**Disinfection as a Source of Diverse By-Products of Potential Health
Concern**

**JA Cotruvo, RJ Bull, J Crook, M Whittaker**

**WateReuse Foundation Project 06-004**

It is well known that chlorine as hypochlorous acid or hypochlorite can
function both as an oxidizing agent and a halogenating agent (Rice,
1987). Oxidation is probably the predominant chemical process occurring
in chlorine's water and food contact applications, but the halogenated
by-products have received the most attention. The chemistry and
distribution of by-products produced differs somewhat with the pH of the
solution as well as the composition of the precursor chemicals that are
available for reaction.

**Table 1 Relative characteristics of oxidants/disinfectants**

(*from Rice and Gomez-Taylor, 1987)*

**Oxidant Disinfecting Oxidizing Halogenation**

**Efficiency Efficiency Capability**

**Chlorine High High High**

**Chlorine dioxide High High Low**

**Monochloramine Low Low Low**

**Ozone High High None (no bromide)**

**Hydrogen peroxide Low Moderate None**

**Bromine High Moderate High**

**Iodine High Low Low**

There are numerous detailed assessments and reviews of the chemistry and
toxicology of chlorine and by-products in water (EHC, 2000; WHO, 1996;
WHO, 2004; Federal Register, 2006, Bull, 2006; Woo, 2002). The
toxicology of numerous DBPs has been studied extensively for more than
30 years, however, the number of by-products is so large and their
individual concentrations are so low that it is questionable whether
there is value in examining many of them in detail. One study applied
structure-activity techniques and genotoxicity data as a method for
prescreening the DBPs in order to rank them in respect to carcinogenic
potential from long term exposure (Woo et al, 2002). Of the 209 DBPs
analyzed, only 20 were of priority concern with Moderate or
High-Moderate rating. Four of those were structural analoges of MX, and
five were haloalkanes that are likely controlled by regulations. The
remaining eleven included halonitriles, haloketones, haloaldehyde,
halonitroalkane and dialdehyde. This project only examined compounds for
which some occurrence data existed. The Bull et al. (2006) report
reported similar conclusions for these identified DBPs, but extended the
work to compounds that were predicted to occur based on the chemistry of
natural organic matter, but for which occurrence data had not been
collected. This study identified haloquinones, nitrosamines, and organic
N-chloramines as additional DBPs that should be of concern.

***Disinfection by-products in drinking water and recycled water***

Chlorination and chlorinated/brominated by-products are the most
extensively studied chemicals produced from disinfectants and sanitizers
in water. One reason is that compared to non-halogenated compounds, they
are more readily separated from water solutions for analysis due to
their hydrophobicity.

The best indication of the complexity is probably best illustrated in
Tables 2 and 3 by the numerous categories of halogenated by-products
that have been detected in one or more studies (longer lists exist).
Naturally occurring polyphenolic compounds are some of the most likely
precursors for many of the products. The trihalomethanes of historical
interest include chloroform, bromodichloromethane, dibromochloromethane
and bromoform (Cotruvo, 1981; Cotruvo, 1982) but several other
brominated/iodinated THMs have been detected at much lower frequencies
and concentrations. Since that time numerous families and hundreds of
individual halogenated disinfection by-products (DBPs) have been
identified and quantified in chlorinated drinking water. Among these are
halogenated acetic acids (HAAs), haloacetonitriles HANs), haloketones,
halopicrins, halophenols, and halofuranones, in addition to
non-halogenated oxidized products such as acids, aldehydes and ketones.
As a group, the THMs and HAAs probably account for the largest portion
of the identifiable DBPs in chlorinated drinking water (perhaps half in
many cases).

Chlorine will oxidize bromide in water to HOBr, which is a more active
halogenating agent than HOCl, so in the presence of bromide the
analogous brominated and mixed halogenated by-products will be formed
and probably predominate, e.g., in chlorinated desalinated water which
often contains milligram amounts of bromide. In the presence of ammonia
or organic amines hypochlorous acid will form N-chloro compounds such as
mono- and dichloramine from ammonia, and monochloramine is used as a
secondary disinfectant *vide infra*.

Several hundred individual DBPs have been identified at parts per
billion to parts per trillion levels in drinking water. The aggregated
total quantity of DBPs in a drinking water may range from a few
micrograms per liter in very low organic carbon groundwater or membrane
treated water, to perhaps a milligram per liter or more in some waters
with high levels of NOM precursors, depending upon the chlorine dosage,
quantity of NOM precursors, pH, temperature and contact time. In the
presence of ammonia and amines, chloramines will rapidly form and they
are poor halogenating and oxidizing agents, so the presence of ammonia
will suppress the formation of many but not all of the halogenated and
oxidized DBPs.

While many DBPs have been identified, there are good comprehensive
quantitative data available for a few dozen in water supplies. Data from
a recent study of 12 utilities using several disinfectants in the U.S.
and Canada by the U.S. EPA (2004; also reported in Krasner *et al*,
2006) provided in Tables 2 and 3 is probably indicative of many water
supplies. The disinfectants used varied among these utilities, with
ozone (1 utility) and chlorine dioxide (4 utilities) employed in some
utilities, but all systems employed chlorine or chloramines at some
stage in the treatment. These data may differ slightly from those
reported because the means represent the average of utility means,
rather than an overall mean of all samples. Since the U.S. EPA survey
included only 12 utilities, it probably does not reflect extreme
occurrences of DBPs. Nevertheless, the variation of DBP concentrations
among the 12 utilities ranges up to two orders of magnitude. It should
not be assumed that the concentrations covary with one another in
dependable patterns among water utilities or even within the same system
in different seasons of the year (Wright *et al*., 2002; Bull *et al*,
2008).

A key consideration for potable reuse of wastewater is that many DBPs
are of low molecular weight and some have low polarity and this has
resulted in their appearance in the product waters after reverse osmosis
and AOX treatment (Project Occurrence Database). DBPs are the only group
of chemicals which occurred in the final product waters at
concentrations that exceed 1 µg/L. Since many of these compounds are
mutagenic, they fall into a category under the threshold of
toxicological concern (TTC) methodology of chemicals that require
chemical specific data to estimate risk.

**^Table\ 2.\ Disinfectant\ by-products\ in\ 12\ drinking\ water\ utilities\ in\ U.S.\ and\ Canada^**a

  ------------------------------- ------------- ----------- ------------ -------------
  **Disinfectant By-Product**     **Number of   **Mean**    **Median**   **Range**
                                  utilities**                            

  Chloroform                      12            16^b^       12           0.5-47

  Bromodichloromethane            12            10          12           2.2-19

  Dibromochloromethane            12            6.5         4.7          0.1-20.5

  Bromoform                       12            2.1         0.7          6.4

  Dichloroiodomethane             12            1.1         0.45         0.08-1.5

  Bromochloroiodomethane          12            0.4         0.3          0-2.5

  Dibromoiodomethane              10            0.29        0            2.5

  Chloroiodomethane               12            0.11        0            0-1.1

  Bromodiiodomethane              12            0.03        0            0-0.4

  Iodoform                        12            0.04        0            0-0.4

  Monochloroacetic acid           12            1.6         0            0-3.9

  Monobromoacetic acid            12            0.3         0.27         0-1.0

  Dichloroacetic acid             12            14          15           1.4-22

  Bromochloroacetic acid          12            5.9         4.4          1.7-11

  Dibromoacetic acid              12            3.4         1.2          0-12

  Trichloroacetic acid            12            9.4         6.1          0.5-35

  Bromodichloroacetic acid        12            4.6         5.5          0-9.4

  Dibromochloroacetic acid        12            2.2         1.5          0-5.9

  Tribromoacetic acid             12            0.12        0            0-0.9

  Chloroacetonitrile              12            0.07        0.055        0-0.26

  Bromoacetonitrile               12            0.005       0            0-0.04

  Dichloroacetonitrile            12            1.4         1.2          0.1-4.1

  Bromochloroacetonitrile         11            0.8         0.6          0-2.6

  Dibromoacetonitrile             12            0.6         0.3          0-2.3

  Trichloroacetonitrile           12            0.02        0            0-0.15

  Bromodichloroacetonitrile       12            0           0            0-0.4

  Dibromochloroacetonitrile       12            0.01        0            0-0.15

  Tribromoacetonitrile            12            0           0            0

  Dichloroacetaldehyde            12            2.2         1.7          0.4-11.1

  Bromochloroacetaldehyde         12            0.5         0.32         0-1.3

  Chloral hydrate                 12            2.2         1.8          0.2-5.9

  Tribromoacetaldehyde            12            0.19        0.04         0-0.93

  Chloropropanone                 12            0.22        0.11         0-1.1

  1,1-Dichloropropanone           12            0.61        0.58         0.12-1.3

  1,3-Dichloropropanone           12            0           0            0

  1,1-Dibromopropanone            12            0.032       0            0-0.12

  1,1,1-Trichloropropanone        12            1.3         1.4          0.03-3.6

  1,1,3-Trichloropropanone        12            0.02        0.02         0-0.13

  1-Bromo-1,1-dichloropropanone   12            0.24        0.2          0-0.95

  1,1,1-Tribromopropanone         12            0           0            0

  1,1,3-Tribromopropanone         12            0.005       0            0-0.033

  1,1,3,3-Tetrachloropropanone    12            0.05        0            0-0.26

  1,1,1,3-Tetrachloropropanone    12            0.08        0.07         0-0.13

  1,1,3,3-Tetrabromopropanone     12            0.05        0            0-0.025

  Chloronitromethane              12            0.04        0            0-0.16

  Bromonitromethane               12            0.02        0            0-0.08

  Dichloronitromethane            12            0.12        0.24         0-0.38

  Bromodichloronitromethane       12            0.11        0            0-0.42

  Dibromonitromethane             12            0.07        0            0-0.19

  Chloropicrin                    12            0.26        0.16         0.04-0.92

  Bromodichloronitromethane       12            0.32        0.24         0-1.0

  Dibromochloronitromethane       12            0.30        0.18         0-0.44

  Bromopicrin                     12            0.35        0            0-0.63
  ------------------------------- ------------- ----------- ------------ -------------

^a^ Weinberg *et al.* 2002; Krasner *et al*. 2006

^b^ Concentrations in µg/L

**Table 3. Additional analyses of disinfection by-products and total
organic halogen in a survey of 12 utilities in the U.S and Canada^a^.**

  -------------------------- ------------- ------------ ------------ ------------
  **Disinfectant             **Number of   **Mean**     **Median**   **Range**
  By-Product**               Utilities**                             

  Monochloroacetaldehyde     12            0.42^b^      0.22         0-1.3

  Dichloroacetaldehyde       12            3.4          2.7          0.5-9.5

  Bromochloroacetaldehyde    11            1.2          1.1          0.1-3.5

  3,3-Dichloropropenoic acid 12            0.43         0.14         0-2.7

  Bromochloromethylacetate   12            0.036        0            0-0.4

  Monochloroacetamide        8             0.14         0            0-0.5

  Monobromoacetamide         8             0.24         0            0-1.1

  2,2-Dichloroacetamide      12            1.5          1.7          0-3.8

  Dibromoacetamide           8             0.87         0.25         0-2.8

  Trichloroacetamide         8             0.51         0.30         0-1.1

  BMX-1^c^                   10            0.034        0            0-0.13

  BEMX-1                     10            0.10         0            0-0.72

  BMX-2                      10            0.028        0            0-0.15

  BEMX-2                     10            0.12         0            0-0.81

  BMX-3                      10            0.004        0            0.04

  BEMX-3                     10            0.097        0            0-0.41

  MX                         12            0.11         0.020        0-0.18

  Red-MX                     2             0.033                     0-0.29

  EMX                        12            0.013        0            0-0.10

  ZMX                        10            0.011        0            0-0.12

  Ox-MX                      10            0            0            0

  Mucochloric acid (ring)    12            0.085        0.01         0-0.71

  Mucochloric acid (open)    12            0.081        0.09         0-0.19

  TOX                        12            169^c^       182^c^       65-236^c^
  -------------------------- ------------- ------------ ------------ ------------

^a^ Weinberg et al. 2002; Krasner et al. 2006

^b^ Concentrations in µg/L

^c^ Abreviations: MX =
3-chloro-4-(dichloromethyl-5-hydroxy-2H(5H)-furanone; BMX-1 =
3-chloro---4-(bromochloromethyl-5-hydroxy-2(5H)-furanone; BMX-2 =
3-chloro-4-(dibromomethyl-5-hydroxy-2H(5H)-furanone; BMX-3 =
3-bromo-4-(dibromomethyl-5-hydroxy-2H(5H)-furanone; EMX
=(E)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid;

BEMX-1, BEMX-2, BEMX-3 = corresponding brominated analogs of EMX.

**N-Chloramines**

N-Chloramines are produced from the chemical reactions between ammonia
or amines and chlorine. The most common form is monochloramine (**(**CAS
10599-90-3). Chloroamines may be deliberately produced by combining the
ammonia or amines with chlorine prior to contact with the medium to be
disinfected or they may be spontaneously formed whenever chlorine is
used if ammonia or amines are present in the medium. Wastewaters are
heavily contaminated with nitrogenous chemicals from human waste
products. In addition to inorganic N-chloramine, there are analogous
organic N-chloramines. N-chlorodimethylamine is an example of an organic
amine formed from dimethylamine. N-chloramines are labile so they will
exchange halogens as well as transfer halogens to other amine or amide
compounds with which they are in proximity.

***N-chloramine chemistry***

Because of its low oxidizing efficiency and low halogenation capability
monochloramine has a lesser tendency to produce halogenated DBPs and
oxidation products. Related chemicals are N-chloroamides that could be
formed by reactions of chlorine with amides such as protein peptides.
N-chloramine can react with secondary amines such as dimethylamine to
produce dimethylhydrazine which can be oxidized in the presence of the
chloramine to N,N-dimethylnitrosamine (Choi, 2002; Mitch, 2002).

**Figure 1**

**NH~2~Cl + (CH~3~)~2~NH  (CH~3~)~2~ N-NH~2~**

**(CH~3~)~2~ N-NH~2~ + NH~2~Cl/OCl**^-^ **(Oxidation)  CH~3~)~2~N-N=O**

***Chloramine and organic chemical exposures***

Human exposure to chloramines is primarily from consumption of
chloraminated drinking water, which is regulated not to exceed 4 mg/l in
the USA. At the default daily consumption level of drinking water, this
could be as much as 6 to 8 mg/day.

***Other DBPs of potential interest***

There are some concerns about the focus on regulated by-products as
being indicative of the hazards associated with disinfection by-products
in general. Efforts to control some of these by-products are likely to
reduce or produce or substantially increase the concentrations of some
other by-products that are likely to be much more potent
toxicologically. The chemistry and detection of numerous DBPs has been
studied extensively for more than 30 years, however, the number of
by-products is so large and their individual concentrations are so low
that it is questionable whether there is value in examining many of the
individual chemicals in detail. In an attempt to identify higher
interest candidates one study applied structure-activity techniques and
genotoxicity data as a method for prescreening of 209 DBPs in order to
rank them in respect to carcinogenic potential from long term exposure
(Woo *et al,* 2002). A subsequent structure activity study of novel
by-product formation from substructures within NOM identified
haloquinones and used QSAR and analogies with related compounds to
identify several other by-products that could be of interest (Bull *et
al*, 2006). Chemicals identified in this study included those identified
by Woo (Woo *et al*, 2002), but provided an additional list of probable
by-products. Those considered to be of most concern were a number of
halogenated quinones, halogenated cyclopentenoic acid derivatives,
halonitriles, and various N-chloramines. In addition nitrosamines (e.g.,
N,N-dimethylnitrosamine etc. are known to be formed in water containing
N-chloramines and secondary amines.

***MX-related chemicals***

Another chemical family of interest that have been detected in ppt
levels in chlorinated drinking water is the MX-related chemicals. MX
(3-chloro-4-(dichloromethyl)-5-hydroxy-2-\[5H\]furanone) is the common
name applied to one member of a group of halomethylhydroxyfuranones
formed from oxidation, halogenation and ring cleavage of phenolic-type
natural organics in the water. They are cyclic lactones or open chain
carboxyl compounds and would not be highly volatile. These chemicals
have been shown to be multitarget carcinogens in the rat, and they are
strongly positive in the Ames chemical mutagenicity assay. Levels of MX
in drinking water have been detected in the range of 3 to 310 parts per
trillion with the 75^th^ percentile concentration of 60 ppt (Krasner *et
al*, 2006).

MX is the common name applied to a group of halomethylhydroxyfuranones
probably formed from oxidation, halogenation and ring cleavage of
phenolic-type natural organics in the water. They are cyclic lactones or
open chain carboxyl compounds and would not be highly volatile. These
chemicals have been shown to be multitarget carcinogens in the rat, and
they are strongly positive in the Ames chemical mutagenicity assay.
Three of the MX compounds were in the highest rank of High-Moderate
concern; the remaining 17 were in the Moderate category. These
halogenated MX compounds included chlorinated and brominated analogues
(Woo et al, 2002). A bioassay was conducted in male and female Wistar
rats at doses ranging from 0.4 mg/kg/day to 6.6 mg/kg/day (Komulainen
*et al*, 1997). Tumors were found at all of the test doses. Levels of MX
in drinking have been detected in the range of 3 to 67 parts per
trillion. An estimated calculation of the risk from lifetime consumption
of 2 litres of drinking water per day containing 67 ppt (the highest
concentration detected at that time) yielded a hypothetical risk of 2 in
1,000,000 (Melnick *et al* , 1997). This is a low risk with respect to
the WHO Guidelines for Drinking-water Quality which utilizes a reference
value of 1 in 100,000. Also, the USEPA drinking water regulations are
considered safe when falling in the hypothetical risk range of 1 in
10,000 to 1 in 1,000,000. However, there is also the possibility that
small amounts of these chemicals are rapidly detoxified by thiols such
as glutathione after ingestion.

There are some concerns about the focus on regulated by-products as
being indicative of the hazards associated with disinfection by-products
in general. Efforts to control some of these by-products are likely to
reduce or produce or substantially increase the concentrations of some
other by-products that are likely to be much more potent
toxicologically. It has long been known that various phenolic precursors
are intermediates in the formation of most of the THMs and HAAs. Excess
chlorine results in cleavage of the phenolic ring to give rise to
haloacids and THMs. If chloramine is utilized in place of free chlorine
to reduce THMs and HAAs, there is a high likelihood that higher
concentrations of halogenated quinones will be encountered than in the
presence of free chlorine (Heasley *et al*., 2004; Bull *et al*., 2006).
Moreover, N-chloramines can interact with other secondary amines in the
water to form N-nitrosamines, usually in the parts per trillion range,
but occasionally at ppb levels. The latter levels have been found
primarily in wastewaters that contain unusually large amounts of ammonia
and secondary amines as compared to typical drinking waters. However,
the question of whether additional nitrosamines may be formed with
certain alkaloids (e.g. 3-methylindole) that occur in surface waters
should be explored. These by-products are likely to be of health concern
if they occur in the ng/L range.

Finally, the hypochlorite in solution can disproportionate to form
significant amounts of chlorate upon storage at warm temperatures for
long periods of time. Therefore, hypochlorite solutions should be stored
under temperate conditions and used reasonably soon after purchase and
not stored for months.

***Haloquinones***

The formation of the major regulated by-products goes through a series
of intermediates with various phenolic and other unidentified precursors
that naturally occur in surface waters, but may not occur in many foods.
It is important to recognize that changing from processes that utilize
free chlorine to the use of chloramine has a high likelihood of
preserving some of the intermediate species. Figure 2 illustrates the
changes in products that would be expected by reactions with phenol
treated with chloramine in place of free chlorine. A variety of quinone
structures have been shown to occur with chloramine that will be
destroyed by ring cleavage with free chlorine (Heasley *et al,* 2004).
Treatment of the related phenol structures, m-cresol and resorcinol, are
the principal sources of THMs in treated drinking water. It has long
been known that various phenolic precursors are intermediates in the
formation of most of the THMs and HAAs. Excess chlorine results in
cleavage of the phenolic ring to give rise to haloacids and THMs. If
chloramine is utilized in place of free chlorine to reduce THMs and
HAAs, there is a high likelihood that higher concentrations of
halogenated quinones will be encountered than in the presence of free
chlorine (Heasley *et al*., 2004; Bull *et al*., 2006). Moreover,
N-chloramines can interact with other secondary amines in the water to
form N-nitrosamines, usually in the parts per trillion range, but
occasionally at ppb levels. The latter levels have been found primarily
in wastewaters that contain unusually large amounts of ammonia and
secondary amines as compared to typical drinking waters. However, the
question of whether additional nitrosamines may be formed with certain
alkaloids (e.g. 3-methylindole) that occur in surface waters should be
explored. Because of their structures and functional mechanisms these
by-products are likely to be of jnterest if they occur in the ng/L
range.

**Figure 2**

![](media/image1.wmf)

Finally, the hypochlorite in solution can disproportionate to form
significant amounts of chlorate upon storage at warm temperatures for
long periods of time. Therefore, hypochlorite solutions should be stored
under temperate conditions and used reasonably soon after purchase and
not stored for months.

***Dissolved organic nitrogen***

Nitrogen compounds are ubiquitous in water but often difficult to
isolate and analyze so they have been mostly studied later in the
evolution of DBP analyses. They are largely composed of degraded amino
sugars, peptides and porphyrins but many other chemical forms can exist.
It is logical to expect that recycled waters being derived from
wastewaters would contain significant quantities of organic compounds
derived from bacterial activity and indeed from the degradation of
bacterial cells. Leenheer and Westerhoff have studied fractionation
techniques involving membrane dialysis, solvent extraction, and use of
XAD resins. Among the fractions they isolated were colloids (amino
sugars which are reflective of bacterial cell wall degradation),
hydrophobic and amphiphilic neutrals (peptides) peptides, amino acids,
and hydrophilic bases.

Many types of nitrogen compounds are biologically active so they are a
mostly untapped reservoir of chemicals of interest. One group of
particular interest includes the organic N-chloramines, that are readily
formed by halide exchange with other N-chloramines, including
monochloramine. This exchange could occur in water during processing or
*in vivo* after ingestion.

**Organic N-Chloramines**

Organic N-chloramines have long been known to form in drinking water
treated with chlorine or chloramine. They are largely regarded as a
nuisance as they reduce disinfection by decreasing the available free
chlorine. There has been little systematic work to characterize the
forms of organic N-chloramine that are present in water beyond the
formation of the N-chloramines of α-amino acids. The broad spectrum of
more diverse organic nitrogen compounds that can occur in wastewater at
relatively high concentrations indicates that it is necessary to better
understand the nature of these by-products and their potential
toxicological effects.

Organic N-chloramines produced from α-amino acids are generally more
readily formed and they degrade more readily than compounds that either
have no carboxyl group or if it is further removed from the amine group.
While slower in formation, dichloramines are more readily formed with
non-amino acid nitrogens at physiological pH and probably in drinking
water (Nightingale et al., 2000). At the macromolecular level, exocyclic
nitrogens of purine and pyrimidine bases react more readily to form
N-chloramines, but over time the chlorine is transferred to cyclic
nitrogens and these under radical decay and are responsible for damaging
DNA (Hawkins and Davies, 2001; Hawkins and Davies, 2002). The same
phenomenon has been demonstrated to occur in chlorinated wastewater
(Bedner et al., 2004). Organic N-chloramines produced in plasma proteins
have a half-life of approximately 2 hours, indicating they are
sufficiently stable to survive to reach critical targets in vivo
(Hawkins and Davies, 19990.

The toxicological properties of administered organic N-chloramines have
only been studied with in vitro systems. In general, dichloramines are
substantially more active than monochloramines (ca 30-fold) (Thomas et
al., 1987). In part, this probably reflects decreased polarity of the
compounds, but may reflect some differences in the specificity of
reactions that occur with dichloramines vs. monochloramines. In a
project being conducted with South Australia water, it appears that
mutagenic activity is greater with those chloramines with the longest
half-lives (e.g. N-chloroglycine among monochloramines and
N-dichloroethanolamine).

More interesting properties of the organic N-chloramines are their
involvement in modifying processes involved in the cell cycle. In
particular, they have been shown to cause apoptosis in some systems
(Englert and Schacter, 2002), but suppress apoptosis in others (Than et
al., 2001). N-chloramines produced by phagocytic cells have been shown
to be inhibitors of DNA repair (Pero et al., 1996) and monochloramine
produces cell cycle arrest (Hosako et al., 2003). Modification of
processes involved in cell cycle control are associated with the
development of cancer in the intact animal.

Organic-N-chloramines that could occur in disinfected water are
potentially quite diverse. As there are no in vivo data for these
compounds (other than monochloramine, itself), in vivo information of
any orally administered organic N-chloramines is available. Some
information is needed on selected chemicals to assess the probable risks
associated with the class as a whole. The few compounds identified below
were selected as likely to be representative of the type of organic
N-chloramines that could be of greatest concern.

**Disinfectant residues and DBPs**

Chlorate (present in stored hypochlorite solutions)

Bromate (formed from ozonation of bromide, and a chlorine contaminant))

**Quinone derivatives**

2-chloro-1,4-dibenzoquinone

2,3-dichloro-1,4-dibenzoquinone

2,3,6-trichloro-1,4-dibenzoquinone

2,6-dichloro-3-methyl-1,4-benzoquinone

2,6-dichloro-1,4-benzoquinone-4-(N-chloro)imine

2,3,5,6-tetrachloro-1,4-dibenzoquinone (probably less toxic and/or
carcinogenic than other members of the class)

**Organic N-chloramines**

N-chloroethanolamine

N-dichloroethanolamine

N-chloroglycine and other N- haloaminoacids

ε-N-chlorolysine and dichloro form on the same nitrogen. The
α-N-chlorolysine of interest for comparison, because it is less likely
to form the dichloramine at pHs used for formation of monochloramine

**Nitrosamines**

N-nitroso-N-dimethylamine

N-nitroso-N-diethylamine

N-nitrosomorpholine

N-nitroso-3-methylindole

**MX-related compounds**

**References**

Bedner, M., W.A. Maccrehan, and G.R. Helz. 2004. Production of
macromolecular chloramines by chlorine-transfer reactions. Environ. Sci.
Technol. 38:1753-1758.

Bull RJ, Rice G, Tueschler L, Feder P 2008. [Chemical Measures of
Similarity among Disinfection By-Product Mixtures. J. Toxicol. Environ.
Health. In press.]{.underline}

Choi, J, Valentine RL 2002. N-nitrosodimethylamine (NDMA) from reaction
of monochloramine: a new disinfection by-product. *Water Res*. 36(4):
817-824.

Cotruvo JA,1981. THMs in Drinking Water. Environmental Science and
Technology, 15:3, 268-274.

Cotruvo JA, 1982. Introduction: Evaluating the Benefits and Potential
Risks of Disinfectants in Drinking Water Treatment. Environmental Health
Perspectives, 46, 1-6.

EHC 2000. Environmental Health Criteria 216, Disinfectants and
Disinfection By-products. World Health Organization, Geneva.

Englert, R.P. and E. Shacter. 2002. Distinct modes of cell death induced
by different reactive oxygen species. J. Biol. Chem. 277:20518-20526.

Hawkins, C.L, and M.J. Davies. 1999. Hypchlorite-induced oxidation of
proteins in plasma: formatoin of chloramines and nitroge-centred free
radicals and their role in protein fragmentation. Biochem. J.
340:539-548.

Hawkins, C.L. and M.J. Davies. 2000. Hypochlorite-induced damage to
nucleosides: formation of chloramines and nitrogen-centered radicals.
Chem. Res. Toxicol. 14:1071-1081.

Hawkins, C.L. and M.J. Davies. 2002. Hypochlorite-induced damage to DNA,
RNA, and polynucleotides: Formation of chloramines and nitrogen-centered
radicals. Chem. Res. Toxicol. 15:83-92.

Heasley VL, Fisher AM, Herman EE, Jacobsen FE, Miller EW, Ramirez AM,
Royer NR, Whisenand JM, Zoetewey DL, Shellhamer DF 2004. Investigations
of the reactions of monochloramine and dichloramine with selected
phenols: Examination of humic acid models and water contaminants.
Environ. Sci. Technol*.***,** 38, 5022-5029.

## Hoenicke K, Gatermann, Hartig L, Mandix M, Otte S 2004. Formation of Semicarbazide in Food by Hypochlorite Treatment: is SEM a Specific Marker for Nitrofurazone Abuse? Food Additives and Contaminants, 21:6, 526-537.

Hosaka, M., T. Ogino, M. Omori, and S. Okada. 2003. Cell cycle arrest by
monochloramine through the oxidation of the retinoblastoma protein. Free
Rad. Biol. Med. 36:112-122.

## Huang WJ, Chen LY, Peng HS 2004. Effect of NOM Characteristics on Brominated Organics Formation by Ozonation. Environment International 29:8, 1049-1055.

## IPCS 2005. Inchem, ICSC 0413

## JECFA 2003. Chemical and Technical Assessment. Joint Expert Committee on Food Additives. Rome 10-19, June.

## Johnson JJ, Ghanbari HA, Wheeler WB, Kirk JR 1983. Chlorine Incorporation in Shrimp, J. Food Sci. 48:668-670. (In Fukayama. 1986)

## KlaiberRG, Baur S, Wolf G, Hammes WP, Carle R 2005. Quality of Minimally Processed Carrots as affected by Warm Water Washing and Chlorination Innovative Food Science and Emerging Technologies 6:351-362.

## Krasner SW, Weinberg HS, Richardson SD, Pastor SJ, Chinn R, Sclimenti MJ, Onstad GD, Thruston, Jr. AD 2006. Occurrence of a new generation of disinfection by-products. Environ. Sci Technol. 40(23), 7175-7185.

## Komulainen H, Kosma VM, Vaittinen SL, Vartiainen T, Kaliste-Korhonen E, Lotjonen S, Tuominen RK, Tuomisto J, 1997. Carcinogenicity of the Drinking Water Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in the Rat. Journal of the National Cancer Institute, 89, 848-856.

Mitch WA,Sedlak DL 2002a. Formation of N-nitrosodimethylamine (NDMA)
from dimethylamine during chlorination. *Environ. Sci. Technol*. 36(4):
588-595.

Mitch WA,Sedlak DL 2002b. Factors controlling nitrosamine formation
during wastewater chlorination. *Water Sci. Technol.* 2(3): 191-198.

Nagy, P. and M.T. Ashby. 2005. Reactive sulfur species: Kinetics and
mechanism of the oxidation of cystine by hypochlorous acid to give N,
N\'-dichlorocystine. Chem. Res. Toxicol. 18:919-922.

## Nicholl P, Mcinerney S, Prendergast M 2003. Growth Dynamics of Indigenous Microbial Populations on Vegetables after Decontaminatioon and During Refrigerated Storage. Journal of Food Processing and Preservation, 28:6, 442-459.

Nightingale, Z.D., A. H. Lancha, Jr., S.K. Handelman, G.G. Dolnikowksi,
S.C. Busse, E.A. Dratz, J.B. Blumberg, and G.J. Handelman. 2000.
Relative reactivity of lysine and other peptide-bound amino acids to
oxidation by hypochlorite. Free Rad. Biol. Med. 29:425-433.

Pero, R.W., Y. Sheng, A. Olsson, C. Bryngelsson, and M. Lund-Pero. 1996.
Hypochlorous acid/N-chloramines are naturally produced DNA repair
inhibitors. Carcinogenesis 17:13-18.

## Qiang Z, Demirkot O, Ercal N, Adams C 2005. Impact of Food disinfection on Beneficial Bithiol Contents in Vegetables 53:9830-9840.

## Robinson D, Mead GC, Barnes KA 1981. Detection of Chloroform in the Tissues of Freshly Eviscerated Poultry Carcasses Exposed to Water Containing Added chlorine or Chlorine Dioxide. Bull. Env. Contamination. Toxicology 27:145-150. (In Fukayama, 1986)

## Tsai LS, Mapes CJ, Huxsoll CC, 1987. Aldehydes in Poultry Chiller Water. Poultry Science 66, 983-989.

U.S. EPA/AMWA (United States Environmental Protection Agency/Americn
Metropolitan Water Association). 1989. *Disinfection By-Products in
United States Drinking Waters, Final Report,* by James M. Montgomery
Consulting Engineers and the Metropolitan Water District of Southern
California.

Weinberg H.S, Krasner SW, Richardson SD, Thruston Jr. AD 2002. The
Occurrence of Disinfection B**y**-products (DBPs) of Health Concern in
Drinking Water: Results of a Nationwide Occurrence Study.
EPA/600/R-02/068. Sept. 2002.

## Valentine RL, Choi J, Chen Z, Barrett S, Huang C, Guo Y, Wehner M, Fitzsimmons S, Andrews A, Werker AG, Brubacher C, Kohut K 2005. Factors Affecting the Formation of NDMA in Water and Occurrence. Awwa Research Foundation, Denver, CO.

## Water Reuse 2006. Water Reuse: Issues, Technologies and Applications. T Asano, F Burton, H Leverenz, R Tsuchihashi, G Tchobanoglous eds. Metalf and Eddy, McGraw-Hill. p. 623-625.

## Water Treatment 1985. Water Treatment Principles and Design. James M Montgomery, John Wiley and Sons. P. 273.

## Westerhoff P, Chao P, Mash H 2004. Reactivity of Narural Organic Matter with Aqueous Chlorine and Bromine. Water Research 38:6, 1502-1513.

## Wikipedia 2008. [**http://en.wikipedia.org/w/index.php?title=Chloramine-T&oldid=181457790**](http://en.wikipedia.org/w/index.php?title=Chloramine-T&oldid=181457790)

WHO 1996. Guidelines for Drinking-water Quality, 2^nd^ edition, Volume
2. Health Criteria and Other Supporting Information. Geneva.

WHO 2004. Guidelines for Drinking-water Quality, 3^nd^ edition,
Volume 1. Geneva.

## WHO 2008. Desalination for Safe Water Supply: Guidance for the Health and Environmental Aspects Applicable to Desalination. World Health Organization, Geneva. i*n press.*

## Woo YT, Lai D, McLain J, Manibuson MK, Dellarco,V 2002. Use of Mechanism-Based Structure-Activity Relationships Analysis in Carcinogenic Potential Ranking for Drinking Water Disinfection By-Products. Environmental Health Perspectives 110, 75-85, Supplement 1, February.

Wright JM, Schwartz J, Vartianen T, Maki-Paakkanen J, Altshul L,
Harrington JJ, Dockery DW 2002.
3-Chloro-4-(dichloromethyl)-5-hydroxy-2H(5H)-furanone (MX) and mutagenic
activity in Massachusetts Drinking Water. Environ. Health Perspect.
110(2):157-163.

Zentox Corp. 2006. Effect of immersion chilling of broiler chicken
carcasses in monochloramine or sodium hypochlorite on volatile
nitrosamine presence in cooked product. Newport News, Virginia.

Chlorine Dioxide

Chlorine dioxide (ClO~2~) (Lee, 2008) is an antimicrobial agent
recognized for its disinfectant properties since the early 1900's.
Chlorine dioxide is a greenish yellow gas at room temperature that is
very soluble in water (EFSA, 2005). Chlorine dioxide is reduced in water
generating chlorite ion; chlorite is reduced to chloride. In the absence
of oxidizable substances and in the presence of alkali in water,
chlorine dioxide is reduced, generating chlorite and chlorate.

Chlorine dioxide is a comparatively weak oxidizing agent, and has a
lower oxidation potential than ozone, chlorine, or hypochlorous acid,
thus it is more selective in its reactions. Typically, chlorine dioxide
will react with compounds that have activated carbon bonds such as
phenols, or with other active compounds such as sulfides, cyanides, and
reduced iron and manganese compounds (Fukayama et al., 1986; SCVPH,
2003). Most importantly, chlorine dioxide is very specific in its
reactivity, and enters into only a few side reactions compared to
chlorine. Further, chlorine dioxide, if pure, does not chlorinate
organic material and therefore does not form trihalomethanes (THMs) and
other chlorinated by-products.

Chlorine dioxide in water and DBP chemistry have been described in an
early review (Rice and Cotruvo, 1978). In the formation of reaction
by-products in aqueous solution, aqueous chlorine dioxide can react with
carbohydrates, lipids, amino acids, peptides and proteins (Fukayama et
al., 1986; Rice and Gomez-Taylor, 1986). Chlorine dioxide in water acts
primarily as an oxidant rather than chlorinating agent, and its redox
potential in aqueous solution (ClO~2~ + e^-^ = ClO~2~^-^, 1.15 V), is
less than that of hypochlorous acid (HClO + H^+^ + 2e^-^ = Cl^-^ +
H~2~O, 1.49 V). Therefore, chlorine dioxide is likely to be less
reactive and produce fewer by-products than chlorine (Tsai et al.,
1995).

Wastewaters can contain large amounts of bioorganic chemicals from food
and animal waste. Chlorine dioxide can oxidize simple carbohydrates
(e.g., glucose) to form carbonyl derivatives that are subsequently
oxidized to carboxylic acids. Polysaccharides (e.g., cellulose) are also
susceptible to oxidation, and may produce gluconic acid. However, some
of these reactions require elevated temperatures (\> 80^o^C), and are
not likely to occur in aqueous chlorine dioxide.

Some unsaturated fatty acids in lipids can react with chlorine dioxide,
and produce a variety of compounds such as unsaturated ketones,
chloroketones, chlorohydrins, dichloro-addition products, and epoxides
(Rice and Cotruvo, 1978; Rice and Gomez-Taylor, 1986). In some instances
chlorinated compounds might have occurred from chlorine dioxide that
also contained some chlorine. Saturated aliphatic hydrocarbons are
neither oxidized nor chlorinated by chlorine dioxide. In commercial
poultry chiller water in the presence of chlorine or chlorine dioxide,
12 saturated and unsaturated aliphatic aldehydes having 5 to 11 carbons
(pentanal, hexanal, heptanal, octanal, trans-2-octenal, nonanal,
trans-2-nonenal, decanal, 2,2-nonadienal, trans-2-decenal,
2,4-decadienal and trans-2-undecenal) were detected by gas
chromatography/mass spectroscopy (GC/MS) analysis, and hexanal and
nonanal were the two major aldehydes detected (Tsai et al., 1987).

Chlorine dioxide is relatively inert toward individual amino acids, and
reactions are pH-dependant (Tan et al., 1987). Chlorine dioxide oxidizes
tryptophan to form indoxyl, isatine and indigo red (Fukayama et al.,
1986). Tyrosine formed dopaquinone upon oxidation by chlorine dioxide.
Sulfur-containing amino acids (cystine and methionine) produce
bisulfoxide and sulfonic acid derivatives (Rice and Gomez-Taylor, 1986).
Reaction of aqueous chlorine dioxide with peptides and proteins is
considered to be mainly due to interaction with individual amino acid
moities in the peptides, but reaction by-products have not been
identified.

Phenols and hydroquinones can be oxidized in the reaction with chlorine
dioxide; *p-*benzoquinone and aromatic carboxylic acids are produced
when chlorine dioxide is present in excess (Wajon et al., 1982). In the
reaction with humic acid and other natural materials in raw water, pure
chlorine dioxide does not produce THMs, but is reported to produce
oxidation products (i.e., benzenepolycarboxylic acids, aliphatic dibasic
acids, carboxyphenylgyloxylic acids, and aliphatic monobasic acids).
Several derivatives of furan and dioxane also were identified in the
reaction with humic acid and other natural materials (Rice and
Gomez-Taylor, 1986).

More than 40 DBPs were detected in finished drinking water from a water
plant using chlorine dioxide (Richardson et al, 1994). Multispectral
identification techniques were employed but the products were not
quantified. The predominant identified products were organic esters,
acids and olefins, and only two aldehydes (benzaldehyde and
ethylbenzaldehyde were detected. A few halogenated compounds were
detected probably from some chlorine in the treatment process. Numerous
aliphatic carboxylic acids were reported, including maleic
acid/anhydride. It is possible that other aldehydes were formed and
oxidized during treatment or processing, and also that some of the
products were formed from precursors that were not ordinarily part of
the natural organic matter (NOM) in the water.

**References**

EFSA, 2005. Treatment of poultry, carcasses with chlorine dioxide,
acidified sodium chlorite, trisodium phosphate and peroxyacids. *The
EFSA Journal*, **297**, 1-27.

EPA, 1999. Alternative Disinfectants and Oxidants Guidance Manual.
Office of water, Chapter 4. Chlorine dioxide. 1-39.

Fukayama MY, Tan H, Wheeler WB, Wei CI, 1986. Reaction of aqueous
chlorine and chlorine dioxide with model food compounds. *Environ.
Health Perspectives*, **69**, 267-274.

Lee H 2008. Chlorine Dioxide, WHO/FAO Active Chlorine, personal
communication, in press.

Rice RG, Cotruvo JA, 1978. Ozone/Chlorine Dioxide Oxidation Products of
Organic Materials, RG Rice and JA Cotruvo, eds. Ozone Press
International. ISBN 0-918650-02-X.

Rice RG, Gomez-Taylor MG, 1986. Occurrence of by-products of strong
oxidants reacting with drinking water contaminants-scope of the
reaction. *Environ. Health Perspect*., **69**, 31-44.

Richardson SD, Thruston Jr AD, Collette TW, Schenck Patterson K, Lykins
Jr BW, Majetich G, Zhang Y, 1994. Multispectral Identification of
Chlorine Dioxide Disinfection By-Products in Drinking Water. *Environ.
Sci. Technol*., **28**: 592-599.

Tan H, Sen C, Wheeler WB, Cornell JA, Wei CI, 1987. A kinetic study of
the reaction of aqueous chlorine and chlorine dioxide with amino acids,
peptides and proteins. *J*. *Food Sci.* **52**, 1706-1711 & 1717.

Tsai LS, Higby R, Schade J, 1995. Disinfection of poultry chiller water
with chlorine dioxide: Consumption and byproduct formation. *J Agric
Food Chem*., **43**, 2768-2773.

## Tsai LS, Mapes CJ, Huxsoll CC, 1987. Aldehydes in Poultry Chiller Water*.* Poultry Sci*., 66, 983-989.*

Wajon JE, Rosenblatt DH, Burrows E, 1982. Oxidation of phenol and
hydroquinone by chlorine dioxide. *Environ. Sci. Technol*., **16**,
396-402.

Young SB, Setlow P, 2003. Mechanisms of killing of *Bacillus subtilis*
spores by hypochlorite and chlorine dioxide. *J. Applied Microbiol*.,
**95**,54-67.

Ozone and peroxides

Ozone and hydrogen peroxide in are widely used as disinfectant (ozone),
oxidant or as a source of peroxide radicals for chemical oxidation
(Arvidison, 2008). UV light is used with both to generate free radicals.

Although the decomposition of gaseous ozone is relatively simple and
produces only oxygen as a byproduct, the decomposition of ozone in the
aqueous phase is far more complex; generating a large number of reactive
species that can participate further in numerous side reactions or
hastening its decomposition. In pure water, ozone decomposes by a
radical chain reaction (Figure 3) by hydroxide and propagated by super
oxide and hydroxyl radicals (Kirk-Othmer, 1996). Peroxides decompose to
hydroxyl radicals with ultraviolet light as well as by the Fenton
reaction (with Fe++) that engaged in free radical oxidation processes.
Hydroxy radicals are the highest energy and most reactive species in
water and can indiscriminately react with most organic chemicals and the
rates are essentially diffusion controlled. If present in large \>
stoichiometric amounts they can produce mineralization of the organic
carbon.

Ozone in water and its DBP chemistry have been described in an early
review (Rice and Cotruvo, 1978). There is an extensive literature going
back more than 60 years on the chemistry and mechanisms of reaction of
ozone and active oxygen species with organic chemicals (e.g.,Criegee,
1938) More recently there is substantial data on the
decomposition/disappearance of chemicals under ozonation and advanced
oxidation water treatment conditions (e.g., AwwaRF, 2007). However, the
identification of the intermediates and by-products produced under those
conditions is much less developed. An early study of mutagenic effects
of 28 model chemicals ozonated under extreme conditions and
identification of some of the by-products was reported in 1977 (Cotruvo
et al, 1977). Depending upon reaction conditions and chemical type some
mutagens were formed and some became less mutagenic after ozonation
(Cotruvo et al, 1977, Caulfield et al, 1979, Burleson, 1982). Due to its
high oxidation potential, ozone reacts

**Figure 3 One example of a proposed decomposition sequence.**

![](media/image2.wmf)

with a large number of chemical types. For example, halogens, with the
exception of fluorine, form hypohalite ions that, in the presence of
excess ozone, are oxidized to halites (Rice and Cotruvo, 1978; Rice and
Gomez-Taylor,1986; Kirk-Othmer, 1996). Metal ions such as Fe^2+^ and
Mn^2+^ are converted to hydroxides (Fe(OH)~3~) or metal oxides (MnO~2~)
(Kirk-Othmer, 1996). In addition, ozone reacts with most active organic
substrates including, but not limited to, olefins, acetylenes,
aromatics, C-H bonds, C=N, N=N, SI-H and Si-C bonds (Kirk-Othmer, 1996).
Under extended reaction times and free radical conditions and high
concentrations of ozone and peroxy compounds, hydrocarbons can be broken
down (mineralized) into carbon dioxide and water (Rice and Gomez-Taylor,
1986). The most common and classical chemical transformation induced by
ozone (Figure 4) is the cleavage of olefin double-bonds forming,
depending on the location and substitution of the double bond, ketones
or aldehydes (Criegee, 1938).

**Figure 4**

![](media/image3.wmf) The reactivity of ozone depends greatly on the
conditions employed during ozonation. For example, in solutions with pHs
below 6 and at or below room temperatures, ozone reacts directly with
organic molecules. Increasing the pH above 8, ozone decomposes to highly
energetic hydroxyl radicals that react non-selectively with materials
via electron transfer, hydrogen abstraction, addition reaction, etc.
Between pH 6 and 8, ozone can react by both pathways (Rice &
Gomez-Taylor, 1986). Therefore, the conditions under which ozone is used
as a disinfectant must be closely monitored and controlled to give the
desired result.

Ozone will oxidize bromide to HOBr, and bromate in water. HOBr is an
excellent brominating agent as evidenced by product distributions reacts
with proteins peptides and amino acids producing brominated tyrosine
(Tyr) and short lived N-brominated species such as bromamines and
bromamides. Hawkins and Davies (2005) reported that greater than 40% of
HOBr generated in the presence of bovine serum albumin (BSA) is
converted to short lived bromamides and bromamines. Above 4 °C, these
protein-derived N-bromo compounds decompose rapidly (either directly or
through the formation of free radicals) by a number of pathways
including oxidation of Tyr, formation of carbonyl functionalities in
proteins, and rearrangement and fragmentation of proteins. Given the
reactive nature of HOBr and the N-bromo compounds and the variation of
the chemical composition of protein chains and their macromolecular
configuration; small quantities of numerous compounds would be expected.
However, specific compounds or classes of compounds were not identified
in the literature.

**Reactions with nucleophiles**

Nucleophiles can be oxidized to oxycompounds as illustrated in Figure 5

R~2~S + O~3~  R~2~SO + O~2~  + O~3~  R~2~SO~2~ + O~2~

R~3~N + O~3~  R~3~NO + O~2~

R~3~P + O~3~  R~3~PO + O~2~

R~3~As + O~3~  R~3~AsO + O~2~

(RO)~3~ + O~3~  (RO)~3~-PO~3~  (RO)~3~PO + O~2~

Sulfides are rapidly converted to sulfoxides and then sulfones. A well
known example of this is the pesticide aldecarb which can be oxidized to
aldecarb sulfoxide and aldecarb sulfone. The toxicology of aldecarb
sulfoxide is similar to aldecarb, and the sulfone is somewhat less
toxic, indicating that oxidation and decline of the measured
concentration of a chemical does not necessarily equal detoxification.
Tertiary amines, phosphines and arsenes are converted to the
corresponding oxides. Those precursors are not probable water
contaminants except for unique industrial discharges. Phosphites are
converted to phosphates. Under non-acidic conditions, tertiary amines
form the N-oxide (protonation in acidic solution would impede
nucleophilic chemical activity). Primary and secondary amines are
converted to several N-oxidized forms including organic nitro (nitrate)
compounds and N-oxides (Oehlschlaeger, 1978), and possibly nitrosamines
if the conditions are not acidic (Cotruvo et al, 1977). For example,
isopropyl amine forms 2 --nitropropane and isopropylammonium nitrate.

Commercially, amine oxides are used as chemical intermediates, and
long-chain alkylamine oxides are used as nonionic surfactants and foam
stabilizers. They have high polarity close to that of quarternary
ammonium salts which would indicate environmental mobility and
resistance to removal by several technologies. Small amine oxides are
hydrophilic, have high water solubility and poor solubility in most
organic solvents. Some examples are pyridine N-oxide and
N-methylmorpholine N-oxide. Medicinal uses of N-oxides are increasing
because they have stable free radical character and are
paramagnetic(Soule, 2007). Some amine oxides of anti-cancer drugs are
metabolized in oxygen-deficient cancer tissue to the active drug. Amine
oxides are common metabolites of medications and psychoactive drugs so
they are potentially present in wastewaters, would be difficult to
analyze and could survive several types of treatment. Drug examples
include nicotine, zolmitriptan and morphine.

**Potential Chemical Residues**

Common aldehydes (e.g., formaldehyde) and ketones

Common carboxylic acids

N-oxy compounds including amine oxides and nitrates

Possibly short lived active oxygen compounds

Bromate and brominated DBPs if bromide is present in water

**References:**

Arvidson K, 2008 Ozone and Peroxide Active oxygen Antimicrobials,
WHO/FAO Active Chlorine, personal communication, in press.

AwwaRF 2007. Removal of EDCs and Pharmaceuticals in Drinking Water and
Reuse Treatment Processes. AwwaRF Report 91188.

Burleson GR, Chambers TM 1982. Effect of Ozonation on the Mutagenicity
of Carcinogens in Aqueous Solution. Environmental Mutagenesis 4:4,
469-476.

Caulfield MJ, Burleson GR, Pollard M 1979. Ozonation of Mutagenic and
Carcinogenic Alkylating Agents, Pesticides, Aflatoxin B~1~ and Benzidine
in Water. Cancer Research 39, 2155-2159.

Cotruvo JA, Simmon VF, Spangord RJ 1977. Investigation of Mutagenic
Effects of Products of Ozonation Reactions in Water. Annals of the New
York Academy of Sciences 298: 124-140.

Crigee, 1938.

Glaze W H, 1986. Reaction products of Ozone: A review. *Environmental
Health Perspective*s, **69**, 151-157.

Hawkins CL , Davies M J 2005. The role of reactive N-bromo species and
radical intermediates in hypobromous acid-induced protein oxidation.
*Free Rad. Bio. and Med.* **39**, 900-912.

Kirk-Othmer 1996. Kirk-Othmer Encyclopedia of Chemical Technology 12^th^
edition, Kroschwitz, J.I. & Howe-Grant, M., Eds. John Wiley & Sons, New
York, **17**, 953-994.

Oehlshlaeger HF 1977. Reactions of Ozone with Organic Compounds in
Ozone/Chlorine Dioxide Oxidation Products of Organic Materials, RG Rice
and JA Cotruvo, eds. Ozone Press International. ISBN 0-918650-02-X.

Rice RG, Cotruvo JA, 1978. Ozone/Chlorine Dioxide Oxidation Products of
Organic Materials, RG Rice and JA Cotruvo, eds. Ozone Press
International. ISBN 0-918650-02-X.

Rice, RG, Gomez-Taylor M 1986. Occurrence or by-products of strong
oxidants reacting with drinking water contaminants-Scope of the problem.
*Environmental health Perspectives*, **69**, 31-44.