Pentapotassium triphosphate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Cross-reference

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

three-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Study not performed to GLP or guideline. But has been reviewed by an expert assessor (see expert report attached) and determined to be suitable for use for the purposes of REACH registration. See overall remarks for further discussion on deficiencies. 1. Only one dose level was included in the study. 2. Test material was not analyzed in diet. No impurity profile of test material was provided. 3. The group size was smaller than the 20 females and 10 males required in OECD guideline 416. 4. Only one dose level was tested with a control group. 5. There was no recorded acclimation period for the P generation. 6. Daily observations of parents and observations of abnormal behaviour of offspring are not reported. 7. Body weights: Parental body weights were not recorded during gestation and lactation. 8. Food consumption was not determined. 9. Estrous cycle was not evaluated. 10. Sperm parameters were not included. 11. Offspring sex and sex ratios were not determined. Litter body weight was reported; however, individual pup body weights were not recorded. 12. There is no report of gross pathology and necropsy observations. 13. Organ weight data for the uterus, epididymides (total and caudal), prostate, seminal vesicles with coagulating gland, pituitary gland, adrenals and thyroid gland were not included. 14. Histopathology was conducted only on the F3b offspring and did not include the following organs: uterus, cervix, vagina, epididymides, seminal vesicles, prostate, coagulating gland, pituitary gland. Note that the known target organ (kidney) was evaluated. 15. Statistics are not reported.

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 followed

Principles of method if other than guideline:

A reproduction study spanning three generations of rats reared and maintained on diets containing 0.0% and 0.5% pentasodium triphosphate (STPP). Per generation two different litters were bred; one was sacrificed and the other was bred to produce the next generation. Matings were carried out between 16 females and 8 males in each group when the rats were 100 days old. Observations were limited to: the number of pups born, pup mortality up to 21 days, organ weights and histopathological changes in the tissues and organs.

GLP compliance:

no

Remarks:

Study predates GLP

Limit test:

no

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:
The parental generation were mated when they were 100 days old. Succeeding generations were also mated at 100 days of age.
- Weight at study initiation: 60g
- Housing: Galvanized iron cages with screen wire doors. The bottoms of the cages were pans filled with wood
shavings.
- Diet: e.g. ad libitum
- Water :e.g. ad libitum


ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
Diets were prepared at weekly intervals by mixing, using a mechanical mixer, the appropriate amounts of STPP as needed into the control ration. Diet mixtures were stored in galvanized iron buckets with covers.

Details on mating procedure:

- M/F ratio per cage: 1 male:2 female
- Length of cohabitation: 7 days.
- Proof of pregnancy: no data.
- Unsuccessful pairing replacement of first male by another male with proven fertility - no.
- Further matings after two unsuccessful attempts: no data.
- After successful mating each pregnant female was caged (how): no data.
- other: As there were two matings per generation the males were rotated so that at each mating a different male would be placed in the cage with the females.

Sixteen females and 8 males will be mated at 100 days of age from each of the above 2 groups (controls and 0.5% tripolyphosphate). They will be mated again 10 days after weaning of the first litter. Sixteen females and 8 males from the second litters will be selected from each group at weaning and continued on their respective diets. When 100 days old they will be mated; then mated again 10 days after weaning the first litter. This procedure will be
repeated with the rats to produce a second litter of the third generation.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not applicable.

Duration of treatment / exposure:

Exposure took place:
- for 100 days prior to mating
- 21 days of gestation
- during lactation (the P1, F1b and F2b)
- the F3b were exposed for their first 21 days after which time they were sacrificed.
- Following weaning of the F1b litter, 8 males and 16 females for the control group and the treated group were fed their respective diets for 100 days. 
Litters were culled to 10 pups with approximately 5/sex/group on postnatal day 5.

Frequency of treatment:

Daily in diet (ad libitum).

Details on study schedule:

See table 1 for details on the study schedule.

Remarks:

Doses / Concentrations:
0.5% in diet
Basis:
nominal in diet

No. of animals per sex per dose:

P1, F1, F2, F3: 16 females and 8 males

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: 0.05% and 0.5% diets were considered. After 100 days the 0.5% group exhibited no depression of bodyweight and was selected for use in the reproduction study.
- Other: The first litters born, the F1a,2a,3a were sacrificed. The second litters, F1b,2b were mated to produce the next generation.

Positive control:

There was no positive control.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were measured weekly during the 100 day pre-mating exposure for each generation.

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

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

Oestrous cyclicity (parental animals):

Not evaluated.

Sperm parameters (parental animals):

Not evaluated.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 5 postpartum: [yes]
- excess pups were sacrificed to leave 10 per litter.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
number of pups, pups/litter, pup mortality up to 21 days of age, weight gain per litter.

GROSS EXAMINATION OF DEAD PUPS: No
NOT EVALUATED: sex of pups, presence of gross anomalies, physical or behavioural abnormalities, no individual pup body weights

Postmortem examinations (parental animals):

SACRIFICE
- The F1a,2a,3a were sacrificed at 30 days postpartum.
- No data on parental fate after the mating and weaning.

GROSS NECROPSY
- no data.

HISTOPATHOLOGY / ORGAN WEIGHTS
Not performed for parental rats.

Postmortem examinations (offspring):

SACRIFICE
- The non-parental litters, F1a , F2a , F3a , and F3b were sacrificed after 30 days.
- Observations amongst these litters were limited to litter weights on the 21st day.
- In the F3b histopathological and organ weight examinations were performed.

GROSS NECROPSY
F3b examined only.

HISTOPATHOLOGY / ORGAN WEIGTHS - The ten males and ten females from final litter, the F3b litter, were evaluated for body weight, histopathology.
- Histopatholigcal examinations performed for: Liver, kidneys, gonads, lungs, brain, stomach, heart, spleen, adrenal, stomach, large and small intestines, bladder, lymph nodes, gut, marrow, pancreas)
- Organ weights recorded for: Liver, kidneys, testes, lungs, brain, stomach, heart, spleen.
- Organ weights not recorded for: Uterus, ovaries, epididymides (total and cauda), prostate, seminal vesicles, pituitary, thyroid, adrenal glands.
- Histopathological examinations not performed for: Vagina, uterus with cervix, epididymis, seminal vesicle, prostate coagulating gland.

Clinical signs:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

based on equivalent numbers of pups born and surviving weaning in the controls and treated groups.

See table 2 (attached document - "reproductive performance") for a comparison of the control and treated groups's reproductive performance.

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Remarks:

test material in diet.

Sex:

male/female

Basis for effect level:

other: No effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

0.5 other: % in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects noted

Key result

Critical effects observed:

no

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

See table 2 (attached)

Body weight and weight changes:

no effects observed

Description (incidence and severity):

See Table 2 (attached)

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

- See Table 2 (attached.) for details on viability and bodyweights.
The attached graphs highlight the similiarity in growth rates between control and treated groups for the F1b and F2b.

- For Organ weights see Table 3 (attached). Treated and control groups were considered to be comparable for all organs weighed.
Inspection shows nearly identical average weights, both fresh weights and on basis of body weights. For both the male and the female rats, the average kidney weights (basis body weight) are slightly greater for the rats maintained on the 0.5% TPP diets than on the control diets. These differences, however, are not statistically significant.

- There were no treatment-related histopathological findings.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

0.5 other: % in diet

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no effects noted

Key result

Critical effects observed:

no

Clinical signs:

not examined

Body weight and weight changes:

no effects observed

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects noted

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

0.5 other: % in diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects noted

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

This study included only one dose level of the test material, 0.5% in the diet. There were occasional fluctuations in the fertility index.  The lower fertility index in the F2a, F3a and F3b litters is considered spurious and not treatment-related.  The fertility indices of the treated group were greater than the control group for some litters (F1a, F2b); the same as the control group for the F1b litter, and less than the control group for other litters (F2a, F3a, F3b).  These variations are not considered to show a treatment-related effect on fertility.  The duration of pregnancy, live birth index, litter size, litter weights, survival index, viability index and lactation index were all comparable between control and treated groups.  Organ weights were similar between control and treated groups.  There were no treatment-related histopathological findings.

Parameter			Control		High dose
		Generation	M	F	M	F
Mortality	Incidence	P	0	0	0	0
		F1	0	0	0	0
		F2	0	0	0	0
		F3	0	0	0	0
Food consumption	% of control		NA	NA	NA	NA
Body weight gain	% of control		100	100	100	100
Clinical Observations specify effects	Incidence		NA	NA	NA	NA
Organ weights (F3b)	% of control		95 -103	95 -103	95 -103	95 -103
Pathology
Histopathologic examination: F3b Immature testes Renal cyst Parasites in intestine Focal pulmonary hemorrhage Parasites in renal pelvis	Incidence		10 - - - -	- - 1 1 -	10 1 1 1 -	- - - - 2
Reproductive Performance
Mating index: P			-	NA		NA
F1			-	NA	-	NA
F2			-	NA	-	NA
F3			-	NA	-	NA
Fertility index: P, la			-	87.5	-	93.8
F1b			-	75	-	75
F2a			-	82.3	-	68.8
F2b			-	76.5	-	81.3
F3a				81.3	-	68.8
F3b				80	-	62.5
Number of implantation sites	Mean		-	NA	-	NA
Duration of pregnancy: P, 1a	Mean days			24.7		24.06
F1b				25.1	-	25.25
F2a				23.36	-	24.91
F2b				25	-	24.4
F3a				25.8	-	25.1
F3b				25.2	-	25
Birth index
Live birth index: P, 1a			-	93.8	-	100
F1b				93.8	-	100
F2a				100	-	100
F2b				100	-	93.8
F3a				93.8	-	100
F3b				100		87.5
Gestation index
Litter size: P, 1a	Mean		-	8.9	-	9.2
F1b				11	-	13
F2a				9.2	-	9.5
F2b				10.7	-	10.2
F3a				10.4	-	10.2
F3b				8.4	-	10.5
Litter weight: P, 1a	Mean, day 21, g		-	307	-	283
F1b				348	-	392
F2a				279	-	341
F2b				379	-	325
F3a				270		349
F3b				319	-	388
Pup weight, 1a	Mean: day 21, g			36.8	-	37.8
F1b				42.2	-	40.5
F2a				42.9	-	42.1
F2b				40.3	-	41.5
F3a				41.4	-	43.7
F3b				45.6	-	41.9
Sex ratio	Male/female			NA		NA
Survival index: P, 1a	Day 5			91.4	-	95.6
F1b				91.6	-	97.4
F2a				93.3	-	88.6
F2b				96.7	-	93.4
F3a				82.4	-	85.2
F3b				74.8	-	98.8
Viability index: P, 1a	Day 21		-	86.2	-	81.1
F1b				75	-	74.3
F2a				74.2	-	84.8
F2b				85	-	77
F3a				72.8	-	72
F3b				76.2	-	88
Lactation index: P, 1a	Day 21			86.2	-	81.1
F1b				75	-	74.3
F2a				74.2	-	84.8
F2b				85	-	77
F3a				72.8	-	72
F3b				76.2	-	88
Sperm characterization				NA		NA
Number	% of control			NA		NA
Deformations	% of control			NA		NA

Conclusions:

Three generations of rats reared and maintained on diets containing 0.5% STPP showed no adverse effects to the test material - Control and test data were comparable across the range of observations made. Observations were limited to reproductive performance, pup mortality, organ weights and tissue and organ histopathology. Based on this evidence sodium metaphosphate is not considered to be classified as a reproductive toxicant according to Regulation (EC) 1272/2008 (EU CLP).

Although this study is limited and deficient by modern standards, it is still possible to make some valid scientific conclusions from the data. Adequate data are reported to show no effects on fertility or reproductive performance or on offspring growth and development over three generations with two litters per generation. Thus, the study should be considered acceptable for the dose level tested, 0.5% test material in the diet.

Results and discussion

Target system / organ toxicity

Critical effects observed:

not specified