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EC number: 232-088-3
CAS number: 7785-84-4
A weight-of-the-evidence approach is applied to support the lack of carcinogenicity of STMP. Inorganic phosphates are not mutagenic or genotoxic and carcinogenicity studies have not found an association of inorganic phosphate administration in the diet with increased tumor incidence of any kind. Taken together collectively, a rationale can be made that STMP is not likely to be carcinogenic using a weight-of evidence approach. Four studies are available to assess the carcinogenicity of trisodium trimetaphosphate and related substances. The test material is not considered to be carcinogenic and therefore further in vivo studies are not deemed to be necessary. Carcinogenicity is not a required endpoint for REACH.
Conversion from % in diet to
mg/kg bw was calculated in accordance with Appendix F of
the guidelines for the preparation of toxicological
working papers for the joint FAO/WHO expert committee on
food additives, December 2000.
carcinogenicity studies of Hodge (1960) and Kitahori (1998) present
reliable evidence that the substance should not be classified for
carcinogenicity according to Regulation (EC) No 1272/2008 on
Classification, Labelling and Packaging (CLP) of substances. Read across
data for similar (poly)phosphates are
to support this conclusion.
The Hodge Report
on STMP partially meets the requirements of the OECD 453 Guideline. The
Hodge Report documents all procedures and parameters conducted. Since it
was conducted prior to formal international guidelines, it did not have
some of the specific requirements included in the OECD 453 guideline for
chronic toxicity/carcinogenicity. Nevertheless, the study was well
documented and scientifically acceptable. Restrictions exist due to lack
of some information and due to a high rate of deaths due to infections
and other causes. Specific areas of deficiency are discussed below.
Characterization: There was no
analysis of the test material for purity and verification of test
material. Specific lot numbers are included, indicating verification of
test material and its origin. The results are consistent with other
studies on STMP. Effects on toxicity parameters are consistent with
those expected for the test article and do not indicate the presence of
a toxic impurity. No unexpected toxicity was found which would suggest
that the test material contained a toxic impurity.
Consumption: Food consumption was
evaluated in control and high-dose animals only at one and four months
only. Body weight was measured for the full 24 months; therefore, it is
possible to conclude that the animals were growing and to evaluate the
effects of the treated diets on growth. Lack of food consumption data
after 4 months is not considered a critical deficiency since body weight
data support the normal growth of the animals and the growth retardation
at the highest dose tested.
tests were conducted for all haematological parameters, except mean
corpuscular volume, mean corpuscular haemoglobin and haemoglobin
concentration, prothrombin time and activated partial thromboplastin
time. Though the study is not robust in this respect, there were
findings of lowered red blood cell counts and haematocrit percentages in
the high-dose female rats (only). All other haematological values in the
treated groups were within the normal range. These data support the
sensitivity of the methods employed to detect haematological findings.
Additional support can be gleaned from other subchronic and chronic
studies for haematological evaluations on STMP and other inorganic
Urinalysis was evaluated approximately every four months, corresponding
to intervals as per specified in the OECD guideline with some variation.
No effects were noted for urinalysis parameters during the study and
this endpoint was adequately addressed in the study for the parameters
measured. The number of animals sampled is not stated. Appearance,
volume, osmolality, specific gravity, pH, and blood were not evaluated.
Chemistry: No clinical chemistry
parameters were evaluated. The clinical chemistry parameters often
detect renal and hepatic toxicity; both organs were essentially normal
in this study. This deficiency could possibly be corrected from studies
on other inorganic phosphates or STMP.
Organ Weights: Organ
weights on ovaries, uterus, epididymides, thyroid and adrenals were not
included as per the current guideline. Adequate numbers of survivors
were evaluated except for the high-dose female group (6 instead of 10
rats). There were no effects on any of the measured organ weights except
for lower liver weights in high-dose males and females. Because the
liver weight: body weight ratios were normal, it was concluded that STMP
did not cause any specific toxic effect on the liver organ weights.
Although ovary weights were not evaluated, histopathology was conducted
on female gonads and no adverse findings were noted. This deficiency is
not considered to be a major one.
study did not evaluate every tissue required under the current guideline
(list in Footnote A of Table 1 in attached document). The lack of data
on the missing tissues constitutes a data gap for STMP. In addition,
tumour incidence data seem to indicate fewer tumours than expected in
normal, untreated rats of the same age. Nevertheless, there were no
obvious increases in tumour incidence across treatment groups with
generally adequate survival (>25%). No specific target organ effects
were identified, including the typical kidney lesions often noted in
rats fed diets high in phosphates. The pathologist specifically looked
for “chronic tubular nephropathy”, but did not find any lesions in the
high dose animals and found only one male in the mid-dose group with
this lesion. Changes to the kidneys were attributed to infection with a
nematode. Nevertheless, a weight-of-the-evidence approach can be used to
support the lack of carcinogenicity of STMP with data from other
inorganic phosphates. Some tissues may not have been evaluated, and lack
of data on these tissues constitutes a data gap for STMP. This
deficiency could possibly be corrected with data from studies on other
inorganic phosphates or STMP.
primary causes of death appeared to be due to respiratory infections and
“other causes”. A thermostat failure during April, 1958 or approximately
13 months into the study caused an increase in the deaths due to “other
causes”; however, the majority of these deaths are not explained. OECD
Guideline 453 requires that a valid test must have no less than 25%
survival in each group after 24 months in rats and no more than 10% of
any group should be lost to autolysis, cannibalism or management
problems, including infections. Table 2 in the attached report
summarizes the survival and causes of death in the Hodge chronic
numbers animals in each group died due to respiratory infections and
“other causes”, the overall survival exceeded 25% for all groups except
the high-dose females (24%); however, the percentages of deaths due to
infections and other causes exceed the criteria. The histopathological
findings were typical of aged rats. There were very few deaths due to
tumours (2-6%) and no obvious relationship of these deaths to treatment.
There did not appear to be an increase in tumours in the animals which
survived to the end of the study. Deaths were primarily due to
respiratory infections and pericarditis-peritonitis (See Table 2 in
The incidence of
tumours at study termination for all animals is shown in Table 3 below.
Not all tumours were considered the cause of death; thus, the numbers of
tumours at termination (Table 2) do not match the number of tumours
evaluated for the study (Table 3 in the attached report). A
weight-of-the-evidence approach will be necessary to review the
carcinogenicity studies of other inorganic phosphates to further support
the lack of carcinogenicity of STMP. Inorganic phosphates are not
mutagenic or genotoxic and carcinogenicity studies have not found an
association of inorganic phosphate administration in the diet with
increased tumour incidence of any kind. Taken together collectively, a
rationale can be made that STMP is not likely to be carcinogenic using a
weight-of evidence approach. The data in this study can be considered
supportive, but not definitive for the carcinogenicity endpoint.
Justification for selection of carcinogenicity via oral route
The dataset has been reviewed by an external assessor (M Weiner,
TOXpertise, LLC) and it is concluded that the data is adequate and
reliable for use as a key study under REACH. Please see expert report
attached in endpoint under 'background information'. The endpoint
selected is taken from a weight of evidence approach based on similar
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