Pentapotassium triphosphate

Endpoint summary

Description of key information

REPEATED DOSE TOXICITY: ORAL.
- Short term toxicity: 
Four studies are available for this endpoint. The two key studies (both Hodge 1956) tested the analogous substance pentasodium triphosphate on rats and dogs. The studies are comparable to modern day guidelines with acceptable deficiencies and were conducted before the implementation of GLP.
Two supporting studies are included, however they are not considered acceptable for assessment due to methodological inadequacies.
- Sub chronic toxicity:
One study is available, however, due to methodological inadequacies it is not considered to be acceptable for assessment. According to Annex IX, section 8.6.2, column 2 of Regulation No. 1907/2006, a subchronic (90 day) study does not need to be conducted as a reliable chronic toxicity study is available.
- Chronic toxicity:
A 2-year study on rats is available for the analogous substance STPP (Hodge 1959). The study is conducted before the implementation of GLP and is comparable to modern day guidelines with acceptable deficiencies (these are described in the toxicologists expert statement which is included in this endpoint record).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category

1. Both substances are inorganic salts of a monovalent cation from Group 1A of the periodic table, and triphosphoric acid. Thus, they share the Na+ or K+ cation and P3O105- anion.
2. Both the Na+ and the K+ cation have a similar biological function and therefore triphosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity.
3. In addition, both salts have been shown to be of similar low toxicity in acute oral studies and therefore comparisons can be drawn to allow read-across. Therefore it is not considered to be scientifically justified to perform any further in vivo studies.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline available

Principles of method if other than guideline:

One dog was fed a diet containing 0.1g/kg bw/day of the test material for a period of 28 days. A second dog received increasing doses from 1.0g up to 4.0 g/kg bw/ day for 5 months, doses were increased after approximately a week or so without any deleterious effects being observed. Observations were limited to bodyweights, at autopsy macroscopic and microscopic organ changes were noted.

GLP compliance:

no

Remarks:

Predates GLP

Limit test:

no

Species:

dog

Strain:

other: The dog fed increasing doses (up to 4 gm/kg bw/day) is desrcibed as a female beagle mongrel. the dog fed 0.1 g/kg bw/ day is described as a male mongrel terrier.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adult dogs.
- Weight at study initiation:
See results tables for weight changes throughout study.

ENVIRONMENTAL CONDITIONS
- No data

Route of administration:

oral: feed

Vehicle:

other: No vehicle

Details on oral exposure:

No data.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

28 days (0.1g/kg bw/ day)
and
up to 20 weeks (increasing doses up to 4.0 g/ kg bw/ day)

Frequency of treatment:

daily in diet.

Remarks:

Doses / Concentrations:
0.1 g /kg
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
Increasing dose 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0 g/kg
Basis:
nominal in diet

No. of animals per sex per dose:

One animal per dose.
The male was treated with 0.1g/kg bw/day for 28 days.
The female was treated with up to 4.0g/kg bw/ day for up to 20 weeks.

Control animals:

no

Details on study design:

MAXIMUM DOSE VOLUME APPLIED:
In the one month study: 0.1g/kg/day; the maximum dose applied was 1g in one day, based on an intial 10 kg bw.
In the 20 week exposure: 4.0g/kg/day the maximum dose applied is not reported by the author, however, given a final bodweight of 11.3 kg the dose is expected to be approximately 45.2g in the daily diet.

Rationale for dose selection.
up to 4.0g/kg/day:
The dog(s) is given a daily dose of the material. If there is no response then the dose is upped after a period of a week or two, and then again until some evidence of a toxic effect is obtained. At an effect level the dog is maintained for a period of atleast four weeks.
0.1g/kg/day:
A second dog is maintained for four weeks on a daily dose much lower; 1/10th - 1/100th of the hightest tolerated dose.

Positive control:

no data.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Low dose: Day -2 and 27
- High dose study: day -6 and day 153
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked: Total red blood count, hemoglobin values, total white cell count, differential counts and observations of a number of characteristics of the red blood cells

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine:
- low dose study: at -2 days then every 7 days following dosing
- High dose study: twice during study, two weeks and 5 months after start of dosing
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: Sugar and protein

NEUROBEHAVIOURAL EXAMINATION: No

ORGAN WEIGHTS: Yes, kidneys, heart, lung, spleen, liver, kidney and brain

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

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:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortalities

BODY WEIGHT AND WEIGHT GAIN
Weight loss was observed in the dog receiving 4000mg/kg bw/day of the test material. No significant effect was seen for the dog fed 100 mg/ kg bw/ day.

HAEMATOLOGY
Blood samples taken initially and near the end of the experiment yielded expected hematological values (almost without exception).

URINALYSIS
Urine analysis for sugar and protein were as expected for both dose groups.

ORGAN WEIGHTS
Organ weights lay in the normal ranges except for an increased heart weight in the dog fed the high dose (up to 4000 mg) of sodium tripolyphosphate. Kidney weights were normal.

GROSS PATHOLOGY
The only gross abnormality was the hypertrophy of the left ventricles in the heart of the dogs given the high dose. No effect was seen in the animal treated with 100 mg/kg bw/day.

HISTOPATHOLOGY: NON-NEOPLASTIC
A thorough histological examination revealed for the most part normal appearing tissues. In the kidneys of the dog receiving up to 4000 mg/kg, tubular changes were observed.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: At this dosing level there were no changes in organ weights

Critical effects observed:

not specified

Please see attachments as results are too large to fit in free-text field.

Conclusions:

When the test material was administered at a dose of 100 mg/kg bw/day the test subject did not demonstrate any adverse effects.
At the highest dose tested, up to 4000 mg/kg bw/ day, the major findings were limited to; an enlarged heart, tubular changes in the kidneys and a loss in bodyweight.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category

1. Both substances are inorganic salts of a monovalent cation from Group 1A of the periodic table, and triphosphoric acid. Thus, they share the Na+ or K+ cation and P3O105- anion.
2. Both the Na+ and the K+ cation have a similar biological function and therefore triphosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity.
3. In addition, both salts have been shown to be of similar low toxicity in acute oral studies and therefore comparisons can be drawn to allow read-across. Therefore it is not considered to be scientifically justified to perform any further in vivo studies.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

no guideline available

Principles of method if other than guideline:

Groups of rats were each fed a diet containing 0.2, 2 and 10% of pentasodium triphosphate. The treatment lased for 28 days. Observations were limited to mortalitity, bodyweights, organ weights and histological organ changes. Animals were sacrificed at regular intervals throughout the 28 day period to assess to rate of any effects of the test material.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: See results tables.
- Age at study initiation: post-weaning, not at maturity.

ENVIRONMENTAL CONDITIONS
- No data.

Route of administration:

oral: feed

Vehicle:

other: not applicable

Details on oral exposure:

No data.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

not applicable

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily in diet.

Remarks:

Doses / Concentrations:
0.2, 2 and 10%
Basis:
nominal in diet

No. of animals per sex per dose:

14 rats per dose.

Control animals:

yes

Details on study design:

no data.

Positive control:

no data.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

ORGAN WEIGHTS: Yes (kidneys)

Sacrifice and pathology:

Rats were sacrificed serially on the 3rd, 7th, 15th and 28th days.

Other examinations:

Histological changes in the kidneys, Body weight.

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):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortalities occurred.

BODY WEIGHT AND WEIGHT GAIN
The 10% dose group exhibited retardations in growth. The groups fed 2% and 0.2% sodium tripolyphosphate grew normally.

ORGAN WEIGHTS
Kidney weights were increased in the 10% dose group.

GROSS PATHOLOGY
Tubular necrosis was observed in kidneys of all rats in the 10% dose group. The rats fed 2% sodium tripolyphosphate exhibited inflammatory changes that were not characteristic tubular necrosis but were probably attributable to the presence of the test material. The kidneys of the rats in the 0.2% dose group were normal.

Dose descriptor:

NOAEL

Effect level:

> 2 other: %

Based on:

test mat.

Sex:

male

Basis for effect level:

other: tubular necrosis and increase in kidney weight in animals fed 10% dietary STPP

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

10 other: % in diet

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Results scanned and attached as too large to fit in free-text field.

Conclusions:

In the 2% group, the test material did not demonstrate any adverse effect and is therefore considered not be classified in accordance with Regulation (EC) no 1272/2008 (EU CLP).
At the highest dose tested, (10% in diet), the major findings were limited to; growth depression, elevated kidney weights and, by the 14th day of study, severe tubular necrosis were reported. It is unclear wether the effects are relevant for humans as rats are particularly susceptible to nephrocalcinosis when exposed to high phosphate levels in the diet (particularly female rats). As adverse effects noted in this study are only seen in high dose animals (well above the recommended classification limits for STOT RE as defined in the Guidance on the Application of Regulation (EC) No 1272/2008) classification for STOT RE is not justified and no classification is proposed.

Reference 3

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category

1. Both substances are inorganic salts of a monovalent cation from Group 1A of the periodic table, and triphosphoric acid. Thus, they share the Na+ or K+ cation and P3O105- anion.
2. Both the Na+ and the K+ cation have a similar biological function and therefore triphosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity.
3. In addition, both salts have been shown to be of similar low toxicity in acute oral studies and therefore comparisons can be drawn to allow read-across. Therefore it is not considered to be scientifically justified to perform any further in vivo studies.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

See attached expert statement.

GLP compliance:

no

Remarks:

Predates GLP

Limit test:

no

Species:

rat

Strain:

other: albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

Groups of 5 animals/cage; cages had bottoms with wood shavings, tap water from local water supply and Purina Fox Chow ad libitum, diets prepared weekly and stored in covered containers. Standard diet is considered to meet the nutritional requirements of the test animals. Information on homogeneity and stability of test material in diet is not included. Frequency of changes in cage bedding and cage cleaning are not documented. Since standard diet and tap water were used; fresh diets were prepared weekly and phosphates are stable in food, this aspect of the study can be considered acceptable.

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

no data.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable.

Duration of treatment / exposure:

2 years

Frequency of treatment:

ad libitum and daily in diet.

Remarks:

Doses / Concentrations:
0.05%, 0.5% and 5%
Basis:
nominal in diet

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

no data.

Positive control:

No data.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
- Assessments: appetite, condition of coat, feces and evidence of illness or tumor

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during the first 3 months and every 2 weeks thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pre-experimentally and at monthly intervals for the first 6 months, every 2 months of the first year, and every 3 months during second year.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5 male and 5 female
- Parameters examined: Hemoglobin, red blood cell counts, white blood cell counts and differential counts

CLINICAL CHEMISTRY: No

HISTOPATHOLOGY: Yes
- Animals: 10 males and 10 females
- Organs examined: brain, lungs, heart, liver, spleen, kidneys, adrenals, gonads, stomach, large and small intestine, urinary bladder, bone marrow and muscle

URINALYSIS: Yes
- Time schedule for collection of urine: At least three times a year
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: sugar and protein

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
BONE ANALYSIS
-Samples of bone removed at time of autopsy for examination to detect any gross abnormalities in morphology or calcification. Femurs of left leg radiographed and lengths measured. Wet weights, dry weights and ash weights recorded.

ORGAN WEIGHTS: Yes
- Organs: liver, kidneys, lungs, brain, stomach, heart, spleen

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table in attachments)
HISTOPATHOLOGY: Yes (see table in attachments)

Statistics:

No data.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

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 examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
Mortalities were high as a result of intercurrent epidemics of infections. The highest mortality (80%) over the 2 year period was observed in females in the 5% dose group. Respiratory infection and pericarditis-peritonitis were the most prominent causes of death.

BODY WEIGHT AND WEIGHT GAIN
Femur lengths and body weights in males and females in the 5% TPP group were smaller than those of control animals, indicating a true reduction in growth.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption measurements made after 1 month and again after 3 months on the experimental regimen showed that there was some effect responsible for the growth retardation in the rats given 5% TPP diet.

HAEMATOLOGY
At 1 year there was evidence of anaemia in male rats of the 5% dose group. The red blood cells counts, haemoglobin values and haematocrits were somewhat lower than those observed in the other groups. Otherwise the haematological indices were within normal limits.

URINALYSIS
Urine analyses for sugar and protein were normal.

ORGAN WEIGHTS
Organ weights, recorded at the time of sacrifice were mostly in the normal ranges but revealed increased kidney weight-body weight ratios on the average in both male and female rats given the diet containing 5% TPP. There were also slight increase in the weights of liver, testes, brain, stomach and heart possibly attributable to the smaller body weight. In some instances increases in liver and kidney weights relative to body weights were observed in female rats in the 5% dose group.

HISTOPATHOLOGY: NON-NEOPLASTIC
A thorough histological study of the tissues in the rats with increased kidney weight showed the presence of a definable 'chronic tubular nephropathy' (a kidney lesion) in all the rats, male and female given the 5% TPP diet. Rats given 0.5% TPP and 0.05% TPP did not exhibit changes that could be identified as chronic tubular nephropathy. There was no indication that TPP is carcinogenic. The tumors observed were of the types usually found in old rats, and their incidence was the same in all groups.

BONE ANALYSIS
The femurs in both sexes in the 5% group contained slightly more water and slightly less organic matter as compared with controls. The ash content and ratios of calcium to phosphorous were normal for both sexes. Radiographically the bones of rats appeared normal for all dose groups.

Dose descriptor:

NOEL

Effect level:

0.5 other: % in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

organ weights and organ / body weight ratios

other: At the next dosing tier effects observed included: Growth depression, increased kidney weight, chronic tubular nephropathy in the kidney

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

5 other: % in diet

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

- See the attached expert statement for further discussion and mortality tables.

- See attached tables.

Summary of results.

1. Growth depression was noted for the male rats given the diet containing 5% TPP during the entire period. Diets containing 0.5% TPP or less did not retard growth.

 

2. Mortalities were high; higher in the female group given the diet containing 5% TPP than in the other groups.

 

3. Food consumption measurements made after 1 month and again after 3 months on the diets indicated that there was some specific toxic effect of 5% TPP in the diet responsible for the growth reduction.

 

4. Urine analyses gave normal values for sugar and protein.

 

5. Repeated blood samples gave, for the most part, normal haematological values. Some evidence of anemia was found, particularly in the male rats given the 5% TPP diet.

 

6. Organ weights were normal except for increased kidney weightbody weight ratios in both male and female rats given the 5% TPP diet. Liver weight-body weight ratios were increased in the female rats on this high level diet.

 

7. A thorough histological study revealed a characterized, "chronic tubular nephropathy" in the kidneys of all rats, male and female, given the 5% TPP diet. No histological changes were found in the tissues of the rats given 0.05% or 0.5% TPP diets that were attributed to the administration of the tripolyphosphate.

Conclusions:

According to the discussion presented in the attached expert statement this study satisfies the regulatory requirements for this endpoint and has therefore been considered suitable as a key study.
At a dose of ca. 250mg/kg bw/day (0.5% in diet), the test material did not demonstrate any adverse effect and is therefore considered not be classified in accordance with Regulation (EC) no 127/2008 (EU CLP).
At the highest dose tested, (5.0% in diet), the major findings were limited to; growth retardation, increased kidney weights and chronic tubular nephropathy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

READ ACROSS ARGUMENT:

Both substances are ionic inorganic compounds containing a triphosphate anion and a group 1 alkali metal cation. Both the Na+ and the K+ cation have a similar biological function and therefore triphosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity.

In addition, both salts have been shown to be of similar low toxicity in acute oral studies and therefore comparisons can be drawn to allow read-across.

Therefore it is not considered to be scientifically justified to perform any further in vivo studies.

Short term repeated dose toxicity:

Pentasodium triphosphate [STPP] was administered for 1 month to groups of 5 male weanling (6-week old) rats at doses of 0.2, 2.0 and 10% in the diet (Hodge, 1959). One control group received the basal diet only, one additional control group received the basal diet supplemented with 10% Sodium chloride, and one control group received 5% orthophosphate. Growth reduction was observed at the high dose of 10%, and in the control group receiving basal diet with 10% sodium chloride. Enough calcium was added to the diet to ensure a "reasonably balanced" ratio of calcium to phosphorus (no further details). Growth was normal in rats receiving 2% sodium tripolyphosphate. No data were available on food consumption, clinical signs, or haematology. An increased relative kidney weight was observed at the highest dose of STPP and in the control group supplemented with NaCl. Histopathological examination showed tubular necrosis in the kidneys of rats treated at 10% sodium tripolyphosphate, and in the control group with 5% orthophosphate. Only inflammatory changes of the renal pelvis were observed at 2%, while normal kidneys were observed at 0.2%. Based on the renal effects, the NOEL was determined to be 0.2%. Assuming a 0.4 kg rat eats about 18 g of food per day, the NOEL for the 1-month diet study is therefore estimated to be 90 mg/kg/day for STPP. Furthermore, in this study, other groups of rats received similar doses of other inorganic condensed phosphates (sodium hexametaphosphate, sodium trimetaphosphate and sodium tetrametaphosphate), which produced similar effects, especially at 10%.

Chronic toxicity:

STPP was further assessed in a 104-week oral repeated dose study in rats (Hodge, 1964). A preliminary assay was conducted with groups of 14 male rats, at doses of 0.2%, 2% and 10% STPP for 1 month. The effects described above for the previous study (growth retardation, increase in kidney weights, and tubular degeneration and necrosis of the kidneys) were again observed at the highest dose.

In the main 2-year study, males and females rats (50 animals per dose group and per sex) received 0.05, 0.5 and 5.0% of STPP in the diet. Mortality, food consumption, body weights were monitored. At the end of the treatment period, organ weights, haematology, urine analysis, bone analysis and histopathology were evaluated. Growth retardation was observed in the high dose group in males (throughout the study period) and females (slight during the first year, then more obvious during the second year). High mortality was reported in males and females due to several epidemics during the study. The high dose group was more affected (up to 80% in females of the 5% dose during the second year of the study). Concerns about potential altered calcium to phosphorus balance were addressed by conducting bone analysis. Femur analysis of the high dose group (5%) showed a slight increase in water content and slight decrease in organic matter as compared to the control group. No anomalies were observed at the bone radiography. The ash contents and ratios calcium to phosphorus were normal in both sexes of the high dose group. The effects observed after repeated oral ingestion of high doses of STPP were anaemia observed after 1 year of treatment at 5% (decrease in red blood cells counts, haemoglobin values and haematocrits), and mainly renal effects. In the high dose group (5%), kidney weights were increased in males, and relative liver and kidney weights were found increased in females. Histopathological examination showed enlargement of the kidney associated with tissue changes such as dilated convoluted tubules, hyaline casts, interstitial fibrosis between the dilated tubules, fibrotic glomeruli and intertubular calcification also in the group receiving the 5 % dose.

Based on the renal effects (nephrocalcinosis), the NOEL was estimated to be 0.5% for the 2-year repeated dose study in rats. Assuming a 0.4 kg rat eats about 18 g of food per day, the NOEL is estimated to be 225 mg/kg/day

The most applicable NOEL is therefore 225 mg/kg/day as this is the highest NOEL below the lowest LOAEL.

Justification for classification or non-classification

Calcification of the kidneys was noted in animals treated with pentasodium triphosphate. However, as the NOAEL are relatively high a classification for STOT-RE (kidneys) is not applicable. Therefore, on the basis of read across, pentapotassium triphosphate is not considered to be classified in accordance with Regulation (EC) No. 1272/2008 (EU CLP).