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Chlorite and Chlorate in Drinking Water

28th September 2007 by Arrow Durfee Posted in Uncategorized

Please remember when you read this article that sodium chlorite is not the same as Chlorine Dioxide. Chlorine Dioxide is what MMS is converted into during the activation process before consumption. One oxygen ion makes all the difference. This article is presented to broaden the understanding of similar chemicals and their use.

CHLORITE AND CHLORATE IN DRINKING-WATER

Sprague-Dawley rats (10 per sex per dose) were exposed to chlorine dioxide in
drinking-water for 90 days at dose levels of 0, 25, 50, 100 or 200 mg/litre
(corresponding to 0, 2, 4, 6 or 12 mg/kg of body weight per day for males and 0, 2, 5,
8 or 15 mg/kg of body weight per day for females). Water consumption was
decreased in both sexes at the three highest dose levels, most likely because of
reduced palatability. Food consumption was decreased in males receiving the highest
dose. Goblet cell hyperplasia was significantly increased in the nasal turbinates of
females given 8 or 15 mg/kg of body weight per day and males at all doses.
Inflammation of the nasal cavity was observed in males at 2 mg/kg of body weight
per day and in both sexes at higher doses. The lesions were likely caused by
inhalation of chlorine dioxide vapours at the drinking-water sipper tube or from offgassing
of the vapours after drinking, rather than by ingestion of drinking-water. The
authors concluded that the lowest dose (2 mg/kg of body weight per day) was a
LOAEL (Daniel et al., 1990).
4.1.2 Long-term exposure
In a drinking-water study, chlorine dioxide was administered to rats (seven per sex per
dose) at concentrations of 0, 0.5, 1, 5, 10 or 100 mg/litre (highest dose equivalent to
about 13 mg/kg of body weight per day) for 2 years. At the highest dose level,
survival rate was substantially decreased in both sexes, and mean life span was
reduced compared with that for control animals. No correlation was observed between
treatment and histopathological findings. In this study, a NOAEL of 10 mg/litre (1.3
mg/kg of body weight per day) was identified (Haag, 1949), although it should be
noted that this 1949 study has serious limitations.
4.1.3 Reproductive and developmental toxicity
In a one-generation study carried out with Long-Evans rats, chlorine dioxide was
administered by gavage at doses of 0, 2.5, 5 or 10 mg/kg of body weight per day to
males (12 per group) for 56 days prior to and during mating to female rats (24 per
group) that were dosed (same as males) from 14 days prior to mating and throughout
pregnancy until weaning on day 21 of lactation. Fertility measures were not
significantly different among the dose groups. There were no dose-related changes in
sperm parameters (i.e., concentration, motility, progressive movement or
morphology). Thyroid hormone levels were altered significantly, but not in a
consistent pattern (Carlton et al., 1991). IPCS (2002) concluded that this study did not
demonstrate any impairment of reproductive function and that there were no signs of
developmental effects among rats receiving up to 10 mg of aqueous chlorine dioxide
per kg of body weight per day.
Female rats were exposed to 0, 1, 10 or 100 mg of chlorine dioxide per litre in
drinking-water (equivalent to 0, 0.1, 1 or 10 mg/kg of body weight per day) for 2.5
months before mating and throughout gestation. At the highest dose, there was a
slight reduction in the number of implants and live births per pregnancy. No effects
were observed at 1 mg/kg of body weight per day, which was identified as the
NOAEL (Toth et al., 1990).
Female Sprague-Dawley rats (13–16 per dose) were supplied with drinking-water
containing 0, 2, 20 or 100 mg of chlorine dioxide per litre for 2 weeks before mating
and throughout gestation and lactation, until pups were weaned on postnatal day 21.
No significant effect on the body weight of either the dams or the pups was observed
at any dose tested. At 100 mg/litre (14 mg/kg of body weight per day for the pregnant
dam), a significant depression of serum thyroxine and an increase in serum
triiodothyronine were observed in the pups at weaning, but not in the dams.
Neurobehavioural exploratory and locomotor activities were decreased in pups born
to dams exposed to 100 mg/litre but not to those exposed to 20 mg/litre (3 mg/kg of
body weight per day), which was considered a NOAEL (Orme et al., 1985).
In a second experiment, rat pups were exposed directly (by gavage) to 14 mg of
chlorine dioxide per kg of body weight per day (equivalent to the dose received by a
pregnant dam drinking water containing 100 mg of chlorine dioxide per litre) on
postnatal days 5–20. In this study, serum thyroxine levels were depressed, a
somewhat greater and more consistent delay in the development of exploratory and
locomotor activity was seen and pup body weight gain was reduced. The decrease in
serum triiodothyronine levels was not statistically significant. Based on decreased pup
development and decreased thyroid hormone levels, a LOAEL of 14 mg/kg of body
weight per day (the only dose tested) was identified (Orme et al., 1985).
Cell number was significantly depressed in the cerebellum of 21-day-old rat pups
born to dams supplied during gestation and lactation with water containing 100 mg of
chlorine dioxide per litre (about 14 mg/kg of body weight per day to the dam). A
group of 12 rat pups dosed directly by gavage with 14 mg/kg of body weight per day
had depressed cell numbers in both the cerebellum and forebrain at postnatal day 11
and displayed decreased voluntary running wheel activity at postnatal days 50–60,
despite the fact that chlorine dioxide treatments were terminated at 20 days of age.
These data suggest that chlorine dioxide is capable of influencing brain development
in neonatal rats. In this study, a LOAEL of 14 mg/kg of body weight per day, the only
dose tested, was identified (Taylor & Pfohl, 1985).
The developmental neurotoxic potential of chlorine dioxide was evaluated in a study
in which it was administered to rat pups by oral intubation at 14 mg/kg of body
weight per day on postnatal days 1–20. Forebrain cell proliferation was decreased on
postnatal day 35, and there were decreases in forebrain weight and protein content on
postnatal days 21 and 35. Cell proliferation in the cerebellum and olfactory bulbs was
comparable to that in untreated controls, as were migration and aggregation of
neuronal cells in the cerebral cortex. Histopathological examination of the forebrain,
cerebellum and brain stem did not reveal any lesions or changes in these tissues. In
this study, a LOAEL of 14 mg/kg of body weight per day (the only dose tested) was
identified (Toth et al., 1990).
Female Sprague-Dawley rats received chlorine dioxide at approximately 0, 0.07, 0.7
or 7 mg/kg of body weight per day in drinking-water. After approximately 10 weeks
of exposure, females were mated with untreated males and continued to receive
chlorine dioxide throughout gestation. On day 20 of gestation, the dams were
sacrificed, their uteri were removed and weighed, and the fetuses were examined; half
of the fetuses were examined for skeletal and half for visceral abnormalities. There
were no clinical signs of toxicity and no exposure-related mortalities among the dams.
There was a slight, but not statistically significant, reduction in body weight gain
among dams at 0.7 and 7 mg/kg of body weight per day during pregnancy
(approximately 14% reduction compared with controls). There was a slight reduction
in the mean number of implants per dam in the two highest dose groups, which was
statistically significant at 7 mg/kg of body weight per day (10.3 per dam compared
with 12.3 per dam in controls). A similar change in the number of live fetuses was
also observed at the two highest doses. These effects may have been related to
maternal toxicity, as there was a slight reduction in body weight gain among dams at
the two highest exposure levels. The incidence of litters with anomalous fetuses was
unaffected by treatment (5/6, 4/6, 6/6 and 7/8 among animals receiving 0, 0.07, 0.7
and 7 mg/kg of body weight per day, respectively) (Suh et al., 1983).
4.1.4 Mutagenicity and related end-points
Chlorine dioxide was mutagenic in Salmonella typhimurium strain TA100 in the
absence of a metabolic activation system (Ishidate et al., 1984). No sperm head
abnormalities were observed in male mice following chlorine dioxide gavage (Meier
et al., 1985). No chromosomal abnormalities were seen in either the micronucleus test
or a cytogenetic assay in mouse bone marrow cells following gavage dosing with
chlorine dioxide (Meier et al., 1985).
In an in vitro cytogenetics assay, Chinese hamster ovary cells were treated with 0, 2.5,
5, 10, 15, 30 or 60 µg of 0.2% chlorine dioxide per ml in phosphate-buffered saline
solution without metabolic activation (-S9). A second experiment was conducted with
Chinese hamster ovary cells treated at 0, 6, 13, 25, 50 or 75 µg/ml with metabolic
activation (+S9). In the first experiment, cell toxicity was observed at 60 µg/ml, and
there was an absence of mitotic cells at 30 µg/ml. At 2.5–15 µg/ml, there was a doserelated,
statistically significant increase in the number of metaphases with
chromosome aberrations. In the second experiment (with metabolic activation), cell
toxicity and absence of mitotic cells were observed at 75 µg/ml. A statistically
significant increase in the number of metaphases with chromosome aberrations was
noted at 50 µg/ml (Ivett & Myhr, 1986).
In a mouse lymphoma forward mutation assay (using L5178Y TK+/-), cells were
treated with 0–65 µg of chlorine dioxide per ml in phosphate-buffered saline with and
without metabolic activation (S9). Without S9, marked toxicity was observed at the
highest concentration used, 37 µg/ml. The relative growth at the next two
concentrations (15 and 24 µg/ml) was 13–18%. There was a dose-related increase in
mutant frequency. With S9, marked toxicity was observed at the highest
concentration, 65 µg/ml, and there was also a dose-related increase in mutant
frequency, indicating positive results both with and without metabolic activation in
this test system (Cifone & Myhr, 1986).
4.1.5 Carcinogenicity
Tumours were not observed in rats following 2-year exposures to chlorine dioxide in
drinking-water, although it should be noted that this study is over 50 years old and has
serious limitations (Haag, 1949).
4.2 Chlorite
4.2.1 Acute exposure
An oral LD50 of 105 mg/kg of body weight has been reported in rats (Musil et al.,
1964). Quail were more resistant than rats; the LD50 was 493 mg/kg of body weight
(Fletcher, 1973).
4.2.2 Short-term exposure
Single doses of sodium chlorite administered orally to cats produced
methaemoglobinaemia (Heffernan et al., 1979). A dose of 20 mg of chlorite per litre
(equivalent to approximately 1.5 mg of chlorite per kg of body weight) caused up to
32% of the haemoglobin to be in the methaemoglobin state and was considered to be
the LOAEL. A dose-dependent increase in methaemoglobinaemia and anaemia was
observed in 12 African green monkeys treated with sodium chlorite at 0, 25, 50, 100
or 400 mg/litre in drinking-water using a rising-dose protocol. Doses of chlorite were
approximately 0, 3, 6, 13 and 50 mg/kg of body weight per day, and each dose level
was maintained for 30–60 days (Bercz et al., 1982).
A more recent study employed doses of sodium chlorite administered by gavage to
male and female Crl:CD (SD) BR rats (15 per sex per group). Doses of 0, 10, 25 or 80
mg of sodium chlorite per kg of body weight per day were administered daily by
gavage for 13 weeks (equivalent to 0, 7.4, 18.6 or 59.7 mg of chlorite per kg of body
weight per day). This study is important because it includes many of the standard
parameters of subchronic toxicological studies, whereas previous studies had focused
almost entirely on blood parameters. A gavage dose of 80 mg/kg of body weight per
day produced death in a number of animals. It also resulted in morphological changes
in erythrocytes and significant decreases in haemoglobin concentrations. At 80 mg/kg
of body weight per day, red blood cell counts in both sexes were significantly less
than control values. In males only, haematocrit and haemoglobin levels were
significantly less than control values, and methaemoglobin level and neutrophil count
were significantly greater than control values. A slight increase in reticulocyte count
was observed at 80 mg/kg of body weight per day in males, but the increase was not
statistically significant. These changes were due to marked changes in two individual
males, which died shortly after the 13-week bleeding. At 80 mg/kg of body weight per
day, methaemoglobin levels in females were significantly less than control values. A
statistical trend test indicated a dose-related downward trend for red blood cell count
in females at 25 mg/kg of body weight per day and in males at 10 mg/kg of body
weight per day. Statistical significance was not confirmed by direct comparison with
the control group, and the group mean values were within the background range;
therefore, a direct association with treatment could not be conclusively established.
As would be expected where haemolysis is occurring, splenic weights were increased.
Adrenal weights were increased in females at 25 and 80 mg/kg of body weight per
day, whereas statistically significant changes were observed only at 80 mg/kg of body
weight per day in males. Histopathological examination of necropsied tissues revealed
squamous cell epithelial hyperplasia, hyperkeratosis, ulceration, chronic inflammation
and oedema in the stomach of 7 out of 15 males and 8 out of 15 females given 80
mg/kg of body weight per day doses. This effect was observed in only 2 out of 15
animals at the 25 mg/kg of body weight per day dose and not at all at the 10 mg/kg of
body weight per day dose. Microscopic evaluations were made in 40 additional
tissues, but no treatment-related abnormalities were found. The NOAEL for this study
was determined to be 7.4 mg/kg of body weight per day for stomach lesions and
increases in spleen and adrenal weights (Harrington et al., 1995a).
Rats were exposed to chlorite ion at 0, 10, 50, 100, 250 or 500 mg/litre in drinkingwater
(equivalent to 0, 1, 5, 10, 25 or 50 mg/kg of body weight per day) for 30–90
days. Haematological parameters were monitored, and the three highest
concentrations produced transient anaemia. At 90 days, red blood cell glutathione
levels in the 100 mg/litre group were 40% below those of controls; there was at least a
20% reduction in the rats receiving 50 mg/litre. In this study, a NOAEL of 1 mg/kg of
body weight per day was identified (Heffernan et al., 1979).
4.2.3 Long-term exposure
The effect of sodium chlorite in drinking-water at 0, 1, 2, 4, 8, 100 or 1000 mg/litre on
the survival and postmortem pathology of albino rats (seven per sex per dose) was
examined in a 2-year study. The life span of the animals was not significantly affected
at any dose. No effects were observed in animals exposed to 8 mg/litre (0.7 mg/kg of
body weight per day) or less. Animals exposed to 100 or 1000 mg/litre (9.3 or 81
mg/kg of body weight per day) exhibited treatment-related renal pathology; the author
concluded that this was the result of a non-specific salt effect. Based on renal effects,
this study identifies a NOAEL of 8 mg/litre (0.7 mg/kg of body weight per day) and a
LOAEL of 100 mg/litre (9.3 mg/kg of body weight per day). This study has limited
value, since there was an insufficient number of animals tested per group, pathology
was conducted on a small number of animals and the study did not provide adequate
evaluations of more sensitive parameters (Haag, 1949).
4.2.4 Reproductive and developmental toxicity
Female mice (10 per dose) were treated with sodium chlorite at 0 or 100 mg/litre in
drinking-water (equivalent to 0 and 22 mg/kg of body weight per day) (US EPA,
2000) from day 1 of gestation and throughout lactation. Conception rates were 56%
for controls and 39% for treated mice. The body weights of pups at weaning were
reduced (14% below the controls) in treated mice relative to controls, so that 22
mg/kg of body weight per day is the LOAEL for this study (Moore & Calabrese,
1982).
In a series of three experiments, sodium chlorite was administered to male rats (12 per
dose) in drinking-water for 66–76 days at concentrations of 0, 1, 10, 100 or 500
mg/litre (equivalent to 0, 0.1, 1, 10 and 50 mg/kg of body weight per day). No
compound-related abnormalities were observed on histopathological examination of
the reproductive tract. Abnormal sperm morphology and decreased sperm motility
were seen at the two highest dose levels, but no sperm effects were observed at 1
mg/kg of body weight per day, which can be identified as the NOAEL. In another part
of the same study, male rats were bred with female rats treated at 0, 0.1, 1.0 or 10 mg
of sodium chlorite per kg of body weight per day dose levels. Males were exposed for
56 days and females for 14 days prior to breeding and throughout the 10-day breeding
period. Females were also exposed throughout gestation and lactation, until the pups
were weaned on day 21. There was no evidence of any adverse effects on conception
rates, litter size, day of eye opening or day of vaginal opening. Decreases in the
concentrations of triiodothyronine and thyroxine in blood were observed on postnatal
days 21 and 40 in male and female pups exposed to 100 mg/litre. Based on
reproductive effects, a NOAEL of 10 mg/kg of body weight per day, the highest dose
tested in this experiment, was identified (Carlton et al., 1987).
Fetuses from maternal Sprague-Dawley rats exposed for 2.5 months prior to mating
and throughout gestation to chlorite ion via drinking-water at levels of 1 or 10 mg/litre
were examined. There was an increase in the incidence of anomalies at both
concentrations; however, because the treatment groups were small (6–9 females per
group), the effects were not considered statistically significant (Ishidate et al., 1984).
Groups of female Sprague-Dawley rats (12 per group) were exposed for 9 weeks to
drinking-water containing 0, 20 or 40 mg of sodium chlorite per litre (0, 3 or 6 mg of
chlorite per kg of body weight per day) beginning 10 days prior to breeding with
untreated males and until the pups were sacrificed at 35–42 days post-conception.
Pups were culled at birth to eight pups per litter (all males if possible). From days 31
to 42 post-conception, six litters of each treatment group were assessed for the
development of exploratory activity. Pups exposed to a dose of 6 mg/kg of body
weight per day exhibited a consistent and significant depression in exploratory
behaviour on post-conception days 36–39, but not on day 40. Exploratory activity was
comparable between treated and control groups after post-conception day 39. Based
on behavioural effects, the NOAEL was identified as 3 mg/kg of body weight per day
(Mobley et al., 1990).
In a two-generation study, Sprague-Dawley rats (30 per sex per dose) received
drinking-water containing 0, 35, 70 or 300 mg of sodium chlorite per litre for 10
weeks and were then paired for mating. Males were exposed throughout mating, then
sacrificed. Exposure for the females continued through mating, pregnancy, lactation
and until necropsy following weaning of their litters. Twenty-five males and females
from each of the first 25 litters to be weaned in a treatment group were chosen to
produce the F1 generation. The F1 pups were continued on the same treatment regimen
as their parents. At approximately 14 weeks of age, they were mated to produce the
F2a generation. Because of a reduced number of litters in the 70 mg/litre F1–F2a
generation, the F1 animals were remated following weaning of the F2a generation to
produce the F2b generation. Doses for the F0 animals were 0, 3.0, 5.6 or 20.0 mg of
chlorite per kg of body weight per day for males and 0, 3.8, 7.5 or 28.6 mg of chlorite
per kg of body weight per day for females. For the F1 animals, doses were 0, 2.9, 5.9
or 22.7 mg of chlorite per kg of body weight per day for males and 0, 3.8, 7.9 or 28.6
mg of chlorite per kg of body weight per day for females. There were reductions in
water consumption, food consumption and body weight gain in both sexes in all
generations at various times throughout the experiment, primarily in the 70 and 300
mg/litre groups; these were attributed to lack of palatability of the water. At 300
mg/litre, reduced pup survival, reduced body weight at birth and throughout lactation
in F1 and F2, lower thymus and spleen weights in both generations, lowered incidence
of pups exhibiting a normal righting reflex, delays in sexual development in males
and females in F1 and F2 and lower red blood cell parameters in F1 were noted.
Significant reductions in absolute and relative liver weights in F0 females and F1
males and females, reduced absolute brain weights in F1 and F2 and a decrease in the
maximum response to auditory startle stimulus on postnatal day 24 but not at
postnatal day 60 were noted in the 300 and 70 mg/litre groups. Minor changes in red
blood cell parameters in the F1 generation were seen at 35 and 70 mg/litre, but these
appeared to be within normal ranges based on historical data. The NOAEL in this
study was 35 mg/litre (2.9 mg/kg of body weight per day), based on lower auditory
startle amplitude, decreased absolute brain weight in the F1 and F2 generations and
altered liver weights in two generations (CMA, 1997; TERA, 1998).

The developmental toxicity of chlorite was examined in New Zealand white rabbits.
The rabbits (16 per group) were treated with 0, 200, 600 or 1200 mg of sodium
chlorite per litre in their drinking-water (equivalent to 0, 10, 26 or 40 mg of chlorite
per kg of body weight per day) from day 7 to day 19 of pregnancy. The animals were
necropsied on day 28. Food consumption was depressed at the top two doses, and
water consumption was depressed at all doses, but more notably in the top two dose
groups. Mean fetal weights were slightly lower at the top two doses as well, with a
slightly higher incidence of incomplete ossification of some bones. There were no
dose-related increases in defects identified. Minor skeletal anomalies were observed
as the concentration of chlorite in water was increased and maternal food
consumption was depressed. A NOAEL of 200 mg/litre (10 mg/kg of body weight per
day) and a LOAEL of 600 mg/litre (26 mg/kg of body weight per day) were identified
based on a decrease in fetal weight and delayed ossification, decreased food and water
consumption of the dams and decreased body weight gain in the dams. There was
some uncertainty surrounding the interpretation of the results because of inadequate
reporting of the number and types of specific abnormalities and variations. In
addition, there was some uncertainty as to whether the decreases in food and water
consumption and body weight gain in the dams were caused by unpalatability or a
direct toxic effect of the chlorite (Harrington et al., 1995b).
4.2.5 Mutagenicity and related end-points

Sodium chlorite produced an increase in revertant colonies in Salmonella
typhimurium strain TA100 in both the presence and absence of metabolic activation
(Ishidate et al., 1984). No chromosomal abnormalities were seen in either the mouse
micronucleus test or a cytogenetic assay in mouse bone marrow cells following
gavage dosing with chlorite (Meier et al., 1985).

In a micronucleus test in bone marrow from male ddY mice after a single
intraperitoneal injection of sodium chlorite at 0, 7.5, 15, 30 or 60 mg/kg of body
weight, a statistically positive response was observed at 15 and 30 mg/kg of body
weight only: 0.38% and 1.05%, respectively, compared with 0.18% for the control
group (Hayashi et al., 1998).

4.2.6 Carcinogenicity
In a long-term study, F344 rats received sodium chlorite in drinking-water at doses of
300 or 600 mg/litre (corresponding to 18 and 32 mg/kg of body weight per day for
males and 28 and 41 mg/kg of body weight per day for females) for 85 weeks. All
groups of rats were infected with the Sendai virus. A slight dose-related decrease in
body weight gain was observed, within 10% of that of the control group. However, no
adverse effects on survival or chlorite-related increases in tumour incidence were
observed (Hayashi et al., 1998).
Sodium chlorite was administered at concentrations of 0, 250 or 500 mg/litre to
B6C3F1 mice (50 per sex per group) for 80 weeks followed by distilled water only for
an additional 5 weeks. The concentrations corresponded to doses of approximately 0,
38.1 and 59.3 mg/kg of body weight per day for females and 0, 43 and 68.6 mg/kg of
body weight per day for males. All animals were sacrificed after 85 weeks. The
incidence of tumour-bearing animals was 32% (control), 34% (low dose) and 26%
(high dose) in female mice and 46% (control), 57% (low dose), and 53% (high dose)
in male mice. The type and incidence of neoplasms that occurred frequently in each
group of both sexes were similar to those observed spontaneously in B6C3F1 mice.
The incidence of lymphomas/leukaemias found in the high-dose group was lower than
that in the control group: 2% versus 15%, respectively. The incidence of pulmonary
adenomas in the high-dose group for males (12%) was higher than the incidence in
the controls (0%). The authors suggested either that the higher incidence of lung
adenomas in the high-dose group could be attributed to a statistical variation resulting
from the low adenoma incidence in control males or that there was a strong case for
further studies on the carcinogenicity of sodium chlorite. Overall, no dose-related
increases of adenoma or adenocarcinoma incidences were observed, and there was no
clear evidence of carcinogenic potential of sodium chlorite in B6C3F1 mice
(Kurokawa et al., 1986).
4.3 Chlorate
4.3.1 Acute exposure
An acute oral dosing study in dogs demonstrated lethality at levels of sodium chlorate
as low as 600 mg of chlorate ion per kg of body weight (Sheahan et al., 1971).
4.3.2 Short-term exposure
Beagle dogs (four per sex per dose) were exposed by gavage to sodium chlorate at
doses of 0, 10, 60 or 360 mg/kg of body weight per day for 3 months. There was no
significant effect at any dose level on body weight, food consumption, clinical
chemistry, organ weights, ophthalmic effects, gross necropsy or tissue histopathology.
Haematological changes were limited to a slight elevation in methaemoglobin level in
highest-dose animals, but this appeared to be within normal limits and was not judged
to be treatment-related. In this study, a NOAEL of 360 mg/kg of body weight per day
in dogs was identified (Bio/dynamics, Inc., 1987a).

Sprague-Dawley rats (14 per sex per dose) were exposed by gavage to sodium
chlorate at doses of 0, 10, 100 or 1000 mg/kg of body weight per day for up to 3
months. No treatment-related effects were observed on mortality, physical appearance
or behaviour, body weight, food consumption, clinical chemistry, gross necropsy or
organ histopathology. At the highest dose, haematological changes indicative of
anaemia included decreases in erythrocyte count, haemoglobin concentration and
erythrocyte volume fraction (haematocrit). In this study, a NOAEL of 100 mg/kg of
body weight per day was identified (Bio/dynamics, Inc., 1987b).
In a 90-day study, chlorate at concentrations of 3, 12 or 48 mmol/litre in drinkingwater
was provided to both male and female Sprague-Dawley rats. These
concentrations correspond to 250, 1000 and 4000 mg of chlorate per litre, equivalent
to 30, 100 or 510 mg/kg of body weight per day in males and 42, 164 or 800 mg/kg of
body weight per day in females, based on measured water consumption of each group.
Body weight gain was sharply curtailed in both sexes at the highest concentration.
These effects were generally paralleled by lower organ weights (except for brain and
testes). Some decreases in haemoglobin, haematocrit and red blood cell counts were
observed at this same dose. Pituitary lesions (vacuolation in the cytoplasm of the pars
distalis) and thyroid gland colloid depletion were observed in both the mid- and highdose
groups of both sexes. The NOAEL in this study was 30 mg/kg of body weight
per day (McCauley et al., 1995).
4.3.3 Carcinogenicity
There are no studies dealing with the carcinogenic potential of chlorate alone. Sodium
and potassium chlorate were evaluated as promoters of renal tumours in N-ethyl-Nhydroxyethyl-
nitrosamine-initiated F344 rats. Sodium chlorate resulted in an increase
in the number of renal tumours, but the effect was not statistically significant due to
the small number of animals used (Kurokawa et al., 1985).
4.3.4 Reproductive and developmental toxicity
No studies were available examining the reproductive or embryotoxic potential of
chlorate. Sodium chlorate was administered to pregnant CD rats by gavage at doses of
0, 10, 100 or 1000 mg/kg of body weight per day on days 6–15 of gestation. There
were no maternal deaths in treated animals or treatment-related effects on maternal
body weight gain, food consumption, clinical observations, number of implantations
or gross necropsy. Examination of fetuses on day 20 revealed no effects on fetal
weight or sex ratio, and no external, visceral or skeletal abnormalities were detected.
In this study, a developmental NOAEL of 1000 mg/kg of body weight per day in rats
was identified (Bio/dynamics, Inc., 1987c).
4.3.5 Mutagenicity and related end-points
Chlorate has long been known to select nitrate reductase-deficient mutants of
Aspergillus nidulans (Cove, 1976). However, it has been demonstrated that there is
also a mutagenic effect of chlorate in Chlamydomonas reinhardtii and Rhodobacter
capsulatus. Chlorate failed to induce mutations in the BA-13 strain of Salmonella
typhimurium. The positive mutagenic effects were separated from simple selection of
nitrate reductase mutants by incubating cells in nitrogen-free media. Lack of nitrogen
prevents cell division during the treatment period. In the case of C. reinhardtii,
significant increases in mutants were observed at concentrations of 4–5 mmol/litre
and above (Prieto & Fernandez, 1993).
No chromosomal abnormalities were seen in either the micronucleus test or a
cytogenetic assay in mouse bone marrow cells following gavage dosing with chlorate
(Meier et al., 1985).
5. EFFECTS ON HUMANS
5.1 Chlorine dioxide
Six different doses of chlorine dioxide (0.1, 1, 5, 10, 18 or 24 mg/litre) in drinkingwater
were administered to each of 10 male volunteers using a rising-dose protocol.
Serum chemistry, blood count and urinalysis parameters were monitored. A
treatment-related change in group mean values for serum uric acid was observed,
which the authors concluded was not physiologically detrimental. The highest dose
tested, 24 mg/litre (about 0.34 mg/kg of body weight per day), can be identified as a
single-dose NOAEL (Lubbers et al., 1981).
The same male volunteers drank 0.5 litres of water containing 5 mg of chlorine
dioxide per litre each day for approximately 12 weeks and were then kept under
observation for 8 weeks.
Serum chemistry, blood counts and urinalysis revealed no abnormalities, except for a slight change in blood urea nitrogen, which the authors concluded was of doubtful physiological or toxicological significance.
This exposure,
equivalent to 36 µg/kg of body weight per day, can be considered a NOAEL (Lubbers
et al., 1981).
In a prospective study of 197 persons, a portion of the population of a rural village
exposed for 12 weeks to a chlorine dioxide-treated water supply (containing 0.25–1.1
mg of chlorine dioxide per litre and 0.45–0.91 mg of free chlorine per litre)
experienced no significant changes in haematological parameters, serum creatinine or
total bilirubin (Michael et al., 1981).

A cross-sectional study was conducted of 548 births at Galliera Hospital in Genoa,
Italy, and 128 births at Chiavari Hospital in Chiavari, Italy, during 1988–1989 to
mothers residing in each city. Women in Genoa were exposed to filtered water
disinfected with chlorine dioxide (Brugneto River wells, reservoir water and surface
water) and/or chlorine (Val Noci reservoir). Women residing in Chiavari used
untreated well water. Assignment to a water source and type of disinfectant was based
on the mother’s address (undisinfected well water, chlorine, chlorine dioxide or both).
Municipal records were used to determine family income, and hospital records were
used to obtain information about mother’s age, smoking, alcohol consumption and
education level and birth outcomes — low birth weight (≤2500 g), preterm delivery
(≤37 weeks), body length (≤49.5 cm), cranial circumference (≤35 cm) and neonatal
jaundice. Neonatal jaundice was almost twice as likely (OR = 1.7; 95% CI = 1.1–3.1)
in infants whose mothers resided in the area where drinking-water from surface water
sources was disinfected with chlorine dioxide as in infants whose mothers used
undisinfected well water. Chlorinated surface water did not produce a similar effect.
Large increased risks of smaller cranial circumference and body length were
associated with water from surface water sources disinfected with chlorine or chlorine
dioxide. The risks for smaller cranial circumference for infants of mothers residing in
areas with chlorine dioxide-treated surface water, compared with infants of mothers
residing in areas with untreated well water, were as follows: OR = 2.2; 95% CI = 1.4–
3.9. For smaller body length, the risks were as follows: OR = 2.0; 95% CI = 1.2–3.3.
Risks of low birth weight were also increased for infants of mothers residing in areas
with drinking-water disinfected with either chlorine or chlorine dioxide, but they were
not statistically significant. For preterm delivery, there were small but non-significant
increased risks associated with chlorine or chlorine dioxide disinfection. This study
suggests possible risks associated with surface water disinfected with either chlorine
or chlorine dioxide, but the results should be interpreted very cautiously. The THM
levels were low in both the chlorine-treated (8–16 µg/litre) and chlorine dioxidetreated
(1–3 µg/litre) surface water, so it seems unlikely that they could be the causal
agents. No information was collected to assess the mothers’ water consumption or
nutritional habits, and the age distribution of the mothers was not considered. It is
possible that bottled water consumption could have confounded the results,
particularly if mothers in areas with chlorinated or chlorine dioxide-treated water
elected to drink bottled water more than those in the area served by untreated well
water. In addition, there are concerns about incomplete ascertainment of births and
whether the populations may be different in respects other than the studied water
system differences. On the other hand, if the observed associations with water source
and disinfection are not spurious, a question is raised about what water contaminants
may be responsible. Exposures to surface water and groundwater sources are
compared in this study, and no information is presented about other possible water
quality differences (Kanitz et al., 1996).

5.2 Chlorite
The effects of sodium chlorite on humans were evaluated in 10 male volunteers in a
rising-dose protocol. Single doses of 0.01, 0.1, 0.5, 1.0, 1.8 and 2.4 mg of chlorite ion
per litre in 1 litre of drinking-water were ingested by each subject. Changes in group
mean values for serum urea nitrogen, creatinine and urea nitrogen/creatinine ratio
were observed, which the authors concluded were not adverse physiological effects.
The highest dose tested, 2.4 mg/litre (0.034 mg/kg of body weight per day), can be
identified as a single-dose NOAEL (Lubbers et al., 1981).

The same volunteers ingested 0.5 litres of water per day containing 5 mg of sodium
chlorite per litre for approximately 12 weeks and were then kept under observation for
8 weeks. Treatment was associated with a change in group mean corpuscular
haemoglobin; however, as there was no trend over time for this change and values
were within the normal ranges, the authors were reluctant to attach physiological
significance to the observation. The dose tested, equivalent to 36 µg/kg of body
weight per day, was identified as the NOAEL (Lubbers et al., 1981).
5.3 Chlorate

Because of its use as a weed killer, a large number of cases of chlorate poisoning have
been reported (NAS, 1987). Symptoms include methaemoglobinaemia, anuria,
abdominal pain and renal failure. For an adult human, the oral lethal dose is estimated
to be as low as 20 g of sodium chlorate (230 mg of chlorate per kg of body weight)
(NAS, 1980).

Ten male volunteers were given six separate doses of sodium chlorate following a
rising-dose protocol, single doses of 0.01, 0.1, 0.5, 1.0, 1.8 and 2.4 mg of chlorate ion
per litre in 1 litre of drinking-water being ingested by each volunteer. Very slight
changes in group mean serum bilirubin, iron and methaemoglobin were observed, but
the authors concluded that they were not adverse physiological effects. The highest
dose tested, 2.4 mg/litre (34 µg/kg of body weight per day), can be identified as a
single-dose NOAEL (Lubbers et al., 1981).

The volunteers also ingested 0.5 litres of water per day containing 5 mg of sodium
chlorate per litre (36 µg/kg of body weight per day) for approximately 12 weeks and
were then kept under observation for 8 weeks. Treatment was associated with slight
changes in group mean serum urea nitrogen and mean corpuscular haemoglobin, but
the authors concluded that these were not physiologically significant, as values
remained within the normal range for each parameter. The NOAEL was 36 µg/kg of
body weight per day (Lubbers et al., 1981).

6. PRACTICAL ASPECTS
6.1 Analytical methods and analytical achievability
Methods are available for the determination of chlorine dioxide, chlorite and chlorate
and total available chlorine (APHA et al., 1995a,b). The limits of detection for these
methods are 8 µg/litre for chlorine dioxide, 10 µg/litre for chlorite and chlorate and 4
µg/litre for total chlorine.

6.2 Treatment and control methods and treatment achievability
Where chlorite formation is a concern, the control of treatment processes to reduce
disinfectant demand and the control of disinfection processes to reduce chlorine
dioxide levels are recommended (US EPA, 2003). If chlorine dioxide and chlorite ion
are not removed prior to post-chlorine disinfection, they will react with free chlorine
to form chlorate ion. Once chlorate ion is present in water, it is very persistent and
very difficult to remove (Gallagher et al., 1994; US EPA, 1999).
There are four available treatment options for lowering chlorite ion concentrations in
drinking-water at the municipal scale: activated carbon, sulfur reducing agents, iron
reducing agents, and tuning of the chlorine dioxide generator.
Activated carbon will remove chlorite ion through adsorption and chemical reduction.
Early break-through has been reported in granular activated carbon (GAC) filters
when the adsorptive sites have been exhausted, perhaps by competing organic
compounds, and only the reduction mechanism remains. The performance of GAC
filters for chlorite removal is further complicated by the oxidation of chlorite to
chlorate, which may occur if free chlorine is present in the feed water. Short bed life,
high operating costs, and the potential for chlorate formation make GAC an
impractical choice for chlorite removal at the municipal scale (Dixon & Lee, 1991).
Sulfur agents such as sulfite, metabisulfite, and thiosulfate will reduce chlorine
dioxide and chlorite ion, thereby lowering their concentrations in water. In the
presence of dissolved oxygen, sulfite and metabisulfite will reduce chlorite to form
chloride ion and the undesirable chlorate ion and, as such, is not recommended for the
removal of chlorite in drinking water. Thiosulfate is effective at reducing chlorine
dioxide and chlorite and does not form chlorate as a by-product, but it requires a long
contact time and is pH dependent, which may limit its effectiveness (Griese et al.,
1991).

Ferrous iron (Fe2+) will chemically reduce chlorite ion, thereby lowering its
concentrations in water. Chlorate ion will form only if the pH drops below 5, which
can occur at localized application points where acidic reducing agents such as ferrous
chloride are added to the water. Good application and rapid mix and/or pH adjustment
to neutral pH 7 may prevent the occurrence of micro-regions of low pH and the
subsequent formation of chlorate (Griese et al., 1992). When the pH exceeds 7, the
subsequent reaction of chlorite and ferrous iron forms insoluble ferric hydroxide,
which may be beneficial by aiding clarification (Iatrou & Knocke, 1992). However, if
the pH exceeds 9, elevated dissolved oxygen and dissolved organic carbon levels
impede the effectiveness of ferrous iron and require increased ferrous dosages to
attain adequate chlorite removal (Hurst & Knocke, 1997). Any residual chlorite will
react with chlorine to form chlorate and should be removed before post-chlorine
disinfectant is applied. Ferrous iron or thiosulfate, when used as treatment options for
chlorite removal, may be fed in excess of the demand and can complicate postdisinfection
(US EPA, 2001).

Chlorine dioxide generator design and performance have a large impact on the
amount of chlorite ion formed during chlorine dioxide production. Precise operation
(“tuning”), proper maintenance, and the generation technology employed with the
chlorine dioxide generator have a large bearing on the chlorine dioxide production
efficiency and the rate at which chlorite and other undesirable by-products such as
chlorate, hydrogen peroxide, and perchlorate are formed. Current commercial chlorine
dioxide generators may be broadly classified as chlorite based, chlorate based, or
electrochemical systems.

Chlorite ion-based systems rely on the oxidation of chlorite ion to chlorite through the
use of an acid, which may attain a maximum conversion efficiency of 80% by
stoichiometry; or through the use of chlorine gas, which can result in chlorite carrythrough
if the chlorine gas feed is too low and chlorate formation if the chlorine gas
feed is too high.

Recently developed chlorate ion-based systems typically depend on the reduction of
chlorate ion through the reaction of sodium chlorate with an acid and hydrogen
peroxide. The product may be quite acidic, and the risk of high hydrogen peroxide
and perchlorate levels in the water may detract from the viability of this method.
Electrochemical systems can either directly or indirectly generate chlorine dioxide.
The direct method involves the electrolysis of chlorite ion to chlorine dioxide at the
anode, and the indirect method is the production of an acid or chlorine gas as a
precursor chemical, resulting in the formation of chlorine dioxide, again at the anode.
When the chlorine dioxide is formed at the anode, it must be extracted as a gas from
the solution by gas-stripping columns, eductors/venturis, low-pressure air flow over a
packed bed, or perstraction, which involves the use of a gas-permeable hydrophobic
membrane. Proper balance and control are required with these systems to prevent the
formation and carry-through of impurities such as acid, chlorate ion, perchlorate ion,
and chlorine (Gordon, 2001).

Currently, there is no known treatment available to remove chlorate ion once it has
been formed in drinking-water. As much as 35% of the chlorate concentration found
in a distribution system can be attributed to the type and performance (tuning) of the
chlorine dioxide generator. If chlorite ion is present in water and is not removed, it
will react with any applied free chlorine to produce chlorate and chloride ions. In
order to control persistent disinfection by-product formation, it is important to
minimize production of chlorate ion in the chlorine dioxide generation process and to
remove the chlorite ion before adding post-chlorine (Gallagher et al., 1994).
7. PROVISIONAL GUIDELINE VALUES
7.1 Chlorine dioxide
Chlorine dioxide has been shown to impair neurobehavioural and neurological
development in rats exposed perinatally. Experimental studies with rats and monkeys
exposed to chlorine dioxide in drinking-water have shown some evidence of thyroid
toxicity; however, because of the studies’ limitations, it is difficult to drawn firm
conclusions.
A guideline value has not been established for chlorine dioxide because of its rapid
hydrolysis to chlorite and because the chlorite provisional guideline value (see below)
is adequately protective for potential toxicity from chlorine dioxide. The taste and
odour threshold for this compound is 0.4 mg/litre.
7.2 Chlorite
IARC (1991) has concluded that chlorite is not classifiable as to its carcinogenicity to
humans (Group 3).
The primary and most consistent finding arising from exposure to chlorite is oxidative
stress resulting in changes in the red blood cells (Heffernan et al., 1979; Harrington et
al., 1995a). This end-point is seen in laboratory animals and, by analogy with
chlorate, in humans exposed to high doses in poisoning incidents. There are sufficient
data available to estimate a TDI for humans exposed to chlorite, including chronic
toxicity studies and a two-generation reproductive toxicity study. Studies in human
volunteers for up to 12 weeks did not identify any effect on blood parameters at the
highest dose tested, 36 µg/kg of body weight per day (Lubbers et al., 1981). Because
this study did not identify an effect level, it is not informative for establishing a
margin of safety.
In a two-generation study in rats, a NOAEL of 2.9 mg/kg of body weight per day was
identified based on lower startle amplitude, decreased absolute brain weight in the F1
and F2 generations and altered liver weights in two generations (CMA, 1997; TERA,
1998). Application of an uncertainty factor of 100 to this NOAEL (10 each for inter-
and intraspecies variation) gives a TDI of 30 µg/kg of body weight. This TDI is
supported by human volunteer studies.
Using the TDI of 30 µg/kg of body weight, a typical human body weight of 60 kg, the
assumption that drinking-water contributes 80% of the total exposure and a typical
consumption of 2 litres of water per day, the provisional guideline value is calculated
as 0.7 mg/litre (rounded figure). This guideline value is designated as provisional
because use of chlorine dioxide as a disinfectant may result in the chlorite guideline
value being exceeded, and difficulties in meeting the guideline value must never be a
reason for compromising adequate disinfection.
7.3 Chlorate
Like chlorite, the primary concern with chlorate is oxidative damage to red blood
cells. Also like chlorite, 36 µg of chlorate per kg of body weight per day for 12 weeks
did not result in any adverse effects in human volunteers (Lubbers et al., 1981).
Although the database for chlorate is less extensive than that for chlorite, a recent well
conducted 90-day study in rats is available, which identified a NOAEL of 30 mg/kg
of body weight per day based on thyroid gland colloid depletion at the next higher
dose of 100 mg/kg of body weight per day (McCauley et al., 1995). Application of an
uncertainty factor of 1000 to this NOAEL (10 each for inter- and intraspecies
variation and 10 for the short duration of the study) gives a TDI of 30 µg/kg of body
weight. This TDI is also supported by the human volunteer studies.
Using the TDI of 30 µg/kg of body weight, a typical human body weight of 60 kg, the
assumption that drinking-water contributes 80% of the total exposure and a typical
consumption of 2 litres of water per day, the provisional guideline value is calculated
as 0.7 mg/litre (rounded figure). This guideline value is designated as provisional
because use of chlorine dioxide as a disinfectant may result in the chlorate guideline
value being exceeded, and difficulties in meeting the guideline value must never be a
reason for compromising adequate disinfection.
A long-term study is currently in progress that should provide more information on
the effects of chronic exposure to chlorate.
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