Registration Dossier

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:
No data
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) 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-referenceopen allclose all
Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
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
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’.
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
read-across: supporting information
Qualifier:
according to
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 3.35, 15.6, 72.3 and 335.0 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. 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
Species:
mouse
Strain:
other: albino CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 26.3 - 29.3 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): No data
- Humidity (%): No data

IN-LIFE DATES: No data
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 25 25
Aspirin 150.0 24 21
FDA 71-61 3.35 25 23
15.6 25 23
72.3 24 23
335.0 25 22
Control animals:
yes, sham-exposed
other: positive control: 150 mg/kg aspirin
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: No
- 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
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 335 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
Dose descriptor:
NOAEL
Effect level:
> 335 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 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin**

3.35

15.6

72.3

335.0

Pregnancies

 

 

 

 

 

 

Total No.

25

21

23

23

23

22

Died or aborted (before Day 17)

0

0

0

0

0

0

To term (on Day 17)

25

21

23

23

23

22

Live litters

 

 

 

 

 

 

Total No.*

25

20

23

23

23

21

Implant Sites

 

 

 

 

 

 

Total No.

286

254

280

279

265

256

Average/dam*

11.4

12.1

12.2

12.1

11.5

11.6

Resorptions

 

 

 

 

 

 

Total No*

17

37

8

3

10

24

Dams with 1 or more sites resorbed

10

13

6

2

9

9

Dams with all sites resorbed

0

1

0

0

0

1

Per cent partial resorptions

40.0

61.9

26.1

8.70

39.1

40.9

Per cent complete resorptions

--

4.76

--

--

--

4.55

Live foetuses

 

 

 

 

 

 

Total No

264

217

271

274

255

229

Average/dam*

10.6

10.3

11.8

11.9

11.5

10.4

Sex ratio (M/F)

0.96

0.75

0.75

0.73

0.82

0.84

Dead Foetuses

 

 

 

 

 

 

Total No.*

5

0

1

2

0

3

Dams with 1 or more dead

4

--

1

2

--

3

Dams with all dead

0

--

0

0

--

0

Per cent partial dead

16.0

--

4.35

8.70

--

13.6

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

0.88

0.84

0.84

0.89

0.86

0.85

* Includes only those dams examined at term

** Positive control: 150 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin**

3.35

15.6

72.3

335.0

Live foetuses examined (at term)

183/25

154/20

188/23

190/23

176/23

159/21

Sternebrae

 

 

 

 

 

 

Incomplete oss.

23/10

34/13

19/11

45/13

33/13

29/9

Scrambled

 

 

 

 

 

 

Bipartite

5/4

6/5

9/7

10/9

5/3

9/6

Fused

 

 

 

 

 

 

Extra

 

1/1

 

 

 

1/1

Missing

35/14

26/11

27/11

39/8

30/10

14/6

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

3/1

 

2/1

 

Fused/split

 

1/1

 

 

 

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

12/7

37/15

34/15

32/14

38/11

31/15

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

4/3

9/5

12/4

8/3

4/2

4/2

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

 

1/1

 

 

 

Missing

 

 

1/1

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

 

 

1/1

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

4/3

6/4

12/6

7/3

7/3

4/2

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

29/12

35/15

39/15

52/16

46/15

33/13

Hyoid; reduced

17/13

23/13

24/12

18/10

17/13

23/10

* 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

A 3911

1

Microblepharia

Gastroschisis

FDA 71-61

3.35

M 3010

1

Umbilical hernia

FDA 71-61

15.6

M3033

1

Umbilical hernia

 

 

M 3053

1

Hydrocephalus

FDA 71-61

72.3

M3078

1

Hydrocephalus

Conclusions:
Under the conditions of the study, the test material administered to pregnant mice for 10 days up to a dose level of 335 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and foetal toxicity is > 335 mg/kg bw.
This study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006) and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as part of a weight of evidence approach.
Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
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
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’.
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female Dutch-belted rabbits were dosed on Day 0 with a single injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. After three hours each doe was artificially inseminated with 0.3 mL diluted semen from a donor buck using 20 x 10E06 motile sperm. Dosing by oral intubation with a control (Vehicle at level equivalent to group receiving the highest dose) or test article in a water suspension at 1.28, 5.95, 27.6 and 128.0 mg/kg was carried out daily on Days 6 to 18 of gestation. The positive control 6-aminonicotinamide at 2.5 mg/kg was dosed on Day 9. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 29 all does underwent Caesarean section. Number of corpora 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. Live foetuses of each litter were then placed in an incubator for 24 hours for evaluation of neonatal survival. All pups underwent detailed visceral examination. All foetuses 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
Species:
rabbit
Strain:
Dutch
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 2.17 - 2.51 kg
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data

IN-LIFE DATES: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: artificial insemination
- Proof of pregnancy: No data
Duration of treatment / exposure:
13 days (Day 6 to Day 18 of gestation)
Frequency of treatment:
Daily
Duration of test:
29 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 17 11
6-AN 2.5 15 10
FDA 71-61 1.28 15 12
5.95 16 12
27.6 20 9
128.0 15 11
Control animals:
yes, sham-exposed
other: positive control: 2.5 mg/kg 6-aminonicotinamide (6-AN)
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, 12, 18 and 29.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- 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
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
No data
Indices:
No data
Historical control data:
No
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 128 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:
No dose related response observed.
Dose descriptor:
NOAEL
Effect level:
> 128 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 2 Reproduction data

Dose (mg/kg)

Sham

6-AN

1.28

5.95

27.6

128.0

Pregnancies

 

 

 

 

 

 

Total No.

11

10

12

12

9

11

Died or aborted (before Day 29)

1

0

0

2

0

0

To term (on Day 29)

10

10

12

10

9

11

Corpora Lutea

 

 

 

 

 

 

Total no.

175

132

146

191

140

159

Average/dam mated

14.6

12.0

12.2

13.6

9.33

12.2

Live litters

 

 

 

 

 

 

Total No.*

10

6

12

9

9

11

Implant Sites

 

 

 

 

 

 

Total No.

53

42

70

64

44

80

Average/dam*

5.30

4.20

5.83

6.40

4.89

7.27

Resorptions

 

 

 

 

 

 

Total No*

--

18

3

9

1

7

Dams with 1 or more sites resorbed

--

6

2

3

1

5

Dams with all sites resorbed

--

4

--

1

--

--

Per cent partial resorptions

--

60.0

16.7

30.0

11.1

45.5

Per cent complete resorptions

--

40.0

--

10.0

--

--

Live foetuses

 

 

 

 

 

 

Total No

52

19

67

55

43

73

Average/dam*

5.20

1.90

5.58

5.50

4.78

6.64

Sex ratio (M/F)

0.73

5.00

0.63

1.04

1.26

0.92

Dead Foetuses

 

 

 

 

 

 

Total No.*

1

5

--

--

--

73

Dams with 1 or more dead

1

2

--

--

--

--

Dams with all dead

--

--

-

--

--

--

Per cent partial dead

10.0

20.0

--

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

42.2

29.7

37.0

36.0

40.0

35.8

* Includes only those dams examined at term

** Positive control: 2.5 mg/kg 6-AN dosed on Day 9

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

6-AN

1.28

5.95

27.6

128.0

Live foetuses examined (at term)

52/10

19/6

67/12

55/9

43/9

72/11a

Sternebrae

 

 

 

 

 

 

Incomplete oss.

2/2

1/1

 

1/1

2/2

 

Scrambled

 

 

 

 

 

 

Bipartite

 

1/1

 

1/1

 

1/1

Fused

 

3/2

 

 

 

 

Extra

 

1/1

2/1

 

 

6/4

Missing

 

2/2

 

 

 

 

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

5/2

 

 

3/1

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

 

 

 

 

 

 

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Scrambled

 

4/2

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

4/3

 

 

 

 

Tail defects

 

13/4

 

 

1/1

1/1

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

1/1

 

 

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

1/1

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

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

** Positive control: 2.5 mg/kg 6-AN dosed on Day 9

a One pup lost in processing

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

6-AN

2.5

Z 6479

1

Medial rotation of hind limbs

 

 

Z 6488

1

Medial rotation of hind limbs

 

 

Z 6489

1

Siamese pups (combined stomach and head)

 

 

Z 6490

3

Anopia, Medial rotation of hind limbs

 

 

 

2

Anopia

FDA 71-61

27.6

M 6051

2

Anopia

Conclusions:
Under the conditions of the study, the test material administered to pregnant rabbits for 13 days up to a dose level of 128 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and foetal toxicity is > 128 mg/kg bw.

This study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006) and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as part of a weight of evidence approach.
Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
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
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’.
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female albino (Wistar derived stock) rats 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 250 mg/kg) or test article in a water suspension at 1.69, 9.24, 42.95 and 169.0 mg/kg was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. Daily room temperature was recorded. On Day 20 of gestation all dams underwent Caesarean section. Number of 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
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 214 - 225 g
- Fasting period before study: No data
- Housing: Individual housing in mesh bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not recorded
- Humidity (%): Not recorded

IN-LIFE DATES: No data
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: No data
- 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:
20 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 25 23
Aspirin 250.0 24 21
FDA 71-61 1.69 25 24
9.24 25 24
42.95 24 24
169.0 25 21

Control animals:
yes, sham-exposed
other: positive control: 250 mg/kg aspirin
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 20.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- 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: No
- 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
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
> 169 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
Dose descriptor:
NOAEL
Effect level:
> 169 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 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

1.69

9.24

42.95

169.0

Pregnancies

 

 

 

 

 

 

Total No.

23

21

24

24

24

21

Died or aborted (before Day 20)

0

1

0

0

0

0

To term (on Day 20)

23

20

24

24

24

21

Live litters

 

 

 

 

 

 

Total No.*

23

18

24

24

24

21

Implant Sites

 

 

293

 

 

 

Total No.

283

234

12.2

284

287

254

Average/dam*

12.3

11.7

 

11.8

12.0

12.1

Resorptions

 

 

 

 

 

 

Total No*

4

35

4

4

4

--

Dams with 1 or more sites resorbed

2

5

4

4

3

--

Dams with all sites resorbed

--

2

--

--

--

--

Per cent partial resorptions

8.70

25.0

16.7

16.7

12.5

--

Per cent complete resorptions

--

10.0

--

--

--

--

Live foetuses

 

 

 

 

 

 

Total No

279

197

288

280

283

254

Average/dam*

12.1

9.85

12.0

11.7

11.8

12.1

Sex ratio (M/F)

1.08

0.80

1.27

1.00

0.98

1.03

Dead Foetuses

 

 

 

 

 

 

Total No.*

--

2

1

--

--

--

Dams with 1 or more dead

--

2

1

--

--

--

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

--

10.0

4.17

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

3.65

2.41

3.71

3.78

3.78

3.75

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

1.69

9.24

42.95

169.0

Live foetuses examined (at term)

191/23

137/18

198/24

193/24

196/24

176/21

Sternebrae

 

 

 

 

 

 

Incomplete oss.

71/20

86/16

83/19

54/19

61/16

47/17

Scrambled

 

 

 

 

 

 

Bipartite

 

7/5

 

 

2/2

4/3

Fused

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Missing

7/6

117/7

9/7

15/8

1/1

5/4

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

1/1

3/2

3/2

 

 

1/1

Fused/split

 

14/4

 

 

 

 

Wavy

14/8

54/14

34/9

12/7

15/8

13/8

Less than 12

 

 

 

 

 

 

More than 13

1/1

89/15

6/5

3/3

 

6/5

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

6/5

120/17

12/4

21/11

5/4

10/8

Scrambled

 

1/1

 

 

 

 

Fused

 

 

1/1

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

3/3

 

 

 

 

Tail defects

 

1/1

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

23/10

60/13

50/16

31/12

25/13

20/11

Missing

 

9/4

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

1/1

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

 

4/3

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

19/11

69/17

37/15

14/9

26/13

7/6

Hyoid; reduced

7/5

20/8

38/14

27/12

35/16

28/12

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

** Positive control: 250 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

Aspirin

250.0

A 4910

1

Encepalomyelocele

 

 

A 4913

1

Exencephaly; exophthalmos

 

 

A 4917

1

Renal agenesis

 

 

A 4921

1

Encephalomyelocele; gastroschisis

 

 

A 4923

3

Encephalomyelocele

 

 

 

1

Exophthalmos; gastroschisis

 

 

A 4925

2

Encepalomyelocele

FDA 71-61

42.95

M 4076

1

Gastroschisis

Conclusions:
Under the conditions of the study, the test material administered to pregnant rats for 10 days up to a dose level of 169 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and foetal toxicity is > 169 mg/kg bw.

This study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006) and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as part of a weight of evidence approach.
Reason / purpose:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1973
Report Date:
1973

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: no data
Deviations:
not specified
Principles of method if other than guideline:
Adult female golden hamsters were mated with mature males (1:1). Observation of motile sperm in the vaginal smear 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 250 mg/kg) or test article in a water suspension at 1.66, 7.71, 35.8 and 166.0 mg/kg was carried out daily on Days 6 to 10 of gestation. Observations of body weight, appearence, behaviour, and food consumption were performed. On Day 14 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses recorded. Body weights of live pups recorded. Genital 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

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FDA 71-61 (sodium acid pyrophosphate)
- Physical state: Fine white powdered material

Test animals

Species:
hamster
Strain:
other: Golden
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 122.2 - 133.4 g
- Fasting period before study: No data
- Housing: Individually housed in mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data

IN-LIFE DATES: No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE: Water
- Amount of vehicle (if gavage): 1 mL/kg bw at doses equal to or below 250 mg/kg bw and 2 mL/kg at doses up to 500 mg/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: 1:1 mating
- Proof of pregnancy: appearence of motile sperm in vaginal smear
Duration of treatment / exposure:
5 days (Day 6 to Day 10 of gestation)
Frequency of treatment:
Daily
Duration of test:
14 days
No. of animals per sex per dose:
Table 1 Number of animals dosed
Material Dose (mg/kg) Total
Mated Pregnant
Sham 0.0 22 20
Aspirin 250 22 21
FDA 71-81 1.66 22 20
7.71 24 20
35.8 22 21
166.0 22 22
Control animals:
yes, sham-exposed
other: positive control: 250 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, 8, 10 and 14.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: uterus and genital 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: No
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
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:
> 166 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:
> 166 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

1.66

7.71

35.8

166.0

Pregnancies

 

 

 

 

 

 

Total No.

20

21

20

20

21

22

Died or aborted (before Day 14)

0

0

0

0

1

1

To term (on Day 14)

20

21

20

20

20

21

Live litters

 

 

 

 

 

 

Total No.*

20

21

20

20

20

21

Implant Sites

 

 

 

 

 

 

Total No.

298

311

292

289

290

300

Average/dam*

14.9

14.8

14.6

14.5

14.5

14.3

Resorptions

 

 

 

 

 

 

Total No*

1

8

1

1

1

8

Dams with 1 or more sites resorbed

1

6

1

1

1

5

Dams with all sites resorbed

--

--

--

--

--

--

Per cent partial resorptions

5.00

28.6

5.00

5.00

5.00

23.8

Per cent complete resorptions

--

--

--

--

--

--

Live foetuses

 

 

 

 

 

 

Total No

295

303

291

288

289

292

Average/dam*

14.8

14.4

14.6

14.4

14.5

13.9

Sex ratio (M/F)

0.89

0.94

0.81

0.78

0.75

0.75

Dead Foetuses

 

 

 

 

 

 

Total No.*

2

--

--

--

--

--

Dams with 1 or more dead

2

--

--

--

--

--

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

10.0

--

--

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

1.70

1.72

1.72

1.82

1.82

1.75

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

1.66

7.71

35.8

166.0

Live foetuses examined (at term)

204/20

209/21

200/20

199/20

202/20

202/21

Sternebrae

 

 

 

 

 

 

Incomplete oss.

131/20

85/20

124/20

69/17

88/18

80/20

Scrambled

 

 

 

 

 

 

Bipartite

18/9

16/11

22/14

20/11

15/9

25/13

Fused

 

 

 

 

 

 

Extra

8/2

 

1/1

6/3

5/3

 

Missing

53/14

48/13

49/12

39/10

33/10

51/14

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

2/1

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

62/17

56/13

46/16

69/17

38/13

60/16

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

2/2

15/5

 

1/1

 

8/2

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

 

 

 

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other

 

 

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

4/4

17/6

 

6/4

 

13/3

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

6/6

14/6

5/4

4/2

2/1

13/3

Hyoid; reduced

7/7

6/5

9/7

7/3

6/5

8/6

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

** Positive control: 250 mg/kg

 

Table 4 Summary of soft tissue abnormalities

Material

Dose level (mg/kg)

Dam

Number of pups

Description

Sham

0.0

S 5908

1

Meningoencephalocele

 

 

S 5914

1

Hydrocephalus

Aspirin

250.0

A 5912

1

Hepatomegaly

FDA 71-61

1.66

M 5013

1

Hydrocephalus

FDA 71-61

166.0

M 5092

4

Hydrocephalus

 

 

 

2

Hydromyelia

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the test material administered to pregnant hamsters for 5 days up to a dose level of 166 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and foetal toxicity is > 166 mg/kg bw.

This study is considered to be adequate and reliable for the purpose of registration under REACH (Regulation (EC) No. 1907/2006) and for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as part of a weight of evidence approach.