FAO Nutrition Meetings 
    Report Series No. 48A 
    WHO/FOOD ADD/70.39


    The content of this document is the 
    result of the deliberations of the Joint 
    FAO/WHO Expert Committee on Food Additives 
    which met in Geneva, 24 June  -2 July 19701

    Food and Agriculture Organization of the United Nations
    World Health Organization


    1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
    Org. techn. Rep. Ser., in press.


          This monograph contains a re-evaluation of the data on phosphoric
    acid and phosphates. It includes the substances listed below for which
    specifications for identity and purity have been issued as indicated:

                Phosphoric acidi1)
                Monosodium monophosphate2)
                Disodium monophosphate2)
                Trisodium monophosphate2)
                Monopotassium monophosphate2)
                Dipotassium monophosphate2
                Tripotassium monophosphate2)
                Monocalcimn monophosphate3)
                Dicalcium monophosphate4)
                Tricalcium monophosphate4)
                Monomagnesium monophosphate4)
                Dimagnesium monophosphate4)
                Trimagnesium monophosphate4)
                Disodium diphosphate2
                Tetrasodium diphosphate2)
                Pentasodium triphosphate2)
                Sodium polyphosphate2)


    1)Specifications for Identity and Purity of Food Additives, Vol. 1,
    Rome FAO, 1962

    2)FAO Nutrition Meetings Report Series, No. 35; Wld Hlth Org.
    techn. Rep. Ser., 1964, 281

    3)FAO Nutrition Meetings Report Series, No. 40; Wld Hlth Org.
    techn. Rep.Ser., 1966, 339

    4)FAO Nutrition Meetings Report Serin, No. 46B; WHO/Food Add./70.37


    Biological Data

    Biochemical aspects

          Phosphoric acid is an essential constituent of the human
    organism, not only in the bones and teeth, but also in many enzyme
    systems. Phosphorus plays an important role in carbohydrate, fat and
    protein metabolism. The level of inorganic phosphate in the blood is
    stabilized by exchange with the mineral depot in the skeleton through
    the action of parathyroid hormone. This hormone inhibits tubular
    reabsorption of phosphates by the kidney and brings about
    demineralization of bone tissue through the action of osteoclasts. The
    amount of parathyroid hormone that enters the circulation is probably
    regulated by the calcium level of the blood. Intestinal absorption
    depends on requirements and is therefore limited. Excretion takes
    place mainly in the faeces as calcium phosphate so that the continuous
    use of excessive amounts of sodium phosphate and phosphoric acid may
    cause a loss of calcium. As a result of physiological regulating
    mechanisms, man and animals can tolerate large variations in phosphate
    intake without the balance being upset.

          Some investigators have considered that the formation in the
    intestinal tract of insoluble salts of phosphate with calcium iron and
    other metal ions might result in decreased absorption of such
    minerals. From studies dealing with this aspect (Lang, 1959; van Esch
    et al., 1957; Lauersen, 1953; van Genderen, 1961) it is concluded that
    moderate dose levels of phosphates do not impair absorption as shown
    by results from carcass analyses or haemoglobin determinations. Doses
    of 2 to 4 g of phosphate act as weak saline cathartics.

          Phosphate supplementation of the diet of rodents has been shown
    to lead to reduction in the incidence of dental caries and different
    phosphates have different powers in reducing the cariogenic potential
    of the carbohydrates in a diet. Phosphate supplements seem to exert
    their cariostatic effect on the tooth surface either directly during
    eating or by excretion in the saliva (Anon, 1968a; Anon, 1968b).

          Little specific toxicological information on potassium
    monophosphates is available. There is no reason to consider that the
    potassium salts, in the amounts that could be used as feed additives,
    behave differently from the sodium salts and are therefore dealt with

    Acute toxicity


    Compound         Animal        Route        Minimum lethal dose     Reference
                                                mg/kg body-weight

    NaH2PO4          guinea-pig    oral         >2000                   Eichler, 1950

    Na2HPO4          rabbit        i.v.         985 - 1075              Eichler, 1950
    Short-term studies

          Rat. There are many reports of short-term studies to determine
    the effects of the addition of monophosphates to the diet of rats
    (House and Hogan, 1955; Maynard et al., 1957; Selye and Bois, 1956;
    MacKay and Oliver, 1935; Behrens and Seelkopf, 1932; McFarlane, 1941;
    van Esch et al., 1957; Sanderson, 1959). Pathological effects in the
    parathyroids, kidneys and bones have been observed in mature male rats
    fed a diet containing an excessively high level 8% of sodium
    orthophosphate for seven months or until the animal succumbed (Saxton
    and Ellis, 1941). Histological and histochemical changes in the
    kidneys have been found in rats fed for 24 to 72 hours on a diet
    containing an excess of inorganic phosphate (10% disodium acid
    phosphate) (Craig, 1957).

          Three groups of 12 rats each were fed diets containing added
    dibasic potassium phosphate so that the calcium and phosphorus
    concentrations in the experimental diets were as follows:


    Diet                          Calcium %         Phosphorus %


    Control                       0.56              0.42
    "normal orthophosphate"       0.47              0.43
    "high orthophosphate"         0.50              1.30

          The experiment was conducted in three stages, with experimental
    observations made when animals had consumed the test diets for 50, 60
    and 150 days. No adverse physiological effects were observed
    clinically at autopsy or on histological examination. All the data
    obtained from this study indicated that there was probably adequate
    absorption and utilization of calcium, phosphorus and iron with both
    high and normal levels of monophosphate (Dymsza et al., 1959).

          Reports of short-term studies do not provide for a
    differentiation between the action of the mono-, di- and trisodium or
    potassium salts; several authors have used "neutral mixtures" e.g. of
    mono- and disodium monophosphates. There is no reason to expect a
    specific action on the part of one of these three monophosphates, the
    relevant factor being the phosphate content and the acidity of the
    food mixture as a whole. On high-dose levels, hypertrophy of the
    parathyroid glands has been observed. A more important and more
    sensitive criterion for the deleterious action of phosphate overdosage
    is the appearance of metastatic calcification in soft tissues,
    especially in the kidney, stomach and aorta. Kidney calcification may
    be observed in a few weeks or months, depending on the dose level. The
    pathology of calcification and necrosis of the tubular epithelium in
    the kidneys (nephrocalcinosis) has been studied in detail (MacKay and
    Oliver, 1935; McFarlane, 1941; Sanderson, 1959; Fourman, 1959).

          It is difficult to indicate a border line between those levels
    that do not produce nephrocalcinosis and those that produce early
    signs of such changes, because; (1) even on diets to which no
    phosphate has been added, rats, in apparently healthy condition, may
    have a few isolated areas of renal calcification; (2) the composition
    of the diet (amount of calcium, acid-base balance, vitamin D) has an
    important influence on the appearance of renal calcification.

          There are numerous reports of experimental phosphate-containing
    diets that do not produce kidney damage by excessive calcification,
    e.g. the Sherman diet (0.47 - 0.51%P) (Lang, 1959; Hahn and Seifen,
    1959; van Esch et al, 1957), the diet used by MacKay and Oliver (1935)
    (0.62%P) and the commercial "Purina A" diet (0.90% P) (Lang, 1959).

          Early calcification has been observed in rats on a Sherman diet
    to which 1% of a 2 : 3 mixture of NaH2PO4 and Na2PHO4 was added,
    bringing the P-content to 0.71% (van Esch et al., 1957). Similar
    effects were observed with the addition of a phosphate mixture
    resulting in a P-content of 0.89% (Hahn and Seifen, 1959), and with
    levels of phosphate in the diet corresponding to a P-content varying
    from 1.25% to 2.85% (Lang, 1959; MacKay and Oliver (1935); Eichler,
    1950; McFarlane, 1941; van Esch et al., 1957; Haldi et al., 1939).

          In recent experiments (Dymsza et al., 1959), however, a diet to
    which K2HPO4 had been added and containing 1.3% P and 0.5% Ca did
    not produce nephrocalcinosis in a group of 12 mice within a period of
    130 days, although the weight of the kidneys was increased. Also food
    and protein efficiency was diminished as compared with animals on the
    control diet. These effects may have resulted from the large amount of
    salts added to the diet in these experiments.

          Guinea pig. Diets containing 0.9% P and 0.8% Ca or higher
    levels of phosphate produced calcification in the soft tissues (House
    and Hogan, 1955; Hogan et al., 1950).

          Man. Studies on 15 students, who drank 2000-4000 mg of
    phosphoric acid in fruit juices every day far 10 days, and on two
    males who received 3900 mg of phosphoric acid every day for 14 days,
    revealed no observable change in urine composition indicative of a
    disturbed metabolism (Lauersen, 1953). The long-continued daily intake
    of 5-7000 mg of NaH2PO4 (corresponding to 1000-1500 mg of P) did not
    produce adverse effects (Lang, 1959). Similarly a daily intake of 6000
    mg of NaH2PO4 2H2O as tolerated without difficulty (Lauersen, 1953).

    Long-term studies

          Rat.  Three successive, generations of rats were fed diets
    containing 0.4% and 0.75% of phosphoric acid for 90 weeks. No harmful
    effects on growth or reproduction could be observed. No significant
    differences were noted in the blood picture in comparison with control
    rats and there was no other pathological finding which was
    attributable to the diets. There was no acidosis, nor any change in
    the calcium metabolism. The dental attrition was somewhat more marked
    than that in the control rats (Lang, 1959). No other long-term studies
    on monophosphates have been found in the literature.


    Biological data

    Biochemical aspects

          In the animal body diphosphate is formed from adenosyl
    triphosphate (ATP) in many enzymatic reactions. It is either utilized
    by entering phosphorolytic reactions, or it is hydrolyzed by an
    inorganic diphosphatase to monophosphate (Long, 1961). Ingested
    diphosphate is readily converted to monophosphate (Fourman, 1959;
    Mattenheimer, 1958); no diphosphate was found in faeces or urine of
    rats treated with diets containing up to 5% tetrasodium diphosphate.
    In these experiments diphosphate was almost completely absorbed by the
    gut and excreted as monophosphate in the urine.

    Acute toxicity


    Animal    Route       Minimum lethal dose     Reference
                          (mg/kg body weight)

    Rabbit    i.v.        approx. 50              Behrens and Seelkopf, 

    Rat       oral        LD50 >4000              Datta et al., 1962

    Short-term studies

          Rat. In a series of successive experiments (Hahn and Seifen,
    1959; Hahn et al., 1958), Na4P2O7 was added in concentrations of
    1.8%, 3% and 5% to a modified Sherman diet and fed to groups of 34-36
    young rats for 6 months. The studies also included control groups and
    groups receiving the same levels of sodium monophosphate. With 3% and
    5% diphosphate diets growth was significantly decreased and at both
    these concentrations nephrocalcinosis appeared as the main toxic
    effect. The degree of damage to the kidneys was about the same as that
    observed in the corresponding monophosphate groups.

          With the 1.8% diphosphate and monophosphate diets, normal growth
    occurred but a slight yet statistically significant increase in kidney
    weight was noted. Microscopic examination revealed kidney
    calcification in some of the animals, both in the diphosphate and
    monophosphate groups. This was more extensive than the calcification
    occasionally found in the control animals. In an additional
    experiment, 1.1% of diphosphate and of monophosphate were used (Hahn,
    1961). There was a slight growth retardation in the first part of the
    experiment. After 39 weeks a slight degree of kidney calcification was
    noted and this was the same for both phosphates (Hahn, 1961).

          In a recent series of experiments (Datta et al., 1962), Sherman
    diets containing 1%, 2.5% and 5% Na4P2O7 were fed for 16 weeks to
    groups of 20 male and female rats weighing between 90 and 115 g; a
    similar group received a diet containing 5% monophosphate. In the
    sodium phosphate groups, growth was normal up to the 2.5% level;
    kidney weight was increased at the 2.5% level (females) and above;
    kidney function was (concentration test) decreased at the 2.5% level
    (males) and above. Kidney damage (calcification, degeneration and
    necrosis) was observed in a greater percentage of rats in the 1% group
    than in the controls. At the higher concentration of sodium
    diphosphate more severe kidney damage occurred and, in addition, some
    of the animals had hypertrophy and haemorrhages of the stomach. The
    latter abnormality was not found in rats in the 5% monophosphate

    Long-term studies

          Rat. No specific studies with diphosphates have been made, but
    in one series of experiments a mixed preparation was used which
    consisted of 2/3 Na2H2P2O7 and 1/3 Kurrol's salt (KPO3)n.
    H2O with n = 400-5000. Concentrations of 0.5%, 1% and 5% were added
    to a Sherman diet and given to groups of 10 male and 10 female rats.
    From these animals a second and third generation were produced, during
    which the treatment with phosphates was continued. Growth and
    fertility and average life-span were normal and the life-span was not
    significantly reduced up to the 2.5% level. Nephrocalcinosis occurred
    at the 1% level and above. At 0.5% no abnormalities were observed that
    were not also present in control animals. At none of the
    concentrations did tumours appear with higher frequency than in the
    controls (van Esch et al., 1957).

    Sodium polyphosphate)

    Biological Data

    Biochemical aspects

          Several studies indicate that polyphosphates can be hydrolyzed 
    in vivo by enzymes with the formation of monophosphates. The
    localisation of different polyphosphates in the nuclei of animal cells
    has been demonstrated (Grossmann and Lang, 1962). Injected
    hexameteaphosphate is more slowly degraded than tripolyphosphate
    (Gosselin et al., 1952), and the highly polymerized Tammann's salt
    (KNa polyphosphate) is even more slowly eliminated from the blood
    after i.v. injection than is Graham's salt (Gotte, 1953). When
    administered parenterally a small part of these products may escape in
    the urine as oligophosphates (Gosselin et al., 1952; Gotte, 1953). The
    higher polyphosphates are probably not absorbed as such in the
    intestinal tract. After hydrolysis into smaller units absorption takes
    place. The larger the molecule, the less the speed of hydrolysis and
    absorption, as shown by studies using P32 labelled polyphosphate
    (Ebel 1958).

          After giving hexametaphosphate to rats and rabbits by stomach
    tube, no more than trace amounts of labile phosphate were found in the
    urine (Gosselin et al., 1952). The oral administration of
    radioactively-labelled Tammann's salt did not give rise to
    radioactivity in the blood (Gotte, 1953). With Graham's salt and
    Kurrol's salt, 10-30% was absorbed as monophosphate and small amounts
    of oligophosphates were found in the urine (Lang et al., 1955; Lang,
    1958). In experiments in rats with labelled tripolyphosphates and
    Graham's salt these polymers were not absorbed as such, but were taken
    up after hydrolysis into monophosphate and diphosphate. In a period of
    18 hours only 40% of the dose of Graham's salt was hydrolyzed and
    absorbed. The bacterial flora of the intestinal tract may contribute
    to the hydrolysis of the polyphosphates (Schreier and Noller, 1955).
    In other experiments, radioactively-labelled Kurrol's salt was given
    orally to rats. About half the radioactivity was recovered from the
    faeces, mainly as polymeric phosphate, and only a small percentage of
    the dose was found in the urine, in this case in the form of

          It is noted that, for practical reasons, in the studies cited
    high dosages were given to the animals. The efficiency of hydrolysis
    and absorption may be greater at lower dose levels, such as were used
    in the short-term and long-term feeding experiments quoted. In some of
    these (van Esch et al., 1957) the "Monophosphate action", as
    demonstrated by the production of nephrocalcinosis, was not much
    smaller than when the same dose level was administered by the addition
    of monophosphate to the food. In another study, this applied only to
    tripolyphosphate, while Graham's salt had definitely less effect on
    the kidney (Hahn et al., 1958).

          The possibility of the intermediate formation of small amounts of
    trimetaphosphate in the hydrolysis of polyphosphates has been
    considered (Mattenheimer, 1958). At present, the only known method of
    production of sodium polyphosphate is by the fusion process. In this
    process metaphosphates are also formed in amounts up to 8% and their
    presence is technically unavoidable. It is of interest to note that
    these metaphosphates (sodium trimetaphosphate and sodium
    tetrametaphosphate) have been tested in short-term experiments in rats
    and dogs in conjunction with polyphosphates (Hodge, 1956). The
    metaphosphates are also hydrolyzed to monophosphates. No specific
    action of these metaphosphates different from that of the other
    phosphates has been observed, and it is concluded that the presence of
    these impurities does not present a hazard. It is also noted that the
    preparation of sodium polyphosphates used in the toxicological studies
    mentioned always contained metaphosphates in amounts up to 8%.

          It has been considered by many authors that the ingestion of
    polyphosphate in the food may result in a loss of minerals (Ca, Fe,
    Cu, Mg) which are bound to the polyphosphate and are lost in the
    faeces with unhydrolyzed polyphosphate. For this reason, in most of
    the toxicological studies cited, particular attention has been paid to
    the mineral composition of the carcass and to the possible development
    of anaemia.

          The experimental results available indicate that such an action,
    if it occurs at all, is not significant. Anaemia is not a
    characteristic feature of treatment with high dose levels of
    polyphosphate, and hexametaphosphate had no effect on iron utilization
    by rats (Chapman and Campbell, 1957).

          The use of polyphosphates for the prevention of scale formation
    in lead pipe water systems may lead to excessive lead levels in
    drinking water (Boydens 1957).

    Acute toxicity

                                                 LD50           Approx.LD100
    Animal    Sustance                 Route     (mg/kg body    (mg/kg body      Reference
                                                 weight)        weight)
    mouse     hexametaphosphate        oral                     > 100            Behrens and
              (neutralized Na salt)                                              Seelkopf,1932

    rabbit    "                        i.v.                     approx. 140      "

    rat       1/3 Kurrol's salt and    oral      4000                            van Esch et
              2/3 tetra- and           i.v.      18                              al. 1957
              disodium diphosphates                                                  "
              (water soluble,
    Short-term studies

    Rat. Groups of 5 male rats were fed for a period of one month on
    diets containing 0.2%, 2% and 10% sodium hexametaphosphate or 0.2%, 2%
    and 10% sodium tripolyphosphate. Control groups were given the
    standard diet, or diets with the addition of 10% sodium chloride or 5%
    disodium phosphate (Hodge, 1956).

          With 10% of either of the polyphosphate preparations and also
    with 10% sodium chloride in the diet, growth retardation occurred, but
    none of the rats died. Increased kidney weights and tubular necrosis
    were, however, observed. With 2% of polyphosphate in the diet, growth
    was normal, but in the kidneys inflammatory changes were found which
    were different from the tubular necrosis observed in the 10% groups.
    With 0.2% of polyphosphate in the diet, normal kidneys were seen. In
    another series of experiments (Hahn and Seifen, 1959; Hahn et al.,
    1958; Hahn et al, 1956), 3% and 5% of sodium tripolyphosphate (pH 9.5
    in 1% solution) and 1.8%, 3% and 5% of Graham's salt (pH 5) were added
    to a modified Sherman diet, which was then fed during 24 weeks to
    groups of 36 male and 36 female rats. Growth retardation was exhibited
    by the rats in the 5% polyphosphate groups. With 3% of either
    preparation, a temporary growth inhibition was observed, and with 1.8%
    of Graham's salt (male animals) growth was normal. Nephrocalcinosis
    was observed in the 3% and 5% groups. It was noted that the degree of
    damage with Graham's salt was less than that in control groups treated
    with the same concentrations of orthophosphate; with tripolyphosphate,
    however, kidney damage was practically identifical with that exhibited
    by the animals in the orthophosphate group. In the animals on a diet
    containing 1.8% Graham's salt, calcification in the kidneys was slight
    or absent and the kidney weights ware normal (Hahn and Seifen, 1959).

          In a further group of experiments (van Esch et al., 1957; van
    Genderen, 1958), Kurrol's salt was used in a commercial preparation
    consisting of 1/3 Kurrol's salt and 2/3 of a mixture of disodium and
    tetrasodium diphosphate (Na2H2P2O7 and Na4P2O7). Kurrol's salt
    is practically insoluble in water, but the mixture with diphosphate
    can be dissolved and a 1% solution had a pH of 7.6. Groups of 10 male
    and 10 female rats were fed for a period  of 12 weeks on a Sherman
    diet to which 0.5%, 1%, 2.5% and 5% of the preparation had been added.
    Normal growth was observed in the groups treated with the 0.5%, 1% and
    2.5% concentrations of the polyphosphate mixture, but in those
    receiving the 5% concentrations growth retardation was exhibited.
    Kidney weights were normal in the 0.5% group, slightly increased
    (males significantly) in the 1% group and further increased in the
    2.5% and 5% groups. The histopathological examination revealed that in
    the kidneys of the animals of the 5% group definite nephrocalcinosis
    had occurred, with extensive damage to the tubular tissue.
    Calcification was also observed in other tissues. In the 2.5% group a
    less extensive nephrocalcinosis was exhibited, and in the 5% group
    isolated areas of calcification with lymphocyte infiltrations were
    found. In the 0.5% group kidney structure was normal. The results
    obtained with this polyphosphate preparation were practically
    identical, qualitatively and quantitatively, with the results of a

    similar experiment made with a neutral mixture of NaH2PO4 and
    Na2HPO4 carried out at a later date in the same laboratory (Hahn et
    al., 1958; Gotte, 1953).

          In other experiments, groups of 12 male rats were treated with
    diets to which 0.9% and 3.5% sodium hexametaphosphate had been added
    (corresponding to 0.46% and 1.20%P). Other groups received the control
    diet alone (0.4% P and 0.5% Ca), or with addition of potassium
    monophosphate. To the experimental diets different amounts of salts
    were added to replace cornstarch in order to equalize the levels of
    major minerals; this resulted in a rather high salt concentration. The
    duration of treatment was up to 150 days. With 3.5% added
    hexametaphosphate growth and food and protein efficiency were poorest.
    The kidneys of the animals fed the high level of hexametaphosphate
    were significantly heavier than those of the control rats. This was
    perhaps a manifestation of the high salt load on the kidneys. No
    histopathological abnormalities were observed in kidney sections from
    animals taken from any of the groups (Dymsza et al., 1959).

          Dog. Sodium tripolyphosphate (Na5P3O10) and sodium
    hexametaphosphate were fed to one dog each in a dose of 0.1 g/kg per
    day for one month; two other dogs received daily doses which increased
    from 1.0 g/kg at the beginning to 4.0 g/kg at the end of a 5 month

          The dog treated with the starting dose of 10 g/kg/day of
    hexametaphosphate began to lose weight when the daily dose reached 2.5
    g/kg, while the one receiving gradually increasing doses of
    tripolyphosphate lost weight only when its diet contained 4.0
    g/kg/day. In other respects (urinalysis, haematology, organ weights)
    the animals were normal, with the exception of an enlarged heart, due
    to hypertrophy of the left ventricle, in the dog receiving gradually
    increasing doses of sodium tripolyphosphate. In addition, tubular
    damage to the kidneys was observed in both dogs on the higher dose
    regime. In the tissues of the dogs fed 0.1 g/kg/day no changes were
    found that could be attributed to the treatment (Hodge, 1956).

    Long-term studies

          Rat. To a Sherman diet containing 0.47% P a mixture of 1/3
    Kurrol's salt and 2/3 diphosphate was added in concentrations of 0.5%,
    1%, 2.5% and 5% and fed to groups of 30 male and 10 female rate from
    weaning to end of their life-span (van Esch et al., 1957). Two
    successive generations of offspring were produced on these diets.
    Significant growth inhibition was observed in the 5% groups of both
    first and second generations. In other groups growth was normal.
    Fertility was normal in the 0.5%, 1% and 2.5% groups, but much
    decreased in the 5% group. Haematology of the 0.5%, 1% and 2.5% groups
    showed a decreased number of erythrocytes in the 2.5% group, second
    generation only. In the 0.5% group no kidney damage attributable to
    the polyphosphate treatment was observed, but in the groups having
    higher intakes renal calcification occurred in a degree increasing
    with the dose level.

          In another series of feeding tests (Hodge, 1960a), diets
    containing 0.05%, 0.5% and 5% sodium tripolyphosphate were given for
    two years to groups of 50 male and 50 female weanling rats. Only when
    5% of polyphosphate was added to the diet was growth reduced; the
    reduction was significant in males but slight and delayed in females.
    A smaller number of rats survived in the 57 groups than in the other
    groups. A low grade of anaemia was sometimes observed in the 5% groups
    only. Increased kidney weights were noted in the 5% group;
    pathological changes which could be ascribed to treatment were not
    observed in the 0.5% and 0.05% groups. In the control group and the
    0.5% tripolyphosphate group, reproduction studies were carried out
    over three generations involving the production of 2 litters in each
    generation. Reproduction was normal and no changes in the offspring
    were observed.

          A long-term study (Hodge, 1960b) of the same design was made with
    sodium hexametaphosphate also at concentrations of 0.05%, 0.5% and 5%
    in the diet. Growth retardation occurred only in the 5% groups.
    Mortality was high in all groups but had no relation to the amount of
    hexametaphosphate in the diet. Periodic blood examination gave normal
    haematological values. Kidney weights were increased in the 5% group
    and calcification was present. Rats given the 0.5% diet did not have
    significant changes in the kidneys. Reproduction studies for three
    generations in the 0.5% group revealed normal performance in every


          The main conclusion from the data on mono- and diphosphates is
    that kidney damage is the most sensitive criterion of its toxic
    action. This damage is of the general type of nephrocalcinosis. From a
    consideration of the complete experimental evidence, it can be
    estimated that diets containing 1% P or more may be nephrocalcinogenic
    in rats. Phosphoric acid does not differ from any other acid used as
    food additive in carrying any special hazard regarding caries
    formation in teeth while its phosphate moiety contributes in a normal
    way to the total dietary phosphate load.

          At higher concentrations in the diet and in acute experiments, an
    additional toxic action of diphosphate has been noted which is
    probably mainly due to the hydrolysis and resulting acidification
    occurring in the intestinal tract. This effect, however, is not
    relevant to the evaluation of ADI's where the more sensitive criterion
    of kidney damage is used. Undesirable acute effects from the
    hydrolysis of diphosphate in the stomach are not likely to occur in
    the concentrations that are at present used in food products, since
    the resulting concentrations in the final product as consumed are much
    below the concentration that produced such effects in the animal
    experiments. Since the nephrotoxic action of diphosphate is no greater
    than that of monophosphate, there is no basis for any estimate of
    ADI's different from that for phosphoric acid or monophosphates.

          Polyphosphates are not absorbed as such to any significant
    extent, but only in the form of monophosphates to which they are
    broken down in the intestine. The biological effects of ingested
    polyphosphate are, therefore, determined by the amount of
    monophosphate formed and absorbed. Since the extent of hydrolysis of
    polyphosphates in the intestine is difficult to predict, the safest
    course is to assume conversion to monophosphate is  complete. Thus,
    for the purposes of toxicological evaluation, polyphosphates may be
    considered equivalent to monophosphates.

          Since nearly every food normally contains phosphates, it is
    impossible to indicate ADI's of these compounds as food additives
    without regard to the phosphate intake from food itself. For this
    reason, ADI's are given as total daily intakes both from food and from
    food additives. Excessively high phosphorus levels in the total diet,
    adverse alterations in the dietary numeral balance (i.e. Ca/P ratio),
    or an appreciable increase in the total mineral content of the diet as
    a whole should be avoided. There is ample evidence to support the
    safety of the addition of small quantities of phosphates to food.
    Recent investigations have shown that greater attention should be paid
    to the contribution to the daily phosphate load from drinking water as
    a result of the general rise in phosphate pollution of water


          It appears rational to treat ingested phosphates from all natural
    and food additive sources as a single entity. The dose levels
    producing nephrocalcinosis were not consistent among the various rat
    feeding studies.

          The lowest dose levels that produce nephrocalcinosis overlap the
    higher dose levels failing to do so. The usual calculation is probably
    not suitable for food additives that are also nutrients. The lowest
    level that produced nephrocalcinosis in the rat (1% P in the diet) is
    used as the basis for the evaluation and, by extrapolation based on
    the daily food intake of 2 800 calories, this gives a dose level of 6
    600 mg P per day as the best estimate of the lowest level that might
    conceivably cause nephrocalcinosis in man.

    Level causing no significant toxicological effect in the rat

    0.75% (= 7 500 ppm) in the diet equivalent to 375 mg/kg body weight of
    P per day.

    Estimate of acceptable total dietary Phosphorus intakes for man 
    (from phosphate additives and natural amounts in food)

                                              mg/kg body weight P

          Unconditional acceptance                   0-30
          Conditional acceptance*                   30-70

          Since acceptable levels of phosphate intake depend on the amount
    of calcium in the diet, no uniform unconditional or conditional zones
    of acceptance can be applied to countries having widely divergent
    levels of dietary calcium. The unconditional acceptance zone may be
    regarded as suitable for communities with a low calcium intake and the
    conditional acceptance zone for those with a high calcium intake in
    the normal diet.


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    See Also:
       Toxicological Abbreviations