available in the
literature in which rats were given high doses of ammonium chloride via
the diet or drinking water and experienced metabolic acidosis and
changes in urinary pH.

Available studies show that ammonium chloride is of low toxicity for
human health endpoints. Although one developmental study did observe 7%
ectrodactyly in the offspring of mice that were given 600 mg/kg four
times a day on day 10 of gestation, another study found no teratogencity
in the fetuses of rats given almost 4 times that dosage (~8.9 mg/kg/day)
during days 7 to 10 of gestation.  Effects of treatment were seen in
regards to fetal weight; however, no fetal malformations were observed.
Because of the negligible anticipated crop residues and subsequent
exposure, the low toxicity of the chemical, and the body’s ability to
achieve homeostasis, the Agency does not feel that there is an increased
risk to infants and children and therefore, a safety factor analysis has
not been used to assess risk.

No evidence of tumors were observed in mice and rats administered
ammonium chloride at doses up to 1% of their diet or drinking water for
up to 652 days. Ammonium chloride is not expected to be carcinogenic. 
Based on available mutagenicity studies, EPA concludes that ammonium
chloride is not mutagenic. Evidence of neurotoxicity exist, however,
effects were only seen at high doses. The Agency feels that the
concentration needed to invoke a neurotoxic response is far greater than
what is expected from use of ammonium chloride as an inert ingredient in
pesticide products. 

The main route of exposure to ammonium chloride, as an inert ingredient
in pesticide formulations is via the oral route. Although residue
studies are not available, based on its high water solubility and the
use of this product in the growing phase of plant life, it is expected
that the majority of this inert ingredient will be washed from the plant
prior to it reaching the consumer market, as a result plant residues
will be limited. Using a dietary exposure model, the chronic exposure
for the total US population is anticipated to be 3.3% of the Rfd. The
subpopulation with the highest degree of exposure is children 1-2 yrs
(10.8% of Rfd). This model is extremely conservative and therefore the
likelihood of ammonium chloride occurring at such high levels in food
commodities and drinking water is unlikely.

. 

Occupational exposure via the oral, dermal, and inhalation routes is not
expected.  Maximum worker exposure levels have been imposed on ammonium
chloride fume.  Workers will be required to personal protective
equipment when mixing and applying this chemical, negating the risk for
dermal and oral exposure. Ammonium chloride is also used as a fertilizer
in residential settings. Home owners are likely to be exposed orally and
dermally; however, the risk is expected to be minimal because ammonium
chloride is not likely to be absorbed by the skin and oral toxicity is
only observed at high doses.  Ammonium chloride is not expected to
volatilize, therefore, the inhalation route of exposure is not a
concern. 

Due to the nature of the chemical, ammonium chloride is not expected to
be absorbed in soil. The Agency does not anticipate increased exposure
from drinking water based on the excess ammonium chloride uptake by the
plant, the rapid disassociation into its anion/cation parts, the
regulation of water treatment plants for nutrients in drinking water,
and the amount of ammonium chloride needed to induce a toxic response
would not be palatable and therefore would not be consumed.  

50 ≥ 42.0 mg/L and a chronic NOEC of ~8.0 mg/L. 

Concentrations needed to evoke a toxic response are far greater than the
anticipated exposure of ammonium chloride when use as an inert
ingredient.  Application rates of the inert ingredient are expected to
be ~12-50% of typical fertilizer application rates. Considering all
available data including the high toxicity threshold and the current
exposure pattern (e.g. in food, as fertilizer, and pharmaceutical use)
the risk from the use of ammonium chloride as an inert ingredient in
food use pesticide products is below the Agency’s level of concern.
Therefore, ammonium chloride is exempt from the requirement of tolerance
under 40 CFR 180.920

I. 	BACKGROUND AND USES

	

On May 8, 2008, SciReg, Inc. submitted a petition to the Environmental
Protection Agency requesting that ammonium chloride (CAS Reg. No.
12125-02-9) be granted an exemption from the requirement of tolerance
under 40 CFR 180.920, when used as an inert ingredient in pesticidal
formulations applied pre-harvest to all raw agricultural commodities. 
Ammonium chloride will be used in biopesticide products and will be
applied to targeted vegetables, fruit trees, spices, bulb crops, and
ornamentals via irrigation or drenching. 

            Ammonium chloride is a naturally occurring chemical found in
volcanic regions where volcanic gases react with organic matter. It is
produced in large quantities throughout the world and used extensively
for its commercial, agricultural, and medicinal properties. In 2007,
China alone produced 7 M tons of ammonium chloride. (Xiling, 2008)

Ammonium chloride is used in a wide variety of products such as
shampoos, cleaning products, fertilizers, dry cell batteries, plastics,
electroplating, and as a mordant in dyeing. It is also used in
galvanizing, tinning, and as a flux in soldering. It has properties that
make it valuable in snow making and lowering the melting temperatures of
certain metals for manufacturing processes. In addition to its
commercial value, ammonium chloride is used in food manufacturing (human
and agricultural) and in pharmaceuticals.  According to Organization for
Economic and Cooperative Development (OECD) in their 2004 SIDS Initial
Assessment Report (SIAR) this chemical is primarily used in the United
States as a food additive to prevent calculi in cattle. 

Therapeutically it is used in the United States to correct electrolyte
imbalances (hypochloremia) and to correct metabolic alkalosis in humans.
In other countries, ammonium chloride is used medicinally as a diuretic,
a weight loss supplement, an aid in treating urinary tract infections,
and as an ingredient in cough medicines. It has been available as a
therapeutic agent in Canada since its introduction in 1925. (OECD, 2004)
  

	

Regulations and Guidelines

Both by the EPA and Food and Drug Administration (FDA) regulate ammonium
chloride. It is generally recognized as safe (GRAS) by the FDA and has
been approved under 21 CFR 184.1138 for use in food when used as a dough
strengthener, a flavor enhancer, a leavening agent, and/or a processing
aid under good manufacturing practices.  

Existing EPA regulations include 40 CFR 180.910 and 40 CFR 180.940(a).
EPA regulation 40 CFR 180.910 gives ammonium chloride an exemption from
the requirement of tolerance as an inert ingredient applied to growing
crops and raw agricultural commodities when used as an intensifier with
ammonium nitrate as a dessicant or defoliant or as a fire suppressant in
aluminum phosphide and magnesium phosphide formulations. Under 40 CFR
180.940(a), ammonium chloride is permitted as an inert ingredient in
antimicrobial pesticide formulations applied to food contact surfaces in
public eating places, dairy processing equipment, and food-processing
equipment and utensils. The end-use concentration cannot exceed 48 ppm. 

Recommendations have been placed on occupational exposure to ammonium
chloride fume. NIOSH, the National Institute for Occupational Safety and
Health, has established a recommended exposure limit (REL) for a 10 hour
time-weighted average (TWA) of 10 mg/m3 and short-term exposure limit
(STEL) of 20 mg/m3 for a 15 minute TWA.  Similarly, the American
Conference of Government Industrial Hygienist (ACGIH) recommends a
threshold limit value (TLV) of no more than 10 mg/m3   for an 8 hour TWA
(Time-weighted average) and 20 mg/m3 for a 15 minute STEL (Short-term
exposure limit). 

II.	PHYSICAL AND CHEMICAL PROPERTIES

  	  HYPERLINK "http://pubchem.ncbi.nlm.nih.gov/summary/" 
http://pubchem.ncbi.nlm.nih.gov/summary/ 

summary.cgi?sid=10500596

CAS Reg. No. 	12125-02-9	CAS online

Molecular Weight	53.49	MERCK, 2001

Chemical Formula	NH4CL	MERCK, 2001

Common Names	Sal Ammoniac, Amchlor, Ammonium muriate, Salmiac	OECD, 2004

Physical State	Colorless, odorless crystals or white granular powder
MERCK, 2001

Melting Point (°C)	Decomposes at 338 °C	OECD, 2004

Boiling Point (°C)	Sublimation at 520 °C	OECD, 2004

Vapor Pressure (units)	1 mmHg (or 1.3hPa) @ 160 °C	OECD, 2004

Specific Gravity	1.5	Michigan, DEQ

Water Solubility	28.3% @ 25 °C, 283 g/L @25°C	Michigan DEQ, OECD, 2004

Henry’s Law Constant	3.88 X 10-13  atm-m3 /mole	HENRYWIN from SIDs

Relative Density	1.53 at 20°C	OECD 2004 

Log Kow	Inaccessible experimentally, is expected to be a very low value
OECD, 2004

III.	METABOLISM/PHARMACOKINETICS

	Ammonium and chloride are integral components of normal human metabolic
processes. Ingested ammonium chloride is rapidly absorbed from the
gastrointestinal tract with almost complete absorption occurring in 3-6
hours. It is utilized by the liver to form amino acids and proteins.
(OECD, 2004)

Once absorbed, this salt dissociates to an ammonium cation and a
chloride anion. The effect of ammonium chloride on the body is
influenced by the ammonia which enters the body and subsequently the
cell. In most biological fluids ammonia exists in two forms and the
toxicity is determined primarily by the pH of the solution. Cell
membranes are relatively impermeable to ionized ammonia (NH4+) also
known as ammonium, whereas un-ionized ammonia (NH3) passes tissue
barriers with ease.

The ammonium cation is converted to urea by the liver via the urea cycle
and a hydrogen cation is released which reacts with a bicarbonate ion to
form water and carbon dioxide. The chloride anion combines with fixed
bases in the extracellular fluid which subsequently reduces the alkaline
reserve of the body. Ammonium chloride will mainly exert its effects in
the mammalian body due to the formation of hydrogen chloride (WHO, 1986)
which subsequently forms hydrochloric acid. (UMMS, 2008)

Chloride anions ultimately displace bicarbonate ions which alters the
bicarbonate:carbonic acid ratio of the body resulting in acidosis. With
the increasing chloride concentration in the extracellular fluid and the
subsequent increased load on the renal tubules, chloride will be
excreted along with cations and water. Although sodium is the principal
cation excreted, potassium may also be excreted. This diuretic response
increases the excretion of electrolytes and water from the body and
lowers the pH of the urine. 

According to FDA in the “Evaluation of the Health Aspects of Certain
Ammonium Salts as Food Ingredients” (1974), “the normal liver so
readily detoxifies ammonium ion from alimentary sources that blood
concentrations of ammonium salts do not rise to the levels necessary to
evoke toxic response.” 

IV.	TOXICOLOGY

 Acute Oral 

Acute oral studies have been conducted on mice and rats with LD50 values
ranging from 1630 mg/kg to1220mg/kg. Other acute oral studies have been
conducted on rats, guinea pigs, rabbits, and sheep which showed no
adverse effect at dose up to and greater than 1000 mg/kg. (OECD, 2004)

Of the studies evaluated in the OECD document, two studies were
identified as key studies based on their reliability.  One study
performed by BASF using Wistar rats resulted in an LD50 for males,
females, and overall of 1,630, 1,220, and 1,410 mg/kg, respectively.
Dyspnea, apathy, abnormal position and staggering were observed at a
dose of 1,000 mg/kg or higher. No abnormalities were detected during
necropsy of surviving animals. 

The second study by Takasaki looked at male CD-1 mice and found an LD50
of 1,300 mg/kg. Diarrhea, cyanosis and ataxic gait were observed at
1,200 mg/kg. At necropsy, swelling and whitening of kidney and
hemorrhage in brain were observed. (OECD, 2004)

	B.  Acute Dermal: No studies available	

C.  Acute Inhalation: No studies available

 

D.  Skin Irritation

 The most reliable skin irritation study, according to the OECD
document, was conducted by MBA Labs using New Zealand White Albino
rabbits according to the Draize method. After 24 hours, redness was
observed but disappeared within 48 hours. The result indicates that this
substance is a moderate skin irritant. A second study also reported
slight erythema and similarly classified ammonium chloride as moderately
irritating to the skin in rabbits. (OECD, 2004)

E.  Eye Irritation

Ammonium chloride is considered to be moderately irritating to the eyes
of rabbits. In one study, approximately 50 mg of ammonium chloride
powder was applied to the conjunctival sac of the rabbit’s eye.  After
10 minutes, 1 and 24 hours, signs of inflammation (e.g. redness,
swelling, or cloudy corneal opacity) were observed. These symptoms were
reversible within 8 days.  There were no differences in the irritation
between the powder and aqueous solution. (OECD, 2004)

F.  Skin sensitization:

In a skin sensitization study on Pribright-White guinea pigs, ten
percent of the animals (2 out of 20) demonstrated a positive reaction
after the challenge exposure. This was below the limit value of 30
percent indicating that the substance had no sensitizing potential.
(OECD, 2004)	

G.  Repeat Dose

According to the World Health Organization (WHO): 

The ingestion of ammonium chloride in doses of around 500-1000 mg/kg
bw/day, for 

periods ranging from 1 to 8 days, has induced metabolic acidosis in
mice, guinea-pigs, 

rats, rabbits, and dogs. However, one study did not report any toxic
effects at doses of up 

to 1 g/kg bw in rats, rabbits, guinea-pigs, and cats (50 animals per
group).” Clinical signs, 

depending on the severity of the acidosis, include: a decrease in
plasma- and urinary-pH; 

decreased appetite; decreased carbon dioxide-combining power; an
increase in BUN and 

chlorides; an increase in plasma proteins; an increase in hematocrit
(hemoconcentration); 

increased gluconeogenesis; increased phosphoenolpyruvate carboxykinase
activity; 

increased urinary ammonium; increased urea, sodium, chloride, calcium,
and titratable 

acid excretion; an increase in malate and oxaloacetate concentrations in
renal tissue; and 

decreased concentrations of glutamine, glutamate, and
alpha-ketoglutarate in the kidney. 

Pulmonary edema, central nervous system dysfunction, and renal changes
are reported 

to have occurred after ingestion of ammonium chloride. Susceptibility to
ammonium 

chloride differs among species. For instance, pulmonary edema is
produced in cats, but 

not in rabbits; yet cats have been shown to be more resistant to oral
poisoning by 

ammonium chloride than other animals studied.

A 70 day toxicity study was conducted using Sprague-Dawley rats fed a
diet containing 684 mg/kg/day (12,300 ppm) of ammonium chloride.  No
effects of treatment were observed in regards to clinical signs, body
weight, food consumption, or necropsy findings. Animals treated with
ammonium chloride showed a reduction in urinary pH to 6.04 compared to a
pH of 7.56 or greater in the control group. The concentration of urinary
calcium was also increased in this group; however, no crystals were
found in the urine. Other urinary parameters such as magnesium,
creatinine, phosphate, protein, and osmolality were not affected by
treatment. In addition, no histopathological changes attributed to this
substance were observed in the stomach, bladder, or kidneys. The NOAEL
for this study is considered to be 684 mg/kg/day (12,300 ppm) in male
rats. (OECD, 2004)

The aforementioned study results are consistent with the findings of a
56 day study on male Fischer 344 rats given a diet containing 580
mg/kg/day of ammonium chloride. No clinical signs of toxicity or
histopathalogical changes were attributed to this chemical. The NOAEL is
considered to be 580 mg/kg/day. (OECD, 2004)

An 8 day dog study administered 100 mg/kg of ammonium chloride every 12
hours for 8 days. Metabolic acidosis occurred in the blood and the
plasma; however, there were no changes in the acid-base system in
erythrocytes. Concentrations of Na+ were significantly decreased in the
plasma and erythrocytes while concentrations of K+ remained constant.
Significant increases were observed in urinary acid excretion. This
study indicates that ammonium chloride causes substantial acidification
of the blood and urine but does not affect the acid-base system of
erythrocytes. (Schober, 1996) 

Several studies have been presented in the OECD document which were
originally published in peer-reviewed journals in the 1960s but have
been given a rating of “4 (not assignable)” in regards to
reliability. In some cases only the OECD summaries were available for
review and they have been presented below.  When available the primary
source was consulted.

●  Sprague-Dawley rats were given 0 or 1.28 g/kg/day of ammonium
chloride either via drinking water or gavage for 5 days. Renal
hypertrophy was observed; however, no increase in uptake of radioactive
thymidine was seen implying that no increase in DNA synthesis or cell
division occurred. No other treatment related
effects眠牥⁥扯敳癲摥‮伨䍅ⱄ㈠〰⤴

●  Female Holtzman rats were given drinking water containing 0 or 1.5%
ammonium chloride for 7 days. Renal hypertrophy was observed along with
increases in total DNA and total RNA of the kidney. Similar effects were
seen in a 6 day study where rats were fed a diet containing 0 or 3%
(about 1500 mg/kg) ammonium chloride. (OECD, 2004) In addition, a study
in the 1920’s looked at the effects of ammonium chloride gavage in
rabbits (average weight 2 kg) for periods of 11 days to 11 months with
doses ranging from 16.2 to 166 g.  Severe acidosis was seen with casts
and albumen appearing in the urine. Histological examination of the
kidneys revealed acute degeneration of the convoluted tubules and marked
pyknosis and karyolysis of the nuclei.  Once the test material was
removed these effects were reversible. (Seegal, 1927)

●  Sprague-Dawley rats were dosed with either 0 or 1.5% ammonium
chloride in drinking water for 330 days. (Barzel et al., 1969) In a
concurrent study by the same laboratory, rats were dosed with 0 or 2%
ammonium chloride in drinking water for 6 months. Test animals (not
specified) developed osteoporosis due to loss of organic bone substance
and bone minerals. This effect was reversible with supplements of
bicarbonate. Calcium supplements were not effective in reversing this
effect.  (OECD, 2004)  “During prolonged metabolic acidosis, the
release of bone mineral by resorption is thought to provide additional
buffering capacity, sparing bicarbonate.”(WHO, 1986)

Reproduction

In the US ammonium chloride is classified under Pregnancy Category C. 
According to the FDA official label this is due to the fact that,
“Animal reproduction studies have not been conducted with Ammonium
Chloride. It is also not known whether Ammonium Chloride can cause fetal
harm when administered to a pregnant woman or can affect reproduction
capacity. Ammonium Chloride should be given to a pregnant woman only if
clearly needed.” (DHHS/FDA, 2008)

Having said this, ammonium chloride is available medicinally to pregnant
women in Japan without restriction. In Australia, ammonium chloride as a
medicinal drug has been classified under Category A meaning that it
“has been used for many pregnant women and women of conceiving age,
and that there is no proof of increase in the frequency of deformation
and the frequency of direct or indirect detrimental action to the
embryo” (OECD, 2004).

I.  Developmental 

 	

Sprague-Dawley rats were orally given 1mL/kg of 1/6 M (~8.9 mg/kg/day)
of ammonium chloride daily during days 7 to 10 of gestation.  Fetuses
were examined on gestation day 20 and no teratogenicity was observed.
Although effects were seen in regards to fetal weight and length, the
author suggested that these effects were a result of maternal acidosis. 
No fetal malformations were observed in the treated group.(OECD, 2004)
According to the Catalog of Teratogenic Agents, mice were given 600
mg/kg four times a day on day 10 of gestation (2.4 g/kg/day) and 7%
ectrodactyly was observed in the offspring. (Shepard, 1986)

	Ammonium chloride and its interaction with salicylate was investigated
for developmental toxicity in rats. The animals received 0.9%
(0.17mol/L) ammonium chloride in drinking water and/or a subcutaneous
injection of salicylate after gestation day 7. Ammonium chloride
administered alone inhibited fetal growth but was not teratogenic. When
ammonium chloride was administered in conjunction with salicylate,
increases in maternal and fetal morality and teratogenic effects were
observed.  Fetal anomaly rates (dorsal midline, ventral midline, and eye
defects) were significantly increased compared with those who were
administered salicylate alone. According to WHO (1986), these effects
were attributed to acidosis and not to ammonia. 

J.  Neurotoxicity

According to the WHO (1986), the addition of ammonium chloride to rat
feed resulted in reduced dietary consumption. A study conducted on male
Wistar rats, showed a direct effect of the ammonium ion on the brain
area that regulates feeding. A unilateral injection of 10mg/L of 2%
NH4Cl/kg was placed in the prepyriform cortical areas of the brain.
Significant reduction in food intake was observed for those animals
given ammonium chloride in the prepyriform cortical areas of brain
versus animals treated in either other areas of the brain with ammonium
chloride or in the prepyiform cortical area treated with sodium
chloride. 

A study was conducted examining the effects of ammonium chloride on the
astrocyte benzodiazepine receptor in the brain. “Scatchard analysis of
the binding of (3H)Ro-5-4864 to homogenates prepared from primary
astrocyte cultures showed a significant decrease in Kd (27% with 2 mM
NH4Cl; 32% with 5 mM NH4Cl; 25% with 10 mM NH4Cl) and Bmax (14% with 10
mM NH4Cl). These findings indicate that ammonium chloride can affect the
astrocyte benzodiazepine receptor, and that such receptor changes may
contribute to ammonia-induced encephalopathy” (Ducis, et al.,1989) 

Endocrine

EPA is required under the Federal Food, Drug and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) “may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen, or other such
endocrine effects as the Administrator may designate.”  Following
recommendations of its Endocrine Disruptor and Testing Advisory
Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as part of the program, the androgen and thyroid hormone
systems, in addition to the estrogen hormone system.  EPA also adopted
EDSTAC’s recommendation that the Program include evaluations of
potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

          When additional appropriate screening and/or testing protocols
being considered under the Agency’s EDSP have been developed, ammonium
chloride may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.

L.  Mutagenicity

A variety of tests have been performed on ammonium chloride to assess
the likelihood of genotoxicity. Two bacterial reverse mutation studies,
at least one conducted in accordance with OECD TG 471, with and without
metabolic activation, revealed negative results. An in vitro chromosomal
aberration test performed on Chinese hamster lung cell without metabolic
activation produced a positive result. According to SIDS, “this result
is ascribable to the acidity of this substance, considering the
physico-chemical properties of this substance”.  An in vivo
micronucleus assay was also negative for clastogenicity up to the
maximum tolerance dose (MTD: 500 mg/kg or greater). (OECD, 2004) Based
on the weight of evidence, this substance is not considered to be
genotoxic. 

M.  Carcinogencity

Three studies have been conducted that test the effect of ammonium
chloride on carcinogenicity. One study administered 1% ammonium chloride
in drinking water to female mice for 652 day. No bladder tumors,
epithelial hyperplasia, and/or calculi were observed. Average survival
was 492 days versus 485 days for controls. A second study administered
1% ammonium chloride in the diet of male and female Fischer 344 rats for
8 weeks; no hyperplasia was observed. (OECD, 2004) The third study
evaluated the effects of ammonium chloride on male Fischer 344/DuCrj
rats treated with BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine for 4
weeks to initiate carcinogenesis. Ammonium chloride given as 1% of the
diet was found to have an inhibitor effect and actually reduced the
incidence of papillomas. Based on the results of these studies ammonium
chloride is not believed to be carcinogenic in humans. 

Epidemiology 

Medical literature gives the signs and symptoms of an ammonium chloride
overdose as nausea, vomiting, thirst, headache, hyperventilation,
progressive drowsiness, profound metabolic acidosis (secondary to
hyperchloremia), and hypokalaemia. Ammonium chloride is irritating to
the gastric mucosa and may cause gastric distress and anorexia. Other
adverse effects of excessive ammonium chloride ingestion include rash,
bradycardia, mental confusion, irregular breathing, local or generalized
twitching, asterixis, tonic seizures, and coma. Calcium-deficient
tetany, hyperglycemia, glycosuria, hyperreflexia, and EEG abnormalities
have also been reported. 

Humans have been ingesting ammonium chloride for centuries because of
its wide use in foods, pharmaceuticals, and other commercial products.
In addition to some reported case studies involving extreme cases of
ammonium chloride ingestion, there have been some studies preformed on
humans in the 1930’s-1950s. These studies were summarized in IUCLID.  

Two examples of excessive human exposures to ammonium chloride have been
outlined in the OECD report. The first case involves a 58-year-old woman
who was taking 6g/day for 6 months to combat a long history of renal
stone disease and urinary tract infections. She presented in the
emergency room with exhaustion and air hunger. Laboratory analysis
showed profound systemic acidosis which resulted from a combination of
impaired renal function and effective hydrogen ion loading. (Levene and
Knight, 1974)

The second example involved an 18 year-old girl who presented in the ER
with hyperventilation and confusion for 1 day.  Upon investigation it
was determined that the individual, in an effort to stay slim, had been
taking up to 15g/day for short periods over the previous 6 months. There
were no symptoms prior to this hospital visit except 4 weeks earlier the
patient became nauseated and weak with transient hyperventilation. Two
days prior to arrival in the ER the woman took 82g of ammonium chloride
over a 48 hour period. Although the patient had not taken medication in
the 2 days prior to her admission, she developed headaches, nausea and
vomiting in the hospital. She was noted to have become progressively
drowsy and confused. Soon after admission she lapsed into a coma.  The
acidosis was corrected using sodium bicarbonate. (Relman et al., 1961)

V.       SPECIAL CONSIDERATIONS FOR INFANTS AND CHILDREN (FQPA     

          	Safety Factor)    

	The database for ammonium chloride is adequate to make a determination
of safety. Although specific reproduction studies have not been
presented, the use of ammonium chloride as a pharmacological agent gives
an understanding of how ammonium chloride will behave. Given the wide
spread use of ammonium chloride in the food supply (both as a direct
food additive and fertilizer), the amount of ammonium chloride
contributed by its use as an inert ingredient in pesticide products will
not significantly increase the overall exposure to infants and children.
 

Available studies show that ammonium chloride is of low toxicity for
human health endpoints. Although one developmental study did observe 7%
ectrodactyly in the offspring of mice that were given 600 mg/kg four
times a day on day 10 of gestation, another study found no teratogencity
in the fetuses of rats given almost 4 times that dosage (~8.9 mg/kg/day)
during days 7 to 10 of gestation.  Effects of treatment were seen in
regards to fetal weight; however, no fetal malformations were observed.
Similar results were seen when rats were given 0.9% (0.17mol/L) ammonium
chloride in drinking water. No evidence was given on maternal toxicity;
however, previous studies have shown that these doses are likely to
cause acidosis in adult rats and mice. Therefore, the Agency believes
there is no increased susceptibility to infants and children. 

Many of the repeat dose studies and human case studies show that the
effects of ammonium chloride were reversible once the exposure was
removed (in some cases sodium bicarbonate was given to reverse the
acidosis).  It was inferred in many of the studies that the toxicity was
secondary to acidosis. 

No clinical signs of neurotoxicity were seen in any of the repeat dose
studies. Although evidence of neurotoxicity was observed in two
specialized studies at high doses, the scenarios presented are not
likely to occur in a natural setting (i.e. the chemical injected
directly into the brain) and do not include the oral, dermal, or
inhalation routes of exposure. After evaluating the available data and
the expected exposure from the intended use pattern of this inert
ingredient, the Agency does not feel that a developmental neurotoxicity
study is needed. 

Because this chemical is a natural part of the metabolic process the
body has buffers in place to bring the system back to homeostasis when
levels of ammonium or chloride exceed normal values. The concentrations
needed to induce a toxic response will not be reached based on the
physical-chemical properties and the intended use pattern of this inert
ingredient; therefore, the 10 fold safety factor has been reduced to 1X.
 

VI.       ENVIRONMENTAL FATE AND DRINKING WATER

At room temperature ammonium chloride exists as a crystal or granular
powder. It is highly soluble in water and dissociates to its respective
ions almost immediately. Depending on the pH and the temperature of the
water,
the椠湯⁳硥獩⁴湩琠敨映汯潬楷杮攠畱汩扩楲浵‮ഠ

NH4+ + Cl- + H2O ↔ H3O+ + Cl- + NH3 ↔ HCl + NH4+ + OH

Based on its physical-chemical properties, water is expected to be the
preferred media for ammonium chloride. The log Kow for ammonium chloride
is outside the estimated domain but is expected to be a very low value.
The melting point, boiling point, and vapor pressure are 338°C
(decomposition), 520°C (sublimation), and 1 mmHg (1.3hPa) @ 160 °C,
respectively.  Ammonium chloride, under the proposed inert ingredient
exemption, will be applied via irrigation after being mixed with water.
Using the Henry’s Law Constant estimate of 3.88 X 10-13  atm-m3 /mole,
it is unlikely that ammonium chloride will volatize from water. Although
ammonium chloride is subject to ion exchange to form inorganic and
organic salts with other counter ions in soil and water, it is not
expected to be absorbed in soil. Because ammonium chloride is also used
as a plant fertilizer it is anticipated that residues that are washed
off into the soil will be absorbed by the plant as a nutrient. 

 Ammonium chloride is easily degraded to nitrite (NO2-) by multiple
species of bacteria. Photodegradation is not expected because this
chemical has no absorption band in the UV and visible region. Based on
the physical-chemical properties of ammonium chloride it is unlikely to
accumulate in living organisms; however, because ammonium and chloride
are components of living organisms relevant data are not available. 

Although ammonium chloride has a high propensity to water, the Agency
does not anticipate increased exposure from drinking water based on the
following:

1) The plant will take up the excess ammonium chloride that is washed
off 

     after application and use it as a nutrient. 

2) Once in water, ammonium chloride will rapidly disassociate into an 

                ammonium cation and a chloride anion. The Food, Drug,
and 

                Cosmetic Act, permits up to 250 mg/L of chloride in
potable bottled                                       

                water, however, this is not a health based guideline,
instead it is based  

                on the taste of the water itself. In other words, the
amount of 

                ammonium chloride needed to induce a toxic response
would not be  

                palatable and therefore would not be consumed. 

3) Additionally, wastewater treatment plants regulate nutrients such as 

     nitrogen; therefore, if any of the chemical does appear in surface
water 

     runoff then there is an additional buffer to ensure that amount
that 

     reaches the consumer via drinking water is safe for human 

     consumption. 

4) Based on the physical-chemical properties of ammonium chloride it is 
   

     not expected to appear in ground water. It should be noted that the
use 

     of ammonium chloride as a fertilizer may cause a concern when 

     assessing the potential eutrophication hazard including drinking
water  

     quality in certain regions. (OECD, 2004)

EXPOSURE ASSESSMENT

A.  Exposure Profile

The main routes of exposure to ammonium chloride, as an inert ingredient
in pesticide formulations, are the dermal and oral route.  As stated
previously, many countries have placed occupational exposure limits on
the inhalation of ammonium chloride fume. Measures have been put in
place to negate occupational exposure; therefore, workers exposed to
ammonium chloride via dust and/or dermal routes would be required to
wear personal protective equipment. Residential exposure from the use of
ammonium chloride as an inert ingredient in pesticide formulations
applied to growing crops is primarily expected via the oral route. 

Ammonium chloride has been ingested by humans for decades.  In some
countries ammonium chloride has been approved for use in food with no
limitations. The proposed exposure to ammonium chloride as an inert
ingredient in pesticide formulations applied to growing crops is very
small compared to the current use patterns in food products (e.g. as a
fertilizer or a direct food additive). Presently, ammonium chloride is
applied directly to the environment both as a fertilizer and a feed
additive for livestock. The intended application rate of ammonium
chloride as an inert ingredient in pesticide products is <50% of what
would be expected from its use as a fertilizer.

Although residue studies are not available to address the amount of
ammonium chloride that will be left on food, based on it’s high water
solubility and the use of this product in the growing phase of plant
life, it is expected that the majority of this inert ingredient will be
washed from the plant prior to it reaching the consumer market;
therefore, the residues on the plant will be limited. 

In order to quantify the anticipated dietary exposure the Agency’s
Dietary Exposure Evaluation Model (DEEM) was employed. This dietary
exposure model addresses oral exposure via food and drinking water and
uses worst case assumptions. These assumptions include the use of the
inert ingredient in all food use pesticide products applied to all crops
and that 100% of the crop is treated. It also assumes that the residues
of ammonium chloride would be present in all crops at levels equal to or
greater than the highest established tolerance levels for any pesticide
active ingredient for pre-harvest use. 

This model uses the default value of 100 ppb for the concentration of
the inert in all sources of drinking water. Based on the
physical-chemical properties and the intended use pattern there is a
potential for ammonium chloride to appear drinking water; however, the
Agency does not anticipate increased exposure from drinking water as
explained in section VI. “ENVIRONMENTAL FATE AND DRINKING WATER”. 

The chronic RfD used in the model is based on a 56 day rat study. The
rats were fed a diet containing 580 mg/kg/day and no clinical signs of
toxicity or histopathologic changes were attributed to this chemical.
Therefore, the NOAEL is 580 mg/kg/day with an uncertainty factor of 100X
for interspecies and intraspecies extrapolation. Because the FQPA safety
factor is reduced to 1X the cRfD is equal to the cPAD. 

Using this model, the chronic exposure for the total US population is
3.3% of the Rfd. The subpopulation with the highest degree of exposure
is children 1-2 yrs (10.8% of Rfd). This model is extremely conservative
and therefore, the likelihood of ammonium chloride occurring at such
high levels in food commodities and drinking water is unlikely. Even
with these highly conservative assumptions the model shows that exposure
to ammonium chloride, by even the most susceptible populations, is still
well below the RfD.  

 Aggregate Exposure 

In examining aggregate exposure, section 408 of FFDCA directs EPA to
consider available information concerning exposures from the pesticide
residue in food and all other non-occupational exposures, including
drinking water from ground water or surface water and exposure through
pesticide use in gardens, lawns, or buildings.

EPA establishes exemptions from the requirement of a tolerance only in
those cases where it can be clearly demonstrated that the risks from
aggregate exposure to pesticide chemical residues under reasonably
foreseeable circumstances will pose no appreciable risks to human
health.  In order to determine the risks from aggregate exposure to
pesticide inert ingredients, the Agency considers the toxicity of the
inert in conjunction with possible exposure to residues of the inert
ingredient through food, drinking water, and through other exposures
that occur as a result of pesticide use in residential settings. If EPA
is able to determine that a finite tolerance is not necessary to ensure
that there is a reasonable certainty that no harm will result from
aggregate exposure to the inert ingredient, an exemption from the
requirement of a tolerance may be established. 

In order to quantify the anticipated dietary exposure the Agency’s
Dietary Exposure Evaluation Model (DEEM) was employed. This dietary
exposure model addresses oral exposure via food and drinking water and
uses worst case assumptions. Using this model, the chronic exposure for
the total US population is 3.3% of the Rfd. The subpopulation with the
highest degree of exposure is children 1-2 yrs (% of Rfd- 10.8%). This
model is extremely conservative and therefore the likelihood of ammonium
chloride occurring at such high levels in food commodities and drinking
water is unlikely. In addition, this highly conservative exposure
assessment is protective of any possible non-occupational exposures to
ammonium chloride as it results in exposure estimates orders of
magnitude greater than the high-end exposure estimates for residential
uses of pesticides routinely used by EPA. 

Cumulative Exposure

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether
to establish, modify, or revoke a tolerance, the Agency consider
"available information" concerning the cumulative effects of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity." 

	Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to ammonium chloride and any
other substances, and these chemicals do not appear to produce toxic
metabolites produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that ammonium chloride
has a common mechanism of toxicity with other substances.  For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA's Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA's website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

VIII.	RISK CHARACTERIZATION

Ammonium chloride has been ingested for centuries all over the world. It
is a naturally occurring compound that is necessary for human life.
Currently, it is used as a flavoring component in food, an ingredient in
many commercial products (e.g. shampoos, cleaning products, and dry cell
batteries) and animal feed, and as a pharmaceutical. It is also used in
the manufacturing process for several industrial procedures and as a
plant fertilizer. 

Many countries have no restriction as to the use of ammonium chloride.
In the United States it is Generally Recognized as Safe (GRAS) by the
Food and Drug Administration and can be added directly to human food. 
Although ammonium chloride is no longer authorized for use as an oral
agent in the Untied States, the usual adult oral dosage of ammonium
chloride given in other countries is 3-12g daily administered in divided
doses. The oral acidifying dose for children is 75mg/kg daily given in
divided doses. 

As an inert ingredient in pesticide products applied to growing crops,
residential exposure to ammonium chloride will be primarily through the
oral route. Acute oral studies on mice and rats given ammonium chloride
showed LD50 values ranging from 1220 mg/kg to 1630 mg/kg.  No acute
dermal or inhalation studies are available; however, skin irritation and
eye irritation studies revealed moderate transient effects. Skin
sensitization studies showed that ammonium chloride has no sensitizing
potential. 

≥7.56 in controls) and an increase in urinary calcium; however, no
crystals were found in the urine. Other urinary chemistries were not
effected by treatment. In addition, no histopathological changes were
noted in the stomach, bladder, or kidneys.  

According to the WHO, “The ingestion of ammonium chloride in doses of
around 500-1000 mg/kg bw/day, for periods ranging from 1 to 8 days, has
induced metabolic acidosis in mice, guinea-pigs, rats, rabbits, and
dogs. However, one study did not report any toxic effects at doses of up
to 1 g/kg bw in rats, rabbits, guinea-pigs, and cats (50 animals per
group)”. It is also noted that susceptibility to ammonium chloride
differs among species. For example, cats have been shown to be more
resistant to oral poisoning by ammonium chloride; however, they are more
susceptible to pulmonary edema which is produced in cats but not in
rabbits. 

An 8 day dog study administered 200 mg/kg/day of ammonium chloride.
Metabolic acidosis occurred in the blood and the plasma; however, there
were no changes in the acid-base system in erythrocytes. This study
indicates that ammonium chloride causes substantial acidification of the
blood and urine but does not affect the acid-base system of
erythrocytes. 

A 330 days study which administered 0 or 1.5 % ammonium chloride in
drinking water to rats showed the development of osteoporosis in test
animals due to loss of organic bone substance and bone minerals. The
effect was reversible with the supplement of bicarbonate. The release of
bone mineral by resorption is thought to provide additional buffering
capacity, sparing bicarbonate.  

Renal effects were also observed at high doses in some of the studies.
One study administered 0 or 1.28 g/kg/day of ammonium chloride via
drinking water or gavage to Sprague- Dawley rats for 5 days. Renal
hypertrophy was observed, however, no increase in uptake of radioactive
thymidine was seen, implying that no increase in DNA synthesis or cell
division occurred.  

Evidence of neurotoxicity exists only at high doses. The Agency feels
that the concentrations needed to invoke a neurotoxic response is far
greater than what is expected from use of ammonium chloride as an inert
ingredient in pesticide products. Studies show that ammonium chloride is
not expected to be carcinogenic or genotoxic. No evidence of endocrine
mediated effects were seen in any of the available toxicological
studies. 

It appears that the primary effect of ammonium chloride is related to
the subsequent metabolic acidosis that occurs as a result of ingesting
high concentrations of the chemical. Fortunately, the body has
compensatory mechanisms used to return it to homeostasis. It is only
after these buffers are exhausted that adverse effects are seen.
According to FDA in the “Evaluation of the Health Aspects of Certain
Ammonium Salts as Food Ingredients” (1974), “the normal liver so
readily detoxifies ammonium ion from alimentary sources that blood
concentrations of ammonium salts do not rise to the levels necessary to
evoke toxic response.” Many of the studies noted that the effects were
reversible. 

Because of the negligible anticipated crop residues and subsequent
exposure, the low toxicity of the chemical, and the body’s ability to
achieve homeostasis, the Agency does not feel that there is an increased
risk to infants and children; therefore, a safety factor analysis has
not been used to assess risk. 

Concentrations needed to evoke a toxic response are far greater that the
anticipated exposure of ammonium chloride when use as an inert
ingredient.  Application rates of the inert ingredient are expected to
be ~12-50% of typical fertilizer application rates. Considering all
available data including the high toxicity threshold and the current
exposure pattern (e.g. in food, as fertilizer, and pharmaceutical use)
the risk from the use of ammonium chloride as an inert ingredient in
food use pesticide products will be below the Agency’s level of
concern. 

IX.	ECOTOXICITY AND ECOLOGICAL RISH CHARACTERIZATION

Acute and chronic studies on ammonium chloride have been performed on
three trophic levels of aquatic organisms (algae, invertebrates, and
fish). Evidence has been presented that toxicity to aquatic organisms
has been attributed to un-ionized ammonia (NH3), and NH4+ is considered
to be non-toxic, or significantly less toxic. Un-ionized NH3 exists in
the aquatic environment and the fraction (NH3/ (NH3 +NH4+) sharply
increases with elevations in pH or temperature. 

An acute growth inhibition test for algae was performed using chlorella
(Chlorella vulgaris). The EC50 (biomass; 0-5 d) was 1,300 mg/L. Acute
toxicity test on invertebrates showed that daphnids (Daphnia magna) and
bivalves (Mulinia lateralis) reported results of 101 mg/L (survival;
48-h LC50) and 42.0 mg/L (growth weight; 10-d EC50), respectively. The
LC50 for bivalves was 82.9mg/L (survival).

Various species of fish were exposed to ammonium chloride for 96 hours.
The 96h LC50 were observed in the range of 74.2 to 218 mg/L (Bluegill
and Green sunfish, respectively).  Available data have been summarized
in Table 2.

 

Table 2 Summary of acute toxicity of ammonium chloride on aquatic
organisms

Organism	Test Duration, pH and temperature (°C)	Result (mg/L)	Reference

Algae

Chlorella

 (chlorella vulgaris)	5d

pH 8.0-8.5

26.0 °C	EC50  (biomass)= 1,300	Przytocka-Jisiak et al., 1977

Invertebrates

Water flea 

(Daphnia magna)	48 h (s)

pH 8.4-8.6

19.5-20.5 °C	LC50  (survival)= 101

EC0  (imm)= 39.7	Gersich and 

Hopkins, 1986

Bivalve

(Mulinia lateralis)	10 d (ss)

pH 7.79

21.8 °C	LC50  (survival)= 82.9

EC50  (growth:weight)= 42.0

EC0  (survival)= 31.3

EC0  (growth:weight)= 8.8	Huber et al., 1997

Fish

Fathead minnow

(Pimephales promelas) 

Walleye (Stizostedion vitreum)

Bluegill (Lepomis macrochirus)	96 h (ft)

pH 7.89-8.39

21.4-22.6 °C	LC50  (survival)= 96.2 (fathead minnow)

LC50  (survival)= 84.0 (walleyes)

LC50  (survival)= 74.2 (bluegill)

	Mayes et al., 1986

Fathead minnow (Pimephales promelas) 

	96 h (ft)

pH 8.06

22.0 °C	LC50  (survival)= 163

	Thurston et al., 1983

Inland silverside (Menidia beryllina)	96 h (ft)

pH 7.9-8.1

25.0 ± 1.0 °C	LC50  (survival)= 174

	Miller et al., 1990

Carp (Cyprinus carpio)	96 h (ss)

pH 7.2-7.8

27.5 °C	LC50  (survival)= 209

	Rao et al., 1973

Green sunfish

(Lepomis cyanellus)	96 h (ft)

pH 7.7

22.4 °C	LC50  (survival)= 218

	McCormick et al., 1984

Rainbow trout 

(Salmo gairdneri)	96 h (ft)

pH 7.84

13.8 °C	LC50  (survival)= 127

	Thurston and Russo, 1983

Cutthroat trout 

(Salmo clarki)	96 h (ft)

pH 7.8

12.8 °C	LC50  (survival)= 144

	Thurston and Russo, 1978

s: static, ss: semi-static, imm: immobilization, ft: flow through, These
values are calculated based on measured concentrations.

Chronic studies performed on algae, invertebrates, and fish showed mild
and transient effects (see Table 3). A growth inhibition test for algae,
performed on Navicula sp., showed a NOEC (growth rate; 0-10d) of 26.8
mg/L. A 21 day reproduction toxicity test using daphnids resulted in a
NOEC of 14.6 mg/L. The NOEC from chronic tests in fish ranging from
28-44 days were in the range of 8.0 to 23.9 mg/L (Inland silverside and
Green sunfish, respectively). In addition to aquatic organisms, earth
worms (Eisenia fetida) were evaluated under EPA/600/3-88/029 for
toxicity resulting from exposure to ammonium chloride. Artificial soil
with a pH of 7.7 and a temperature of 22 ± 2 °C resulted in an LC50 of
163 mg/kg soil. (OECD, 2004)

Table 3 Summary of chronic toxicity of ammonium chloride on aquatic
organisms

Organism	Test Duration, pH and temperature (°C)	Result (mg/L)	Reference

Algae

Marine diatom 

(Navicula sp.)	10 d

pH 8.0

12.0 °C	NOEC (gr) = 26.8

LOEC (gr) = 53.5	Admiraal, 1977

Invertebrates

Water flea 

(Daphnia magna)	21 d  (ss)

pH 8.3-8.6

19.5-20.0 °C	NOEC (rep) = 14.6

LOEC (rep) = 30.2	Gersich and 

Hopkins, 1986

Fish

Fathead minnow (Pimephales promelas)	28 d (ft)

pH 8.0

24.0 °C	NOEC = 11.8

	Mayes et al., 1986

Inland silverside (Menidia beryllina)	28 d (ft)

pH 7.36-7.86

23.5-25.0 °C	NOEC = 8.0

LOEC = 16.0	Miller et al., 1990

Green sunfish (Lepomis cyanellus)	44 d (ft)

pH 7.9

21.0 °C	NOEC = 23.9

LOEC = 53.2	McCormick et al., 1984

Cutthroat trout 

(Salmo clarki)	36 d (ft)

pH 7.8

12.8 °C	LC50 = 123	Thurston and Russo, 1978

ss: semi-static, ft: flow through, gr: growth rate, rep: reproduction,
These values are calculated based on measured concentrations

In summary, the lowest acute toxicity value for ammonium chloride was a
10 day EC50 of 42.0 mg/L seen in bivalves. The lowest chronic toxicity
value observed was a 28 day NOEC of 8.0 mg/L seen in Inland silverside
(Menidia beryllina) fish. According to OPP’s classification, ammonium
chloride is considered slightly toxic to aquatic organisms. 

REFERENCES 

Barzel, U.S. and Jowsey, J. (1969). The effects of chronic acid and
alkali administration on bone turnover in adult rats. Clin. Sci. 36,
517-524

Department of Environmental Quality. (Revised Sept 18, 2001) Michigan
Government. Accessed December 9, 2008 at
http://www.deq.state.mi.us/documents/deq-ess-lab-AmmoniumChloride.pdf

DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic
Equivalence Evaluations. Accessed on February 24, 2009 from:   HYPERLINK
"http://www.fda.gov/cder/ob/" \t "new"  http://www.fda.gov/cder/ob/  

 

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"http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22D
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esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus"  Norenberg, M.D
. (1989) Effect of ammonium chloride on the astrocyte benzodiazepine
receptor. Brain Res 493 (2): 362-365 

Hazardous Substances Data Bank [Internet]. National Library of Medicine
(US); [Last Revision 12/20/2006]. Ammonium chloride; Hazardous
Substances Databank Number: 483; Available from:   HYPERLINK
"http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB" 
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB 

Levene, D.L. & Knight, A. (1974) Ammonium chloride poisoning in chronic
renal disease. Can. Med, Assoc. J.; Vol 111 , p 335-338.

Medical Encyclopedia Index (2009) University of Maryland Medical Center.
Accessed December 9,2008 at   HYPERLINK
"http://www.umm.edu/altmed/drugs/ammonium-chloride-006100.htm" 
http://www.umm.edu/altmed/drugs/ammonium-chloride-006100.htm 

O’Neil, M.J. (ed.). The Merck Index-An Encyclopedia of Chemicals,
Drugs, and Bioloigicals. 13th Edition, Whitehouse Station, NJ: Merck and
Co., Inc., 2001

Organization for Economic and Cooperative Development (OECD), (2004)
Screening Information Data Set (SIDS) Initial Assessment Report (SIAR)

 for Ammonium Chloride (CAS No. 12125-02-9).

Relman, A.S., Shelburne, P.F., & Talman, A. (1961) Profound acidosis
resulting from excessive ammonium chloride in previously health
subjects. A study of two cases. N. Engl J Med. 264(17): 848-52.

Schober K.E. (1996) Investigation into intraerythrocytic and
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Appendix A

U.S. Environmental Protection Agency                                
Ver. 2.00

DEEM-FCID Chronic analysis for INERTS                           (1994-98
data)

Analysis Date 09-08-2009/14:15:24     Residue file dated:
04-14-2009/09:54:49/8

Reference dose (RfD, Chronic) = 5.8 mg/kg bw/day

NOEL (Chronic) = 580 mg/kg bw/day

COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

========================================================================
=======

                    Total exposure by population subgroup

------------------------------------------------------------------------
-------

                                                    Total Exposure

                                        
-----------------------------------

          Population                         mg/kg       Margin of  
Percent 

           Subgroup                       body wt/day   Exposure 1/  of
RfD 

--------------------------------------   -------------  ---------- 
---------

U.S. Population (total)                     0.191509        3,029       
3.3%

U.S. Population (spring season)             0.195512        2,967       
3.4%

U.S. Population (summer season)             0.193733        2,994       
3.3%

U.S. Population (autumn season)             0.188144        3,083       
3.2%

U.S. Population (winter season)             0.188739        3,073       
3.3%

Northeast region                            0.208249        2,785       
3.6%

Midwest region                              0.190460        3,045       
3.3%

Southern region                             0.171478        3,382       
3.0%

Western region                              0.209414        2,770       
3.6%

Hispanics                                   0.201698        2,876       
3.5%

Non-hispanic whites                         0.187723        3,090       
3.2%

Non-hispanic blacks                         0.185288        3,130       
3.2%

Non-hisp/non-white/non-black                0.246967        2,348       
4.3%

All infants (< 1 year)                      0.397082        1,461       
6.8%

Nursing infants                             0.212711        2,727       
3.7%

Non-nursing infants                         0.467077        1,242       
8.1%

Children 1-6  yrs                           0.495834        1,170       
8.5%

Children 7-12 yrs                           0.239839        2,418       
4.1%

Females 13-19 (not preg or nursing)         0.138939        4,174       
2.4%

Females 20+ (not preg or nursing)           0.149292        3,885       
2.6%

Females 13-50 yrs                
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	㜀$␸䠀$摧࢞ᰀMales 13-19 yrs                            
0.148194        3,914        2.6%

Males 20+ yrs                               0.144142        4,024       
2.5%

Seniors 55+                                 0.152430        3,805       
2.6%

Children 1-2 yrs                            0.624005          929      
10.8%

Children 3-5 yrs                            0.461958        1,256       
8.0%

Children 6-12 yrs                           0.255310        2,272       
4.4%

Youth 13-19 yrs                             0.144122        4,024       
2.5%

Adults 20-49 yrs                            0.144401        4,017       
2.5%

Adults 50+ yrs                              0.152076        3,814       
2.6%

Females 13-49 yrs                           0.145389        3,989       
2.5%

------------------------------------------------------------------------
-------

  Table 2 adopted from Organization for Economic and Cooperative
Development (OECD), (2004) Screening Information Data Set (SIDS) Initial
Assessment Report (SIAR) for Ammonium Chloride. 

 Table 2 adopted from Organization for Economic and Cooperative
Development (OECD), (2004) Screening Information Data Set (SIDS) Initial
Assessment Report (SIAR) for Ammonium Chloride. 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

                                                                        
                                                                        
                                         

OFFICE OF PREVENTION, 

PESTICIDE, AND TOXIC SUBSTANCES