Registration Dossier

Diss Factsheets

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

A carcinogenicity study has been performed on the analogous substance pentasodium triphosphate. Athough pentasodium triphosphate is subject to widespread dispersive use, it is not classified as a mutagen or genotoxic. The basic structure of pentapotassium triphosphate has no structural alerts for carcinogenicity or genotoxicity and therefore can be expected to behave in a similar way to pentasodium triphosphate. 
Read across from pentasodium phosphate to pentapotassium phosphate is justified on the following basis:
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. 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:
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. Carcinogenicity is not a required endpoint for REACH.

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:
Yes: No test material analysis, no diet analysis, no information on clinical observations, food consumption conducted only at 1 and 3 months, no ophthalmology, no clinical chemistry; incomplete urinalysis; hematology included only 5 animals/sex/group
GLP compliance:
no
Remarks:
Study predates GLP
Species:
rat
Strain:
other: Rochester Strain (Ex-Wistar 1923)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 21 days
- Weight at study initiation: 78-86 g
- Diet: ad libitum
- Water: ad libitum
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily ad libitum
Post exposure period:
None
Remarks:
Doses / Concentrations:
500, 5,000 and 50,000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

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


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 consumption was evaluated after one and three months on study on 5/sex/group from the control and high dose groups. After one month, food consumption was evaluated daily for 5 consecutive days. After three months, food consumption was evaluated daily for 4 consecutive days. Each animal was provided with a set amount of basal or treated diet for the daily recording of food consumption. Body weights were also monitored during this measurement period.


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:After 1, 3, 4.8, 6.4, 8, 12, 16, 18, 21 and 24 months
of treatment
- 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, total and differential leukocyte count, plasma cell.
-Parameters not evaluated: mean corpuscular volume, mean corpuscular haemoglobin and haemoglobin concentration, platelet count, , prothrombin time, activated partial thromboplastin time.


CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine:Pre-test and After 4 months, 10 months, 13 months
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: protein, glucose


NEUROBEHAVIOURAL EXAMINATION: No
Other examinations:
Histopathology
from: Ten animals/group of the surviving animals at terminal sacrifice were examined for histopathology.
Organs: Brain, spinal cord, small and large intestines, stomach, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, gonads, urinary bladder, bone marrow.
Organs not evaluated: : gross lesions, aorta, cervix, coagulating gland, epididymis, Haderian gland, lacrimal gland, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, uterus, female mammary gland, prostate, lymph node, peripheral nerve, , seminal vesicles, salivary gland, skin, eyes, aorta, skeletal muscle, stomach, vagina, femur with joint, thymus, caecum, cervix, rectum.
Other: skeletal muscle, bone.
Organs not evaluated: pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, pancreas, adrenals, uterus, female mammary gland, prostate, lymph node, peripheral nerve, bone marrow, skin, eyes, aorta.
Bone analysis of all dose groups and control: length and weight of the femurs, composition of bone (%water, dry weight, ash weight, % organic material, % calcium, % phosphorus, calcium:phosphate ratio).
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 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:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Relevance of carcinogenic effects / potential:
See attached expert report.
Dose descriptor:
NOEC
Effect level:
> 5 other: % in diet
Sex:
male/female
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Body weight

Male rats fed the high dose of test material showed reduced body weight by 90 days on test which continued at significantly reduced levels throughout the study to week 103. Female rats fed the high dose of test material had body weights which were only slightly less than control rats at 90 days but more significantly reduced by one year and for the duration of the study.  There were no effects on body weight in the medium and low dose groups. See Table A 6.7-4

Food consumption

High dose animals showed growth retardation while food consumption was similar to control levels at 1 and 3 month intervals.  Even on restricted food intake, there was a greater body weight gain in the controls compared to the high dose animals in a paired food consumption evaluation.

Macroscopic investigations

Gross necropsy examination found no treatment-related lesions associated with test material dose administration, other than enlarged kidneys. See Table A6.7 Overall Summary

Haematology

There was a reduction in red blood cell counts and haemoglobin values in the male rats fed the high dose of test material.  The haematological values for all other parameters and other groups were within normal ranges. See A 6.7 Table 4.7.

Urinalysis

No effects on glucose or protein in urine at any dose level.

Pathology

The primary findings among high dose males and females were confined to the kidney.  Findings included the following: dilation of the convoluted tubules with some atrophy; extreme dilation of tubules of the loop of Henle with atrophy of epithelium; mild dilation of some collecting tubules; hyaline casts within dilated tubules; interstitial fibrosis, interstitial and intertubular deposition of laminated, calcified bodies, particularly within the inner 2/3 of the cortex; relative paucity of inflammatory cell infiltrate; glomerular fibrosis and hyalinization; minimal alteration of large or small arteries and gross overall enlargement of the kidney. These lesions, termed chronic tubular nephropathy or chronic pyelonephritis, were found across all dose groups.  The severity and incidence of chronic pyelonephritis was greatest among high dose animals: 8/8 females and 10/10 males.  No other treatment-related lesions were reported. See Table A6.7 Overall Summary and Tumour Incidence Data.

Organ Weights

Kidney weight-body weight ratios were increased among the high dose group animals at study termination.  Liver weight-body weight ratios were somewhat elevated in the small number of surviving female rats in the high dose group.  Due to the small number of high dose females examined, the significance of this finding is considered questionable.  The liver and kidney weight changes were not seen in the medium and low dose groups.  There were no other effects in the other organs examined in any dose group.  See A 6.7 Table

Histopathology

The incidence of tumours among survivors at terminal sacrifice did not show any significant increase in any particular tumour type related to treatment. See Table A6.7 Overall Summary and Tumour Incidence Data.

Other examinations

Male and female rats of the high dose group exhibited shorter length femurs, indicating that the lower body weight of the high dose animals is also accompanied by a reduction in growth.  The percentage of water was slightly higher and the percentage of organic matter was slightly lower in the high dose animals.  All other parameters were normal in the high dose animals.  All parameters in the medium and low dose animals were normal.

Time to tumours

Monthly counts of tumours were provided.  No specific treatment-related trend in time-to-tumour development was observed.

Table A6.7  Mortality and Causes of Death

Group

Sex

24 Month Sacrifice (%)

Deaths due to Respiratory Infections (%)

Deaths due to Pericarditis – Peritonitis

Deaths due to Tumors

Control

Male

17/50 (34%)

13/50 (26%)

20/50 (40%)

0/50 (0%)

Low dose

25/50 (50%)

18/50 (36%)

6/50 (12%)

1/50 (2%)

Medium dose

22/50 (44%)

15/50 (30%)

11/50 (22%)

2/50 (4%)

High dose

12/50 (24%)

25/50 (50%)

12/50 (24%)

1/50 (2%)

Control

Female

21/50 (42%)

8/50 (16%)

19/50 (38%)

2/50 (4%)

Low dose

30/50 (60%)

11/50 (22%)

8/50 (16%)

1/50 (2%)

Medium dose

27/50 (34%)

12/50 (24%)

11/50 (22%)

0/50 (0%)

High dose

10/50 (20%)

28/50 (36%)

10/50 (20%)

2/50 (4%)

Table A6.7-4.1: Body Weights: Mean Values at Initiation, One, Three, Twelve and Twenty-four Months

Group

Sex

Initial: g

1 Month: g

3 Month: g

12 Month: g

24 Month: g

Control

Male

86

212

315

412

409

Low dose

85

217

319

417

419

Medium dose

85

217

321

417

426

High dose

86

191

292

381

374

Control

Female

78

153

201

263

289

Low dose

78

152

203

252

274

Medium dose

78

155

209

261

292

High dose

79

146

202

243

257

Table A6.7-4.11 Summary of Significant Organ Weights and Weight Ratios

% Test Material in Diet

Sex

Number of Animals at termination

Terminal Body Weight (g)

Liver Weights (g)

Liver: Body Weight Ratio

Kidney Weights (g)

Kidney: Body Weight Ratio

0

M

17

409

13.22

0.032

3.58

0.0088

0.05

25

419

13.19

0.031

3.79

0.0090

0.5

22

426

13.42

0.032

3.63

0.0085

5.0

12

374

12.79

0.034

4.69

0.0125

0

F

20

290

10.99

0.038

2.63

0.0090

0.05

28

274

9.79

0.036

2.69

0.0098

0.5

25

292

10.39

0.036

2.79

0.0096

5.0

6

257

11.37

0.044

4.41

0.0172

Table A 6.7 Overall Summary and Tumour Incidence Data

Parameter

Control data

study

low dose

medium dose

high dose

dose-response + /

m

F

m

f

m

f

M

f

m

f

Number of animals sacrificed

 at termination

17

21

25

30

22

27

12

10

Mortality

33

29

25

20

28

23

38

40

+

+

body weight gain

+

+

food consumption

Haematology

+

Organ weights: kidney weights

+

+

No. of animals examined for histopathology

10

11

10

13

10

12

10

8

Non-neoplastic lesions: chronic pyelonephritis

7/10

6

Mild,

1 mod-erate

4/11

2 mild

7/10

2 mild

6/13

1 mild

3/10

4/12

10/10

8/8

+

+

No. of animals with tumours

6

9

3

9

6

11

6

2

Breast fibroadenoma

6

7

6

Lymphoma

1

2

2

1

1

3

1

Adrenal medullary tumours

3

1

1

1

2

Testis interstitial adenoma

1

1

4

2

Large bowel leiomyoma

1

Pituitary adenomas

1

Bowel, lymphangioma

1

Bladder, papilloma

1

Liver, granuloma

1

Uterus, carcinoma

1

Conclusions:
NOEC > 5% of test material in diet.

Justification for classification or non-classification

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.

Due to the common structural features as inorganic phosphate salts of sodium ion, the evaluation for the same endpoints on all three salts and the same or similar findings in all three studies on chronic toxicity/carcinogenicity, it is concluded that pentasodium triphosphate is not expected to be carcinogenic in rats and that the current study on STPP(Hodge 1959, 1964) and the studies on sodium hexametaphosphate and sodium trimetaphosphate provide adequate data to support this conclusion. It is considered to be scientifically justified to read across the results from pentasodium triphosphate to pentapotassium triphosphate.

Additional information

The major effect of feeding high doses of pentasodium triphosphate for two years is toxicity to the kidneys and reduced red blood cell counts and haemoglobin concentration in the blood. The Hodge study (1959, 1964) 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 regarding the hazard identification of pentasodium triphosphate are supported by data on sodium hexametaphosphate (SHMP) and sodium trimetaphosphate (STMP), both of which are structurally similar to pentasodium triphosphate. 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 pentasodium triphosphate. In a chronic toxicity/carcinogenicity study on sodium hexametaphosphate (SHMP), 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% in the diet for 24 months (IUCLID Robust Study Summary included as supplemental information). Similarly, in a chronic toxicity/carcinogenicity study on sodium trimetaphosphate (STMP), no treatment-related increase in tumour incidence was observed at any dose in rats administered the salt at doses of 0.1, 1.0 and 10.0% in the diet for 24 months (IUCLID Robust Study Summary included as supplemental information). For both compounds the studies were conducted prior to good laboratory practice guidelines and OECD Guideline 453; thus, these studies have similar deficiencies to the study on pentasodium triphosphate.