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Carcinogenicity

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Description of key information

Two studies are available for this endpoint (both are scored reliability 2 according to the Klimisch scale.).
- Kitahori Y (1998) - Fischer (344/DuCrj) rats were fed diets which comprised 3% of the test material for a period of 108 weeks.
- Hodge HC (1960) - Albino Rochester rats were fed diets which comprised 5% of the test material for a period of 104 weeks . The study was comparable to OECD Guideline 453 (combined chronic toxicity/ carcinogenicity).
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.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
please see 'any other information on materials and methods'
GLP compliance:
no
Remarks:
study predates GLP
Species:
rat
Strain:
other: albino Rochester strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 21 days, post weaning.
- Weight at study initiation: 88-90 g for the males, 78-80 g for female rats.
- Housing: In groups of 5 the rats were housed in galvanized iron cages with wire screen doors. The bottom of the cage was a pan containing wood shavings.
- Diet (e.g. ad libitum): ad libitum, Purina Fox Chow Meal,
- Water (e.g. ad libitum): ad libitum, Rochester tap water.
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
no data


IN-LIFE DATES: From: 13/08/1957 To: 12/08/1959
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
Diet mixtures were prepared using a basal ration of Purina Fox Chow Meal into which the appropriate amounts of sodium hexametaphosphate were mixed by a mechanical mixer. At weekly intervals. Diets were stored during the week in galvanized iron pails with covers.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not applicable
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily, in feed - ad libitum
Post exposure period:
not applicable - animals sacrificed at end of study.
Remarks:
Doses / Concentrations:

Basis:
nominal in diet
0.0% (controls), 0.05%, 0.5%, 5.0%
No. of animals per sex per dose:
50/sex/dose
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale:

The acute oral toxicity of the test material was determined in a group of 81 female albino rats. The LD50 was estimated to be 2900 mg/kg ± 258 mg/kg.

In a pilot study of 1 month duration, groups of 5 male rats each were maintained on diets containing: 0.2%, 2.0% and 10%.
The 10% group showed showed growth retardation, the 2% group grew in the same manner as the controls. For unknown reasons the group given the 0.2% diet grew less well than the 2% group. None of the rats died during the 30 day study. A serial sacrifice program was instituted where rats from each group were terminated on the 3rd, 7th, 15th and 28th days. Increased kidney weights were observed in the 10% group. Normal kidney weights were recorded in the 2% group. Kidney injury characterized by tubular degeneration and necrosis ("phosphate nephritis") was seen in the sections taken from the rats maintained on the 10% diet. Some kidney damage was seen in the 2% group but none in the 0.2% group.



- Rationale for animal assignment (if not random):


- Rationale for selecting satellite groups:


- Post-exposure recovery period in satellite groups:


- Section schedule rationale (if not random):
Positive control:
no positive controls.
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first twelve weeks, biweekly thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption was evaluated after 90 and 210 days on study on 5/sex/group from the control and high dose groups daily for 3 consecutive days. Each animal was provided with a set amount of basal or treated diet for the daily recording of food consumption for the 90 day measurement. For the 210 day measurement, control animals were provided with the amount of diet consumed by the treated animal on the preceding day. Body weights were also monitored during this measurement period.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Pre-study and on days 23, 76, 94, 118, 153, 183, 247, 295, 379, 447, 546, 631, 713 and at termination (day 728) on all surviving rats.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 animals/ sex/ group
- Parameters examined: Haematocrit, haemoglobin concentration, erythrocyte count, erythrocyte characteristics, total and differential leukocyte count, plasma cell.
- Parameters not evaluated: platelet count, prothrombin time, activated partial thromboplastin time, mean corpuscular volume, mean corpuscular haemoglobin and haemoglobin concentration.

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: Pre-test and After 2, 5, 8, 11, 14, 17, 20 and 23 months on study.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: Protein % and Sugar %.


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table in attachments)
HISTOPATHOLOGY: Yes (see table in attachments)

At sacrifice samples of a number of tissues were removed and placed in fixative solution to prepare for examination. Staining was achieved with hematoxylin and eosin. The tissues sampled included the following: brain, heart, lung, spleen, liver, large and small intestine, adrenals, kidneys, urinary bladder, gonads, stomach, bone marrow and skeletal muscle.
Other examinations:
no data
Statistics:
no data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY
Mortality was due primarily to respiratory infections and other causes. Deaths related to tumours did not show a relationship to treatment. There was no increase in mortality with increasing dose of test material. There was a small decrease, probably insignificant, in the median survival time with increasing dose of the test material in the female rats.

BODY WEIGHT AND WEIGHT GAIN
Growth retardation was observed in rats of both sexes at the high dose (5.0% in the diet). Among males the growth retardation was considered detectable, but not marked. Among females the growth retardation was considered only slight. There were no effects on body weight in the medium and low dose groups.

FOOD CONSUMPTION AND COMPOUND INTAKE
90-day evaluation: male and female rats in the high dose group consumed more food per day than controls: 14.8-18.3 g/day for control males and 18.8-19.5 g/day for high dose males; 7.2-13.4 g/day for control females and 13.9-15.1 g/day for high dose females. Body weight gains at 90 days and 210 days were slightly higher among treated animals, compared to control animals, used for the food consumption evaluations. These data are consistent with a mild cathartic action of the test material.
210-day evaluation in a paired-feeding design: 18.1-19.6 g/day for control males and 18.8-19.9 g/day for high dose males; 12.5-13.6 g/day for control females and 13.4-17.5 g/day for high dose females. There is an indication of a slight excess of eating by the high dose animals. Thus, the food consumption measurements showed that the general body weight growth retardation in the high dose group of both sexes was related to some interference with absorption or assimilation of food, but not due to reduced food intake.

HAEMATOLOGY
Periodic haematology evaluations found that all values in the treated groups were within the normal ranges. There was no indication of any effect from the addition of the test material to the diet.

URINALYSIS
Only the usual trace values of protein and sugars were found in all dose groups and at all timepoints. There was no indication of a toxic effect of the test material in these data.

ORGAN WEIGHTS
Kidney weights were increased among the high dose group animals at study termination. There were no other effects on organ weights in the other organs examined in any dose group. The fresh kidney weights for the male rats were about 3.5g for the control group contrasted with 4.1, 4.3, and 4.2 g for the 0.05%, 0.5% and 5.0% groups, respectively. Thus, there seems to be a distinction between the control and all experimental groups.


GROSS PATHOLOGY
There was an increase in calcification in the tubules of the kidneys of male and female rats in the 5.0% dose group. The calcification is believed to be an intensification of severity of naturally occurring processes of infection and degeneration. Some of the rats given the 5.0% diet had normal kidneys. No other changes were attributed to the administration of the test material.
The conclusion that the calcifications were not simply or solely phosphate effects is shown by the fact that there were histologically normal kidneys in some of the rats given the 5.0% diet. It is considered likely that phosphates in quantity were a factor in the incidence rate of the calcifications is demonstrated by the fact that in the group of rats, 13 of 20 did exhibit calcification. With the exception of 1 female rat in the 0.5% group, these were the only rats that exhibited calcification.
None of the rats in any of the control groups exhibited any calcifications.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
The incidence of tumours among survivors at terminal sacrifice did not show any significant increase in any particular tumour type related to treatment.

BONE ANALYSES:
Analyses of bones of the bones from all the rats showed normal compositions. Bone ash analyses on femurs of the rats given the 5% diet gave normal calcium phosphorus values.
Dose descriptor:
NOAEL
Effect level:
ca. 250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects Growth, mortality, food consumption, urine analyses, haematology, organ weights, bone analyses, gross and histo- pathology
Remarks on result:
other: NOEL based on toxicity effect

see the attached file for tabulated data.

Conclusions:
The test material showed no toxicity when administered in the diet of rats at a level of 5000 ppm for two years. The no-observed effect level for chronic toxicity in this study is 5000 ppm in the diet. At the high dose (50,000 ppm) there were effects on body weight gain and kidney weights. Histopathological evaluation indicated a treatment-related increase in calcification of the kidneys. There was no apparent increase in tumour incidence to suggest a carcinogenic effect, though the number of survivors at termination was generally low due to infections or other causes in all dose groups.

Additional information

Hodge data

The Hodge study (1960) was conducted prior to the institution of good laboratory practice guidelines and to the current OECD Guideline 453. Therefore, the study has deficiencies when examined according to today’s standards. The study is considered a Klimisch Code 2, reliable with restrictions. The conclusions for sodium hexametaphosphate (SHMP) are shared structurally similar phosphate salts: sodium tripolyphosphate (STPP) and sodium trimetaphosphate (STMP). All three inorganic phosphate salts exhibited a lack of carcinogenicity when tested in two year chronic toxicity/ carcinogenicity studies.

In the Manual for Investigation of HPV Chemicals, Chapter 3: Data Evaluation (2005), Section 3.1.6 Weight-of-the-Evidence Analysis, requires the use of a weight-of-the-evidence analysis during the assessment of data quality and adequacy.  The guidance permits the pooling of several studies, one or more of which may be inadequate, to satisfy a specific SIDS element. In the current case, available data exist on two other sodium inorganic phosphate salts which are similar in structure to sodium metaphosphate. In chronic toxicity/carcinogenicity study on SHMP, STPP and STMP no treatment-related increase in tumour incidence was observed at any dose in rats administered the salt at doses of 0.05, 0.5 and 5.0% (or 0.1, 1.0 and 10.0% for STMP) in the diet for 24 months (The IUCLID Robust Study Summary are included as supplemental information).

Taken together, all three chronic toxicity/carcinogenicity studies indicate a common toxicity profile for all three salts: (1) no treatment-related increase in tumour incidence at the highest dose or any dose tested; (2) no increased mortality due to treatment; (3) some growth retardation at the highest dose tested, occasionally at the mid-dose level; (4) only minor effects on some red cell haematological parameters and organ weights and (5) target organ generally identified as the kidney, though effects were not observed with STMP.

Kitahori data

The study was conducted according to the US NTP program and there was no data on whether the facility was GLP accredited, although it is likely. The test material was considered devoid of carcinogenic potential.

Justification for classification or non-classification

The chronic 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 also provided to support this conclusion.