Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
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.
Effect on fertility: via oral route
Dose descriptor:
NOAEL
225 mg/kg bw/day
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.

Assessment of the key study

The Hodge reproduction study (1960) was conducted prior to the institution of good laboratory practice guidelines and to the current OECD Guideline 416. 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 STPP are supported by data on sodium hexametaphosphate (SHMP) and sodium trimetaphosphate (STMP), both of which are structurally similar to STPP. All three inorganic phosphate salts had no adverse effects on reproductive toxicity and fertility when tested in rats over three generations (Hodge 1959, 1960). 

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 STPP.  Three generation reproduction studies have been conducted on SHMP and STMP which are similar to the one on STPP in that they were conducted prior to good laboratory practice guidelines and the existence of OECD Guideline 416; nevertheless, they provide additional supplemental support for the hazard assessment of STPP (IUCLID Robust Study Summary included as supplemental information). Because all three sodium phosphates showed no effects on reproductive performance, these data show similar responses which allows a more robust conclusion for the individual salts. STPP and SHMP were both tested at a dose level of 0.5% in the diet. STMP was tested at a dose of 0.05% in the diet. These dose levels were viewed as appropriate levels based on the results of the chronic toxicity/carcinogenicity studies for each salt.


Short description of key information:
Regulation EC 1907/2006 - Annex VIII - Section 8.7.1. Screening for reproductive toxicity.

Screening for reproductive toxicity does not need to be conducted if a study is available for a two-generation reproductive toxicity study (Annex IX, Section 8.7.3). An Annex IX 8.7.3 study can be found in section 7.8.1 of this dossier.


Regulation EC 1907/2006 - Annex VIII - Section 8.7.3. Two generation reproductive toxicity study.

The Hodge reproduction study (1960) was conducted with analagous substance pentasodium triphosphate, but is considered suitable for the assessment of pentapotassium triphosphate for the reasons described in the discussion below.
Three generations of rats were reared whilst being exposed to the test material. Parents were fed diets containing 0.5% pentasodium triphosphate during the 100 days prior to mating, during the 21 days of gestation and during lactation (where applicable). This exposure pattern was repeated for the next generation of rats following weaning. There were two litters per generation, the second litter FXb parented the following generation. The F3b were the final generation and were exposed for their first 21days after which time they were sacrificed.
Observations were limited to body weight, histopathology (liver, kidneys, gonads, lungs, brain, stomach, heart, spleen, adrenal, stomach, large and small intestines, bladder, lymph nodes, gut, marrow, pancreas) and organ weights (liver, kidneys, testes, lungs, brain, stomach, heart, spleen).
The study was conducted before the institution of GLP and the modern standard test Guideline OECD 416. This result provides evidence for the assumption that there is no concern with regard to effects of pentasodium triphosphate on reproduction.
Supplemental evidence for the assessment is provided - similar reproduction studies are summarised for SHMP (sodium hexametaphosphate) and STMP (sodium trimetaphosphate).

Effects on developmental toxicity

Description of key information
Regulation EC 1907/2006 - Annex VIII - Section 8.7.1. Screening for developmental toxicity.
Screening for developemental toxicity does not need to be conducted if a pre natal developmental toxicity study is available (Annex IX, Section 8.7.3). An Annex IX 8.7.3 study can be found in section 7.8.1 of this dossier.
Section 8.7.2, Prenatal developmental toxicity.
Studies are available for the analogous substance pentasodium triphosphate (STPP) which is considered to be suitable for the assessment of pentapotassium triphosphate (KTPP) for the reasons discussed below.
Four prenatal developmental toxicity studies (Morgareidge K 1973) were performed by the US food and drug administration. The tests were conducted before the instituation of GLP but are comparable to modern guideline OECD 414. The test material was not found to be a teratogen when tested on rats, mice, rabbits and hamsters.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restrictions. 1. There were not 20 female animals with implantation sites at necropsy in each dose group as described in OECD414. 2. Dosing was carried out from day 6-18, OECD 414 recommends from day 5-28 (the day prior to caesarean section) 3. No data on assessment of gravid uteri.
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 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
1. There were not 20 female animals with implantation sites at necropsy in each dose group as described in OECD414. 2. Dosing was carried out from day 6-18, OECD 414 recommends from day 5-28 (the day prior to caesarean section) 3. No data on assessment of gravid uteri.
Deviations:
yes
Remarks:
See remarks
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
Dutch
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENT
- The animals were housed in temperature and humidty controlled rooms.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable.
Details on mating procedure:
- On day 0 the doe's pretreated with human chorionic gonadotrophin were, 3h later, artificially inseminated with sperm from proven buck.
Duration of treatment / exposure:
On day 6 and continuing through to day 18 the females were dosed with the test material.
Frequency of treatment:
Daily through treatment period.
Duration of test:
13 days of treatment.
No. of animals per sex per dose:
15 - sham treated control; 13 - positive control; 16 - 2.5 mg/kg; 15 - 11.6 mg/kg; 16 - 54 mg/kg; 13 - 250 mg/kg.
Control animals:
yes, concurrent vehicle
other: Positive control fed 2.5 mg/kg of 6-aminonicotinamide, dosed on day 9
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, for appearance and behaviour.
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 12, 18 and 29 of gestation

POST-MORTEM EXAMINATIONS: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was monitored to rule out abnormalities as a result of anorexic effects.
Ovaries and uterine content:
The urogenital tract of each animal was examined.
(and included:)
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: gross examination - all per litter
- Pup survival - Following caesarean section the pups were placed in an incubator for 24 hours to assess neonatal survival.

The pups were then sacrificed and examined as follows:

- visceral exminations.
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data
- Bodyweight of live pups also recorded.
Statistics:
No data
Indices:
No data.
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: please see below.

Details on maternal toxic effects:
Cage-side observations and periodic recording of bodyweight suggested no signs of toxicity. There were no discernible effects on nidation.
Dose descriptor:
NOEC
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control.
Dose descriptor:
NOEC
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1 - Reproduction data

Dose (mg/kg)

0

Positive control*

2.5

11.6

54

250

Pregnancy

Total no

15

13

16

15

16

13

Died or aborted

5

2

1

3

8

1

To term

10

11

15

12

14

12

Total corpora lutea

216

166

227

242

263

200

Average corpora lutea

10.8

9.76

11.4

12.1

12.0

9.52

Total live litters

8

8

14

12

14

10

Average implant site no

6.20

4.91

5.13

6.08

5.71

5.33

Resorptions

Percent partial resorptions

50.0

72.7

26.7

16.7

50.0

50.0

Percent complete resorptions

10.0

27.3

6.67

-

-

16.7

Average live foetus

4.7

3.73

4.27

5.42

5.07

4.42

Sex ratio (m/f)

1.35

1.16

1.29

1.16

1.29

0.83

Dead foetuses

6

1

4

-

1

-

Percent partial dead

10.0

9.09

13.3

-

7.14

-

percent all dead

10.0

-

-

-

-

-

Average foetus weight (g)

37.2

33.5

41.8

39.7

41.0

38.9

*2.5 mg/kg 6-aminonicotinamide dosed on day 9

Table 2 - Summary of skeletal findings

Dose (mg/kg)

0

Positive control

2.5

11.6

54.0

250

Sternebrae

Incomplete oss

-

6/2

-

-

4/3

-

Bipartite

-

-

-

-

1/1

-

Fused

-

10/5

6/3

1/1

2/2

1/1

Extra

2/2

1/1

-

2/2

3/3

2/1

missing

-

1/1

-

-

1/1

-

Ribs

Fused/split

-

13/6

-

-

-

-

Vertebrae

Scrambled

-

16/6

-

-

-

-

Scoliosis

-

13/6

-

-

-

-

Tail defects

1/1

35/8

-

-

1/1

-

Skull

Incomplete closure

-

1/1

-

-

-

-

(number of foetuses effected/number of litters)

Soft tissue abnormalities were only observed in the positive control group.

Conclusions:
Under the conditions of the study, the test material administered to pregnant rabbits for 13 days up to a dose level of 250 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetoxicity is > 250 mg/kg bw. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham treated controls.

This study is considered to be of adequate reliability and relevance to be submitted as the key study for this endpoint.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restrictions. 1. The study is performed in mice, not rats or rabbits as suggested in OECD 414. 2. No data on assessment of gravid uteri.
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
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
1. The study is performed in mice, not rats or rabbits as suggested in OECD 414. 2. No data on assessment of gravid uteri.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: Disposable plastic housing
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
Temperature and humidity controlled environment.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug (vaginal plug considered as day 0 of gestation.)
Duration of treatment / exposure:
Day 6 through to 15 of gestation
Frequency of treatment:
Daily
Duration of test:
Treatment began on day 6 and ended on day 15, at day 17 the mice underwent caesarean section.
No. of animals per sex per dose:
22 - 2.4 mg/kg; 22 - 11.0 mg/kg; 23 - 52.0 mg/kg; 24 - 238.0 mg/kg; 21- sham treated; 22- positive control.
Control animals:
yes, sham-exposed
other: positive control, dosed with 250 mg/kg of aspirin.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, for appearance and behaviour
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 11, 15 and 17

POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 17

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption was monitored to rule out abnormalities of anorexic effects.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: gross examination - all per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two third per litter
- The bodyweights of live pups was also recorded.
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: please see below.

Details on maternal toxic effects:
Cage-side observations and periodic recording of bodyweight suggested no signs of toxicity. There were no discernible effects on nidation.
Dose descriptor:
NOEC
Effect level:
238 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control group.
Dose descriptor:
NOEC
Effect level:
238 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1 - Reproduction data

Dose (mg/kg)

Sham

Positive control*

2.4

11.0

52.0

238.0

Pregnancy

Total no

21

22

22

22

23

24

Died or aborted

0

1

0

0

0

0

To term

21

21

22

22

23

24

Total corpora lutea

315

419

308

373

397

414

Average corpora lutea

11.7

11.3

12.8

12.4

13.7

12.6

Total live litters

20

21

22

21

22

24

Average implant site no

11.0

11.7

12.3

11.0

12.5

11.8

Resorptions

Percent partial resorptions

38.1

52.4

40.9

54.5

43.5

29.2

Percent complete resorptions

-

-

-

4.55

-

-

Average live foetus

9.67

10.9

11.5

9.95

10.6

11.0

Sex ratio (m/f)

0.77

0.96

0.88

0.94

0.69

0.72

Dead foetuses

15

2

5

2

18

3

Percent partial dead

19.0

9.52

18.2

9.09

30.4

12.5

percent all dead

-

-

-

-

4.35

-

Average foetus weight (g)

0.89

0.88

0.81

0.83

0.76

0.77

*Aspirin 150.0 mg/kg

Table 2 - Summary of skeletal findings

Dose (mg/kg)

Sham

Positive control*

2.4

11.0

52.0

238.0

Sternebrae

Incomplete oss

83/18

54/15

124/22

45/14

81/19

113/23

Scrambled

1/1

-

-

-

-

-

Bipartite

5/4

3/3

1/1

6/3

7/6

3/2

Fused

-

-

-

-

1/1

-

Extra

1/1

-

1/1

-

-

1/1

missing

23/9

40/10

48/15

42/13

83/18

59/20

Ribs

More than 13

31/14

28/13

36/16

19/12

15/9

28/14

Vertebrae

Incomplete oss

1/1

19/6

15/8

19/7

18/8

12/5

Skull

Incomplete closure

-

-

-

-

1/1

-

(number of foetuses effected/number of litters)

No soft tissue abnormalities observed

Conclusions:
Under the conditions of the study, the test material administered to pregnant mice for 10 consecutive days up to a dose of 250 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetoxicity is >238 mg/kg bw. The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control group.

This study is considered to be of adequate reliability and relevance to be submitted as the key study for this endpoint.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restrictions. 1. No data on assessment of gravid uteri.
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 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
1. No data on assessment of gravid uteri.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
Temeprature and humidity controlled environment
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug (vaginal plug considered as day 0 of gestation.)
Duration of treatment / exposure:
Day 6 through to 15 of gestation

Frequency of treatment:
Daily
Duration of test:
Treatment began on day 6 and ended on day 15, at day 20 the dams underwent caesarean section.
No. of animals per sex per dose:
22 - sham treated; 19 - positive control group; 22 - 1.7 mg/kg; 21 - 8.0 mg/kg; 23 - 37.0 mg/kg; 20 - 170.0 mg/kg.
Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg Apirin.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, for appearance and behaviour.
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 11, 15 and 20

POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 20

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was monitored to rule out abnormalities of anorexic effects.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: no data.
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two third per litter
- The body weight of live pups was also recorded.
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: please see below.

Details on maternal toxic effects:
Cage-side observations and periodic recording of bodyweight suggested no signs of toxicity. There were no discernible effects on nidation.
Dose descriptor:
NOEC
Effect level:
170 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: positive control: Aspirin 250.0 mg/kg

Details on embryotoxic / teratogenic effects:
The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control group.
Dose descriptor:
NOEC
Effect level:
170 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed
Abnormalities:
no effects observed
Developmental effects observed:
not specified

Table 1 - Reproduction data

Dose (mg/kg)

Sham

Positive control*

1.7

8.0

37.0

170.0

Pregnancy

Total no

22

19

22

21

23

20

Died or aborted

1

0

0

0

0

0

To term

21

19

22

21

23

20

Total corpora lutea

281

253

264

246

286

250

Average corpora lutea

11.7

10.5

12.0

10.7

11.9

11.9

Total live litters

21

18

22

21

23

20

Average implant site no

11.4

11.6

11.5

11.5

11.9

12.1

Resorptions

Percent partial resorptions

9.52

26.3

-

9.52

-

25.0

Percent complete resorptions

-

5.26

-

-

-

-

Average live foetus

11.2

9.95

11.5

11.4

11.8

11.8

Sex ratio (m/f)

0.97

0.85

1.17

1.01

0.93

0.73

Dead foetuses

1

6

-

-

1

-

Percent partial dead

4.76

10.5

-

-

4.35

-

percent all dead

-

-

-

-

-

-

Average fetus weight (g)

3.78

2.82

3.95

3.91

3.81

3.71

*Aspirin 250.0 mg/kg

Table 2 - Summary of skeletal findings

Dose (mg/kg)

Sham

Positive control*

1.7

8.0

37.0

170.0

Sternebrae

Incomplete oss

65/19

99/18

35/14

70/19

26/11

35/12

Bipartite

-

7/7

-

1/1

2/2

-

Extra

-

-

-

1/1

-

-

missing

22/11

92/16

16/6

11/7

9/4

6/3

Ribs

Wavy

12/7

46/14

17/6

11/7

20/7

12/6

Less than 12

-

-

1/1

-

-

-

More than 13

-

68/17

-

12/7

-

4/1

Vertebrae

Incomplete oss

18/9

69/17

17/10

22/11

15/10

21/9

Skull

Incomplete closure

34/13

92/17

35/12

34/12

25/13

38/11

Missing

-

1/1

-

-

-

-

Extremities

Incomplete oss

-

15/7

-

-

-

-

Missing

-

-

-

-

-

1/1

Miscellaneous

Hyoid; missing

37/14

70/18

19/12

27/13

29/17

28/10

Hyoid; reduced

18/9

18/11

23/10

25/13

26/8

29/12

(number of foetuses effected/number of litters)

No soft tissue abnormalities were observed except in the sham control and positive control groups

Conclusions:
Under the conditions of the study, the test material administered to pregnant rats for 10 consecutive days up to a dose of 170 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetoxicity is >170 mg/kg bw. The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control group.

This study is considered to be of adequate reliability and relevance to be submitted as the key study for this endpoint.
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Comparable to OECD guideline 414 with acceptable restrictions. 1. This study is performed on hamsters not on the rat or rabbit as recommended. 2. There is no data on the assessment of gravid uteri.
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 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
1. This study is performed on hamsters not on the rat or rabbit as recommended. 2. There is no data on the assessment of gravid uteri.
GLP compliance:
not specified
Limit test:
no
Species:
hamster
Strain:
other: Golden
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Housing: mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
Temperature and humidity controlled environment.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation.
Duration of treatment / exposure:
Days 6 through to 10 of gestation.
Frequency of treatment:
Daily
Duration of test:
Treatment began on day 6 and ended on day 10, at day 14 all animals were subjected to caesarean section.
No. of animals per sex per dose:
21 - sham treated control;
20 - positive control;
21- 1.41 mg/kg;
20- 6.5 mg/kg;
20 - 30.0 mg/kg;
21 -141.0 mg/kg
Control animals:
yes, sham-exposed
other: positive control - Aspirin 250.0 mg/kg
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, for appearance and behaviour
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 8, 11 and 14

POST-MORTEM EXAMINATIONS: No data
- Sacrifice on gestation day 14

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was monitored to rule out abnormalities of anorexic effects.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data.
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two third per litter
Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: please see below.

Details on maternal toxic effects:
Cage-side observations and periodic recording of bodyweight suggested no signs of toxicity. There were no discernible effects on nidation.
Dose descriptor:
NOEC
Effect level:
141 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham treated control group.
Dose descriptor:
NOEC
Effect level:
141 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1 - Reproduction data

Dose (mg/kg)

Sham

Positive control*

1.41

6.5

30.0

141.0

Pregnancy

Total no

21

20

21

20

20

21

Died or aborted

2

2

3

4

1

2

To term

19

18

18

16

19

19

Total corpora lutea

299

277

289

276

287

295

Average corpora lutea

13.6

11.5

12.0

11.0

11.0

12.3

Total live litters

18

18

18

16

19

18

Average implant site no

13.6

12.3

12.9

12.5

12.3

14.0

Resorptions

Percent partial resorptions

36.8

22.2

50.0

31.3

5.26

26.3

Percent complete resorptions

-

-

-

-

-

5.26

Average live foetus

12.3

11.8

12.3

12.1

12.0

13.0

Sex ratio (m/f)

0.97

0.97

0.91

0.82

0.85

0.82

Dead foetuses

16

1

1

-

3

1

Percent partial dead

15.8

5.56

5.56

-

15.8

5.26

percent all dead

-

-

-

-

-

-

Average foetus weight (g)

1.76

1.75

1.87

1.81

1.77

1.82

*Aspirin 250.0 mg/kg

Table 2 - Summary of skeletal findings

Dose (mg/kg)

Sham

Positive control*

1.41

6.5

30.0

141.0

Sternebrae

Incomplete oss

64/18

50/15

41/14

31/13

65/18

68/17

Bipartite

37/16

16/12

27/11

18/13

18/12

24/12

Fused

-

1/1

1/1

-

1/1

-

Extra

2/2

3/1

7/2

2/1

2/2

3/3

missing

25/10

18/6

31/8

10/6

32/12

24/11

Ribs

Fused/split

-

-

1/1

-

-

-

More than 13

35/13

24/10

20/10

9/5

34/14

29/12

Vertebrae

Incomplete oss

12/18

19/8

10/5

4/2

12/6

17/9

Skull

Incomplete closure

-

-

1/1

-

3/1

-

Extremities

Incomplete oss

46/13

42/12

38/9

23/9

36/12

42/13

Missing

4/3

-

4/3

2/1

-

-

Extra

-

-

2/1

1/1

-

-

Miscellaneous

Hyoid; missing

2/1

4/3

3/3

-

1/1

-

Hyoid; reduced

3/2

4/4

2/2

2/2

7/5

4/2

Ischium; missing

-

1/1

-

-

-

-

(number of foetuses effected/number of litters)

Two foetuses from the 1.41 mg/kg dose group and one from the 30 mg/kg dose group showed soft tissue abnormalities (not at the highest doses).

Conclusions:
Under the conditions of the study, the test material administered to pregnant hamsters for 5 consecutive days up to a dose of 141 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetoxicity is >141 mg/kg bw.

This study is considered to be of adequate reliability and relevance to be submitted as the key study for this endpoint.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
170 mg/kg bw/day
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. Assessment of the key study: In the prenatal developmental toxicity studies, pregnant females received pentasodium triphosphate (anhydrous) during the gestation period by oral intubation. Control groups received the vehicle only (water). At the end of gestation period, all dams were subjected to caesarean section and the number of implantation sites, resorption sites, as well as live and dead foetuses were recorded. The body weights and sex of the live pups were taken. The urogenital tract level of dams was examined for abdominal abnormalities. All foetuses were examined for the presence of external congenital abnormalities. One-third of the foetuses were examined for visceral abnormalities and the remaining two-third were examined for skeletal abnormalities. No maternal toxicity or teratogenic effects were observed at up to the maximum dose levels tested in each species. The NOEL for maternal and foetal toxicity corresponded to the maximum dose tested.

Table 1- Summary of teratogenicity studies with sodium tripolyphosphate

Organism tested

animal / group

Dose

(mg/kg bw)

Treatment period (gestation day)

End of gestation

Result

(NOEL)

Mouse

24

2.4, 11, 52, 238

6-16

Day 17

238 mg/kg

Rat

24

1.7, 8, 37, 170

6-15

Day 20

170 mg/kg

Hamster

22-25

1.41, 6.5, 30, 141

6-10

Day 14

141 mg/kg

Rabbit

12 -15

2.5, 11.6, 54, 250

6-18

Day 29

250 mg/kg

 

The study conducted in rats is comparable to the modern day guideline OECD 414 - the only deficiency being that gravid uteri were not weighed (it is worth noting that uteri displayed no gross abnormalities when examined at necropsy).

Taken together all 4 studies provide reliable evidence that the test material is not a developmental toxicant.

Justification for classification or non-classification

The NOAEL recorded in the developmental and reproductive toxicity endpoints are for the highest doses tested and are above the limits for classification according to Regulation (EC) 1272/2008 (EU CLP), it is therefore considered that pentapotassium triphosphate will not be classified.

Additional information