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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1/9/74 - 5/10/74
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights not determined One third used for visceral examination; should be 50% Test substance identification (Batch etc) missing No details on housing conditions/source of animals Administration only during periods of organogenesis, not until day before pregnancy
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) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74-anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the genotoxicity of the substances therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group.

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’.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974
Report date:
1974

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female albino CD-1 mice were mated with young adult males. Observation of a vaginal sperm plug was considered as Day 0 of gestation. Dosing by oral intubation with a control (Vehicle at level equivalent to group receiving the highest dose or aspirin at 150 mg/kg) or test article in a water suspension (10 mL/kg bw) at 1.3, 6.0, 28.0 and 130.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. Sex, numbers of corporea lutea, Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third foetuses of each litter underwent detailed visceral examination and the remaining two thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
GLP compliance:
no
Remarks:
Study predates GLP
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrasodium pyrophosphate
EC Number:
231-767-1
EC Name:
Tetrasodium pyrophosphate
Cas Number:
7722-88-5
Molecular formula:
H4O7P2.4Na
IUPAC Name:
tetrasodium diphosphate
Details on test material:
- Name of test material (as cited in study report): FDA 73-1 (tetrasodium pyrophosphate, anhydrous)
- Physical state: Fine white powdered material

Test animals

Species:
mouse
Strain:
other: albino CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 29 - 31 g
- Fasting period before study: No data
- Housing: Gang housing in disposable plastic cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26.67
- Humidity (%): 62 - 76

IN-LIFE DATES: 1/9/74 - 5/10/74

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 10 mL/kg bodyweight
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days (Day 6 to Day 15 of gestation)
Frequency of treatment:
Daily
Duration of test:
17 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 30 21
Aspirin 150.0 25 20
FDA 71-3 1.3 24 20
6.0 27 20
28.0 26 18
130.0 29 21
Control animals:
yes, sham-exposed
other: positive control: 150 mg/kg aspirin

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Appearence, behaviour, food consumption and weight observed daily.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on days 0, 6, 11, 15 and 17.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: uterus and urogenital tract
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: one third per litter
- Soft tissue examinations: Yes: one third per litter
- Skeletal examinations: Yes: two thirds per litter
- Head examinations: Yes: two thirds per litter
Statistics:
No data
Indices:
No data
Historical control data:
No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 130 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 130 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

1.3

6.0

28.0

130.0

Pregnancies

 

 

 

 

 

 

Total No.

21

20

20

20

18

21

Died or aborted (before Day 17)

0

0

0

0

0

0

To term (on Day 17)

21

20

20

20

18

21

Corpora Lutea

 

 

 

 

 

 

Total no.

277

253

239

254

224

261

Average/dam mated

9.23

10.1

10.4

9.41

8.62

9.32

Live litters

 

 

 

 

 

 

Total No.*

21

20

20

20

18

20

Implant Sites

 

 

 

 

 

 

Total No.

250

220

231

237

209

243

Average/dam*

11.9

11.0

11.6

11.9

11.6

11.6

Resorptions

 

 

 

 

 

 

Total No*

9

11

11

13

17

18

Dams with 1 or more sites resorbed

6

8

7

9

10

9

Dams with all sites resorbed

--

--

--

--

--

1

Per cent partial resorptions

28.6

40.0

35.0

45.0

55.6

42.9

Per cent complete resorptions

--

--

--

--

--

4.76

Live foetuses

 

 

 

 

 

 

Total No

240

209

219

223

191

223

Average/dam*

11.4

10.5

11.0

11.2

10.6

10.6

Sex ratio (M/F)

0.86

0.99

0.92

1.14

1.01

1.05

Dead Foetuses

 

 

 

 

 

 

Total No.*

1

--

1

1

1

2

Dams with 1 or more dead

1

--

1

1

1

2

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

4.76

--

5.00

5.00

5.56

9.52

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

0.90

0.91

0.91

0.90

0.91

0.88

* Includes only those dams examined at term

** Positive control: 150 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

1.3

6.0

28.0

130.0

Live foetuses examined (at term)

165/21

146/20

150/20

157/20

134/18

157/20

Sternebrae

 

 

 

 

 

 

Incomplete oss.

28/9

66/18

12/7

61/18

14/10

19/9

Scrambled

 

 

 

 

 

 

Bipartite

1/1

3/3

 

 

 

 

Fused

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Missing

17/7

21/10

9/6

17/8

13/7

10/7

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

 

Wavy

 

 

1/1

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

25/13

32/12

31/16

21/11

29/13

38/13

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

7/6

4/4

4/3

2/1

5/4

6/4

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

 

 

 

 

2/1

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

 

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

4/2

5/4

2/2

3/2

1/1

5/4

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

32/11

33/14

26/12

40/15

37/12

31/14

Hyoid; reduced

13/8

23/11

11/8

21/11

13/8

20/13

* Numerator = Number of foetuses affected; Denominator = Number of litters affected

** Positive control: 150 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

Aspirin

150.0

23629

1

Cleft palate

FD 73-1

6.0

23700

1

Exophthalmos; encephalomeningocele

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the test material administered to pregnant mice for 10 days up to a dose level of 130 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and fetotoxicity is > 130 mg/kg bw.