**Halofuranones, haloquinones, and related compounds**

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

**WateReuse Foundation 06-004**

**Background**

3-Chloro-4-(dichloromethyl)5-hydroxy-2(5H)furanone (MX) is well known as
a disinfection by-product. There are a large number of analogs of MX
that have been identified.

A study was commissioned by the AwwaRF to predict likely reaction
products with substructures in natural organic matter. A series of
haloquinone derivatives and some related cyclohexene and cyclopentene
derivatives were identified as likely DBPs (Bull et al., 2006). The
later compounds have at least a superficial resemblance to MX. Quinones
are known as reactive intermediates of well known carcinogens as benzene
and PAHs. The further activation of quinones to toxic forms are known to
be accelerated with halogen substitution in the ring. It is anticipated
that these compounds will be preferentially formed in chloraminated
water vs. chlorinated water (Bull et al., 2006). In fact, haloquinones
are likely major intermediates in the formation of THMs and HAAs, which
are currently regulated in drinking water. Excess chlorine destroys the
ring structure to give rise to these more commonly recognized DBPs.
Heasley et al., (2004) have demonstrated the formation of the
haloquinones from phenol and cresol precursors in laboratory studies.

**Occurrence**

A recent study documented the occurrence of several chlorinated and
brominated analogs of MX (Krasner et al. 2006). These data are provided
in DBP-1. Concentrations of MX were found to occur at mean
concentrations of 0.020 and with the highest concentration being 0.18
µg/L. The concentrations found in this survey exceeded those previously
reported. MX has apparently been rarely measured in wastewater intended
for potable reuse. Only one survey of MX concentrations in chlorinated
sewage was located, where a range of concentrations from 2-142 ng/L was
reported (Fukui et al., 1992). In our industry data base a concentration
of 5 ng/L was reported by one system following reverse osmosis
treatment. The molecular weight of MX is over 200, so it seems
improbable that it would penetrate reverse osmosis membranes. Other
related compounds, such as mucochloric acid, have molecular weights as
low as 168. There appears to be no data indicating whether MX is removed
by soil aquifer treatment or GAC.

Analogs of MX occurred at concentrations of up to 0.81 µg/L
(3-chloro-4-(bromochloromethyl-5-hydroxy-2(5H)-furanone) (Krasner et
al., 2006). While MX was detected in all waters, the median
concentrations of the other forms were below detection. This variation
undoubtedly reflects the variation in the bromide concentration of the
treated water.

The occurrence of the halogenated quinones, cyclohexene, and
cyclopentene derivatives is being investigated in a new AwwaRF project.
Preliminary data should be available on selected members of these
classes within a year. Considering that much of the mass of the
haloquinones are converted to THMs and HAAs with excess chlorine, the
collective concentration of chemicals in this class in excess of a µg/L
could be possible in chloraminated water. The likely concentrations of
other cyclohexene and cyclopentane concentrations are more difficult to
estimate. The smallest haloquinone, 2-chloro-1,4-dibenzoquinone has a
molecular weight of 148 and is non-polar. These two properties might
allow it to penetrate reverse osmosis membranes. We were unable to
identify chemicals of comparable polarity and molecular weight that have
been studied.

**TTC Analysis**

MX and several of its congeners are mutagenic. MX has been shown to be
carcinogenic in rats with a TD~50~ of approximately 1 mg/kg per day.
These compounds were subjected to QSTR analysis and predicted to be
non-carcinogenic. However, MX was also predicted to be non-carcinogenic.
Thus, chemicals related to MX were identified as important DBPs that
required toxicological characterization (Woo et al., 2002; Bull et al.,
2006)

A QSTR analysis predicted chronic LOAELs for these the haloquinones in
the µg/kg per day range (approximating the potency of NDMA). The program
also predicted that several of the haloquinone structures would be
carcinogenic and mutagenic and these predictions are consistent with
what is known of quinone toxicity, more generally (Bolton et al. 2000).
Examples of haloquinones that were predicted to be carcinogenic include
2,6-dichloro-1,4-dibenzoquinone, 2,3,6-trichloro-1,4-dibenzoquinone,
2,3,6-dichloro-1,4-benzoquinone-4-(N-chloro)amine.

The predicted cyclohexene and cyclopentene DBPs had varied structures.
Examples of the type of compounds that were identified were predicted to
be of likely toxicological importance included
3,5-dichloro-1-hydroxy-4-keto-cyclopent-2-enoic acid and
2,3,6-trichloro-4,5-diketophenylprop-2-enol (Bull et al., 2006). Several
were predicted to be probable carcinogens, but these compounds, like MX,
fell largely outside the predicitve space of the QSTR models.

Given the above information a TTC analysis is not appropriate for these
compounds. Chemical-specific data are necessary to assess the risk they
might pose to the public health.

**Research Recommendations**

We propose to nominate chemicals in these three groups for study by the
U.S. Environmental Protection Agency if the AwwaRF study suggests they
occur in drinking water at substantive concentrations (based on their
predicted toxic effects, substantive amounts would be as little as 10
ng/L as the predicted potency is in the same range as the
dialkylnitrosamines). We believe the key group of DBPs will be the
haloquinones as the prediction of carcinogenic activity by the\
QSTR program could be supported by a systematic literature search of the
mechanisms of toxic effects produced by quinones.

Based upon QSTR analyses, the endpoint of primary concern for these
chemicals will be potential carcinogenic effects. However, because of
the potentially large number of chemicals within this group that could
be produced, we would suggest that preliminary short-term in vivo
testing be conducted to determine which members of the class are most
likely to be a carcinogenic hazard at the concentrations that are
identified in drinking water. The QSTR predictions of carcinogenicity
are qualitative, although there was an attempt to estimate potency using
a predicted chronic LOAEL. These predictions could well be in error for
individual chemicals. Considerations of the basic mechanisms that are
involved in the toxicology of quinones, some confidence can be expressed
in the likelihood that the kidney will be a important, but not
necessarily the only, target organ for the haloquinones. The likelihood
that multiple mechanisms are likely to be involved in cancer induced by
these compounds indicate that other target organs cannot be ignored.

There is less pressure to do novel research with MX as one can use the
MX cancer data can at least allow a ballpark prediction of the likely
potency of the more closely related analogs of MX (i.e. the brominated
analogs). It is probable that the other analogs will be less potent. To
establish that, however, would require a broader set of toxicological
data on these related compounds than is presently available (largely
limited to mutagenic activity). The problem of assessing the
carcinogenic potency of compounds related to MX would be the second
priority for this proposed project, if haloquinones are seen not too
occur in appreciable concentrations in chloraminated water.
Toxicological evaluation of selected cyclohexene and cyclopentene
derivatives would be proposed within the group of MX-like compounds.

**Agencies to be Approached**

Developing a toxicological database for chemicals in these classes will
be a major undertaking. Some of these chemicals are not commercially
available, requiring synthesis to conduct studies. These structures were
predicted based upon substructures that occur in NOM, but there is a
high probability that compounds will be substituted with substituents
not anticipated in the predictive chemistry effort (Bull et al., 2008).
Therefore, pursuing the toxicology of these compounds will be a program,
not a single project.

We will suggest that if the haloquinones, in particular, are detected in
substantive concentrations in chloraminated water, that a coordinated
research effort be mounted involving both the U.S. EPA and the National
Toxicology Program. This would allow for a coordination of the synthesis
and purification of any test materials and an interagency planning and
coordination effort to minimize the costs of the studies. It is
anticipated that NHEERL might be in a better position to perform some of
the screening studies and NTP would be called upon to conduct chronic
bioassays using their usual contractual mechanisms.

**References**

Bolton, J.L., M.A. Trush, T.M. Penning, G. Dryhurst, and T.J. Monks.
2000. Role of quinones in toxicology. Chem. Res. Toxicol. 13(3):135-160.

Bull, R.J., Reckhow, D.A., Rotello, V., Bull, O.M., and Kim, J. (2006).
Use of Toxicological and Chemical Models to Prioritize DBP Research.
Report for AWWA Research Foundation Project 2867. Awwa Research
Foundation, Denver CO

Fukui, S., S. Ogawa, H. Kita, Y. Hanazaki, and H. Kami. 1992.
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in chlorinated
domestric sewage. Chemosphere 24:927-934.

Heasley, V.L., A.M. Fisher, E.E. Herman, F.E. Jacobsen, E.W. Miller,
A.M. Ramirez, N.R. Royer, J. M. Whisenand, D.L. Zoetewey, and D.F.
Shellhamer. 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.

Krasner, S.W., H.S. Weinberg, S.D. Richardson, S.J. Pastor, R. Chinn,
M.J. Sclimenti, G.D. Onstad, and A.D. Thurston, Jr. 2006. Occurrence of
a new generation of disinfection byproducts. Environ. Sci. Technol.
40(23)7175-7185.

Woo, Y.T., D.Lai, J.L. McLain, M.K., Manibusan, and V. Dellarco. 2002.
Use of mechanistic based structure activity relationships analysis in
the carcinogenic potential ranking for drinking water disinfection
by-products. Environ. Health Perspect. 110 Suppl 1:75-87.