Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data is available with the test substance regarding toxicity to reproduction.

A data waiver is set in place to justify that no further testing on reproductive toxicity is required.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are currently no experimental data available to assess reproductive toxicity for the test substance.

A combined repeated dose and reproduction study (Test Guideline OECD 422) was conducted on dipotassium orthophosphate in the rat on behalf of the National Institute of Environmental Research, and reported publicly in the OECD SIDS (1) dossier for that substance.Since the phosphorus is considered to be the critical part in calcium phosphates (see discussion below) this study is reliable to be used as read across. The OECD study design allows for an evaluation of key aspects of the reproductive cycle including oestrous cycle and spermatogenic cycle, mating performance, fertility, pregnancy and early post-natal offspring development. The test material was administered orally to rats throughout this period of reproduction (approximately 40 - 50 days) at dose levels up to 1000 mg/kg bw per day. There was no evidence to suggest an effect upon reproduction or offspring development and the NOAEL was determined to be >1000 mg/kg bw, considered to be a “limit dose” in the OECD. The lead registrant has sought to access this data however it has not been possible to agree data sharing terms for all co-registrants. As soon as this data is available it will be integrated in the dossier. Nonetheless, the lack of effects on reproduction or offspring development at dose levels well in excess of normal human exposure suggests that calcium and potassium orthophosphates are not a significant risk to the reproduction in females or males and not a significant risk to the developing foetus. Further studies are unlikely to show any significant effects on reproductive performance or development.

Magnesium and calcium phosphates are approved for use as food additives (the EU food reference for calcium phosphate is E341 and for magnesium phosphate is E343). No evidence exists to show that magnesium or calcium phosphates are likely to pose a risk of reproductive or developmental toxicity. In addition, the Mg2+and Ca2+cation have a similar and essential biological function and excess of this ion results in well documented toxicity; this does not include toxicity to reproduction or developmental toxicity. The World Health Organisation, reports that the maximum tolerable daily intake (MTDI) for phosphates for all individuals is 70 mg P/kg bw (2), this value is considered to be well below that observed for developmental toxicity and as such human exposure is likely to be considerably less that the level required for reproductive toxicity testing. No effects on development were observed at the highest dose tested in animal studies. Reference values for the intake of calcium are considerably higher than that for phosphorus: Adequate intake (AI) value for calcium in 19-30 years old is 1000 mg/dayand the Estimated Average Requirement (EAR) for magnesium in males aged 19-30 is 330 mg/day and for females aged 19-30 is 255 mg/day(3). These values indicate that humans will generally be exposed to relatively high daily levels with no adverse effects. In conclusion, an additional extended one-generation reproductive toxicity study in the rat is unlikely to result in providing further evidence of reproductive toxicity as the existing studies have demonstrated a lack of effect at dose levels well in excess of expected human exposure. A study would therefore be scientifically and ethically unjustified.

(1)http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=545E2F43-CF57-4AED-8784-

C0391BCCC562

(2)Evaluation of certain food additives and contaminants. Twenty-sixth report of the joint FAO/WHO expert committee of food additives. World Health Organisation. Technical Report Series 683. 1982. ISBN92 4 120683 7

(3)Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, of. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride., Press, 1997.

Effects on developmental toxicity

Description of key information

No data are available for magnesium hydrogenorthophosphate.

Reliable data is available for calcium dihydrogenorthophosphate monohydrate (CAS 10031-30-8):

Prenatal developmental toxicity (similar to OECD 414), mice: NOAELmaternal ≥ 465 mg/kg bw/day; NOAELdevelopmental ≥ 465 mg/kg bw/day

Prenatal developmental toxicity (similar to OECD 414), rat: NOAELmaternal ≥ 410 mg/kg bw/day; NOAELdevelopmental ≥ 410 mg/kg bw/day

Prenatal developmental toxicity (similar to OECD 414), rabbit: NOAELmaternal ≥ 217 mg/kg bw/day; NOAELdevelopmental ≥ 217 mg/kg bw/day

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Description (incidence and severity):
Urogenital tract was observed but no data regarding this point were described in the report.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
For sham- and test substance treated animals no abortions were observed. In the control group with Aspirin 1 animal died or aborted.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implant sites (total number/average per dam):
0 mg/kg bw: 261 / 11.9
4.65 mg/kg bw: 283 / 11.8
21.6 mg/kg bw: 225 / 11.8
100 mg/kg bw: 244 / 11.1
465 mg/kg bw: 265 / 11.5
Aspirin: 224 / 11.8
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Resorptions:
Group (mg(kg bw): 0 4.65 21.6 100 465 Aspirin
Total number: 8 19 4 12 28 20
Dams with >=1 site resorbed: 7 13 3 10 12 9
Dams with all sites resobred: - - - - 1 -
% partial resorption: 31.8 54.2 15.8 45.5 52.2 47.4
% complete resorption: - - - - 4.35 -
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Description (incidence and severity):
Dead fetuses:
Group (mg/kg bw): 0 4.65 21.6 100 465 Aspirin
Total: 1 - - 2 4 3
Dams with 1 or more dead: 1 - - 2 3 3
Dams with all dead: - - - - - -
% partial dead: 4.55 - - 9.09 13.0 15.8
% all dead: - - - - - -
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
> 465 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
> 465 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
number of abortions
pre and post implantation loss
dead fetuses
necropsy findings
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Description (incidence and severity):
Fetal body weights after Caesarean section were determined. The average body weights of fetuses were similar in all groups (see table 2 below).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
see table 2 for details
Changes in sex ratio:
no effects observed
Description (incidence and severity):
see tabel 2 for details
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
increase of incomplete ossification of sternebrae and extremities was observed in the highest dose group (see table 3 below for details)
Visceral malformations:
no effects observed
Description (incidence and severity):
see details in table 4 below
Key result
Dose descriptor:
NOAEL
Remarks:
fetal toxicity
Effect level:
>= 465 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
>= 465 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations
visceral malformations
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

4.65

21.6

100.0

465.0

Pregnancies

 

 

 

 

 

 

Total No.

22

20

24

19

22

23

Died or aborted (before Day 17)

0

1

0

0

0

0

To term (on Day 17)

22

19

24

19

22

23

Live litters

 

 

 

 

 

 

Total No.*

22

19

24

19

22

22

Implant Sites

 

 

 

 

 

 

Total No.

261

224

283

225

244

265

Average/dam*

11.9

11.8

11.8

11.8

11.1

11.5

Resorptions

 

 

 

 

 

 

Total No*

8

20

19

4

12

28

Dams with 1 or more sites resorbed

7

9

13

3

10

12

Dams with all sites resorbed

--

--

--

--

--

1

Per cent partial resorptions

31.8

47.4

54.2

15.8

45.5

52.2

Per cent complete resorptions

--

--

--

--

--

4.35

Live foetuses

 

 

 

 

 

 

Total No

252

201

261

221

230

233

Average/dam*

11.5

10.6

10.9

11.6

10.5

10.1

Sex ratio (M/F)

1.02

0.88

0.78

0.92

1.13

0.93

Dead Foetuses

 

 

 

 

 

 

Total No.*

1

3

--

--

2

4

Dams with 1 or more dead

1

3

--

--

2

3

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

4.55

15.8

--

--

9.09

13.0

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

0.84

0.81

0.88

0.87

0.82

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

4.65

21.6

100.0

465.0

Live foetuses examined (at term)

179/22

141/19

186/24

155/19

162/22

164/22

Sternebrae

 

 

 

 

 

 

Incomplete oss.

10/8

31/10

18/9

27/15

22/10

28/15

Scrambled

 

 

 

 

 

 

Bipartite

8/7

3/3

11/8

9/7

10/8

9/6

Fused

 

 

 

 

 

 

Extra

 

6/3

 

 

 

 

Missing

23/10

28/11

13/9

13/6

32/14

23/7

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

9/4

Fused/split

 

2/2

 

 

 

 

Wavy

 

1/1

2/2

 

 

 

Less than 12

1/1

 

1/1

 

 

1/1

More than 13

48/18

30/12

42/18

18/11

32/15

34/17

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

9/6

9/3

2/2

1/1

11/4

13/4

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

2/2

 

 

 

 

Missing

 

 

1/1

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

 

 

 

 

2/1

Extremities

 

 

 

 

 

 

Incomplete oss.

7/5

5/3

2/2

 

10/5

14/4

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

37/16

33/11

31/15

22/12

52/15

33/13

Hyoid; reduced

17/11

25/12

17/11

21/14

15/11

27/14

* 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 6068

1

Cleft palate; gastroschisis

Conclusions:
Under the conditions of the study, calcium dihydrogenorthophosphate monohydrate administered to pregnant mice for 10 days up to a dose level of 465 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 465 mg/kg bw. Therefore, a NOAEL for magnesium hydrogenortophosphate is also estimated to be > 465 mg/kg bw for both maternal and developmental toxicity.
Executive summary:

The maternal and developmental NOAEL for magnesium hydrogenorthophosphate was estimated to be > 465 mg/kg bw, which was the highest dose tested. As explained in the justification for type of information, the differences in molecular structure between magensium hydrogenorthophosphate and calcium dihydrogenorthophosphate monohydrate are unlikely to lead to differences in the developmental toxicity.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Clinical signs:
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Total died/Total in group:
0 mg/kg bw 2/21
2.17 mg/kg bw 2/21
10.10 mg/kg bw 5/27
46.7 mg/kg bw 1/15
217 mg/kg bw 0/27
6-AN mg/kg bw 2/18
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Description (incidence and severity):
Urogenital tract was observed but no data regarding this point were described in the report.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
for details see table 2 below
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
for details see table 2 below
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
for details see table 2 below
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Description (incidence and severity):
for details see table 2 below
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
decreased number of corpora lutea in highest dose group observed (see table 2 below)
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
> 217 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
> 217 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
number of abortions
pre and post implantation loss
total litter losses by resorption
dead fetuses
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
for details see table 2 below
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
for details see table 2 below
Changes in sex ratio:
no effects observed
Description (incidence and severity):
for details see table 2 below
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
for details see table 3 below
Skeletal malformations:
no effects observed
Description (incidence and severity):
for details see table 3 below
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 217 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table 2 Reproduction data

Dose (mg/kg)

Sham

6-AN

2.17

10.10

46.7

217.0

Pregnancies

 

 

 

 

 

 

Total No.

12

9

12

17

10

10

Died or aborted (before Day 29)

2

0

1

4

0

0

To term (on Day 29)

10

9

11

13

10

10

Corpora Lutea

 

 

 

 

 

 

Total no.

160

117

132

191

110

121

Average/dam mated

11.4

9.75

9.43

9.55

8.46

6.37

Live litters

 

 

 

 

 

 

Total No.*

10

8

10

13

9

8

Implant Sites

 

 

 

 

 

 

Total No.

58

57

62

79

50

49

Average/dam*

5.80

6.33

5.64

6.08

5.00

4.90

Resorptions

 

 

 

 

 

 

Total No*

7

6

9

3

7

4

Dams with 1 or more sites resorbed

4

4

2

2

4

2

Dams with all sites resorbed

--

1

1

--

1

2

Per cent partial resorptions

40.0

44.4

18.2

15.4

40.0

20.0

Per cent complete resorptions

--

11.1

9.09

--

10.0

20.0

Live foetuses

 

 

 

 

 

 

Total No

51

49

49

76

43

45

Average/dam*

5.10

5.44

4.45

5.85

4.30

4.50

Sex ratio (M/F)

0.96

1.13

1.29

1.30

0.87

1.05

Dead Foetuses

 

 

 

 

 

 

Total No.*

--

2

4

--

--

--

Dams with 1 or more dead

--

2

1

--

--

--

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

--

22.2

9.09

--

--

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

39.6

37.0

39.3

39.7

36.0

39.7

* 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

2.17

10.10

46.7

217.0

Live foetuses examined (at term)

51/10

49/8

49/10

76/13

43/9

44/8

Sternebrae

 

 

 

 

 

 

Incomplete oss.

1/1

 

 

1/1

1/1

 

Scrambled

 

 

 

 

 

 

Bipartite

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra

 

 

 

 

3/1

1/1

Missing

 

 

 

 

 

1/1

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

 

 

 

 

More than 13

 

 

 

 

 

 

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

 

 

 

 

 

 

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

1/1

 

1/1

1/1

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

 

 

 

3/1

 

 

Missing

 

 

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

 

 

 

 

 

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 No soft tissue abnormalities observed.

Conclusions:
Under the conditions of the study, calcium dihydrogenorthophosphate monohydrate administered to pregnant rabbits for 13 days up to a dose level of 217 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 217 mg/kg bw. Therefore, a NOAEL for magnesium hydrogenortophosphate is also estimated to be > 217 mg/kg bw for both maternal and developmental toxicity.
Executive summary:

The maternal and developmental NOAEL for magnesium hydrogenorthophosphate was estimated to be > 217 mg/kg bw, which was the highest dose tested. As explained in th justification for type of information, the differences in molecular structure between magnesium hydrogenorthophosphate and calcium dihydrogenorthophosphate monohydrate are unlikely to lead to differences in the developmental toxicity.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Clinical signs:
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality occurred.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Description (incidence and severity):
Urogenital tract was observed but no data regarding this point were described in the report.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
see table 2 below for details
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
see table 2 below
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
see table 2 below
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Description (incidence and severity):
see table 2 below
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
> 410 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
> 410 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
number of abortions
pre and post implantation loss
total litter losses by resorption
dead fetuses
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Description (incidence and severity):
Fetal body weights after Caesarean section were determined. The average body weights of fetuses were similar in all groups except the group with aspirin which showed decreased body weights (see table 2 below).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
for details see table 2 below
Changes in sex ratio:
no effects observed
Description (incidence and severity):
for details see table 2 below
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The results indicate that the number of wavey ribs (47 foetuses affected/ 12 litters) observed at the highest dose level in the study (410.0 mg/kg) might be significant in relation to the sham control. However, the same result is not observed in either of the other two species tested (mice and rabbit) so can be discounted. For details see table 3 below.
Visceral malformations:
no effects observed
Description (incidence and severity):
one pup in the lowest dose group (4.1 mg/kg bw) had a hydrocephalus which was considered to be a spontanous effects since it was not observed in any other dose group or in the other two tested species mice and rabbits.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 410 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
skeletal malformations
visceral malformations
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: rib
Description (incidence and severity):
increased wavy ribs only in the highest dose group
Key result
Developmental effects observed:
no

  Table 2 Reproduction data

Dose (mg/kg)

Sham

Aspirin

4.1

19.1

88.5

410.0

Pregnancies

 

 

 

 

 

 

Total No.

21

21

22

22

19

22

Died or aborted (before Day 20)

0

0

0

0

0

0

To term (on Day 20)

21

21

22

22

19

22

Live litters

 

 

 

 

 

 

Total No.*

21

19

22

22

19

22

Implant Sites

 

 

 

 

 

 

Total No.

235

235

257

257

196

244

Average/dam*

11.2

11.2

11.7

11.7

10.3

11.1

Resorptions

 

 

 

 

 

 

Total No*

2

63

3

3

3

2

Dams with 1 or more sites resorbed

2

13

3

3

2

1

Dams with all sites resorbed

--

2

--

--

--

--

Per cent partial resorptions

9.52

61.9

13.6

13.6

10.5

4.55

Per cent complete resorptions

--

9.52

--

--

--

--

Live foetuses

 

 

 

 

 

 

Total No

233

170

253

253

192

242

Average/dam*

11.1

8.10

11.5

11.5

10.1

11.0

Sex ratio (M/F)

1.33

1.07

0.92

0.92

0.92

0.87

Dead Foetuses

 

 

 

 

 

 

Total No.*

--

2

1

1

1

--

Dams with 1 or more dead

--

2

1

1

1

--

Dams with all dead

--

--

--

--

--

--

Per cent partial dead

--

9.52

4.55

4.55

5.26

--

Per cent all dead

--

--

--

--

--

--

Average foetus weight (g)

3.62

2.43

3.85

3.85

3.56

3.65

* Includes only those dams examined at term

** Positive control: 250 mg/kg

 

Table 3 Summary of skeletal findings

Findings

Dose (mg/kg)

Sham

Aspirin

4.1

19.1

88.5

410.0

Live foetuses examined (at term)

165/21

124/19

174/22

162/21

133/19

168/22

Sternebrae

 

 

 

 

 

 

Incomplete oss.

45/18

49/16

31/12

36/16

42/15

45/15

Scrambled

 

1/1

 

 

 

 

Bipartite

1/1

13/7

 

 

 

1/1

Fused

 

1/1

 

 

 

 

Extra

 

 

 

 

 

 

Missing

27/12

92/18

6/4

5/4

22/10

16/7

Other

 

 

 

 

 

 

Ribs

 

 

 

 

 

 

Incomplete oss.

 

1/1

 

 

 

9/3

Fused/split

 

8/4

 

 

 

 

Wavy

17/10

51/14

16/9

15/7

11/8

47/12

Less than 12

 

1/1

 

 

 

 

More than 13

5/5

71/17

2/2

1/1

2/2

4/3

Other

 

 

 

 

 

 

Vertebrae

 

 

 

 

 

 

Incomplete oss.

26/14

92/19

10/6

6/5

22/11

29/10

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

Other

 

 

 

 

 

 

Skull

 

 

 

 

 

 

Incomplete closure

29/12

38/12

25/11

12/6

14/10

28/10

Missing

 

1/1

 

 

 

 

Craniostosis

 

 

 

 

 

 

Other; facial bones, inc

 

9/6

 

 

 

 

Extremities

 

 

 

 

 

 

Incomplete oss.

 

6/3

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Miscellaneous

 

 

 

 

 

 

Hyoid; missing

15/8

51/16

13/7

14/9

8/6

22/12

Hyoid; reduced

22/11

11/7

24/10

12/7

9/8

30/14

* 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 7065

1

Encephalomyelocele

 

 

A 7066

1

Gastroschisis

 

 

A 7070

1

Meningoencephalocele

 

 

A 7076

2

Meningoencephalocele

FDA 71-81

4.1

H 6028

1

Hydrocephalus

 

Conclusions:
Under the conditions of the study, the calcium dihydrogenorthophosphate monohydrate administered to pregnant rats for 10 days up to a dose level of 410 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 410 mg/kg bw. Therefore, a NOAEL for magnesium hydrogenortophosphate is also estimated to be > 410 mg/kg bw for both maternal and developmental toxicity.
Executive summary:

The maternal and developmental NOAEL for magnesium hydrogenorthophosphate was estimated to be > 410 mg/kg bw, which was the highest dose tested. As explained in th justification for type of information, the differences in molecular structure between the magnesium hydrogenorthophosphate and calcium dihydrogenorthophosphate monohydrate are unlikely to lead to differences in the developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
217 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The available information comprises studies which each alone are regarded insufficient for assessment from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarities of the calciumphosphate and magnesiumphosphate compounds and their similarities in PC/ECO/TOX properties (refer to read across justification for further details). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are currently no experimental data available to assess developmental toxicity / teratogenicity for the magnesium hydrogenorthophosphate.

 

For the structural similar substance calcium dihydrogenorthophosphate monohydrate (CAS 10031 -30 -8) three studies are available which were done before guidelines were available (Morgareidge, 1974). These studies were conducted similar to OECD 414 in three different species - mice, rats and rabbits. Although the report is not as detailed as required according to todays standards these three studies are considered reliable in order to assess the developmental toxicity of calcium dihydrogenorthophosphate monohydrate. A reason for the dosage levels are not given which in fact are considered too low since no maternal toxicity was observed. But since the tests were conducted in three different species and in none of these studies developmental effects were observed these studies are considered as reliable on the basis of weight of evidence. 

Mice: 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) or test article in a water suspension (10 mL/kg bw) at 4.65, 21.6, 100.0 and 465.0 mg/kg bw was carried out daily on Days 6 to 15 of gestation. Observations of body weight, appearance, behaviour, and food consumption were performed. On Day 17 of gestation all dams underwent Caesarean section. Implantation sites, resorption sites and live/dead foetuses as well as body weights of live pups were recorded. Urogenital tract of each dam were examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third of the 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. No deaths and no abortion were observed. One full resorption in the highest dose was found which is considered to be a spontaneous occurrence. An increase in incomplete ossification of the sternabrae and extremities were observed but not considered treatment-related since it seems not to be dose-related. The total number of resorptions, number of dams with 1 or more resorption sites and number of dead fetuses was increased in the low dose group and at the two highest concentrations applied. However, due to missing dose-response and considering the fact that no similar effect was observed in rats, the effect is considered rather spontaneous than treatment-related. The administration of up to 465 mg/kg bw of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. 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.

 

Rats: 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 test article in a water suspension at 4.1, 19.1, 88.5 and 410.0 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 20 of gestation all dams underwent Caesarean section. Number of implantation sites, resorption sites and live/dead foetuses as well as body weights of live pups were recorded. Urogenital tract of each dam examined for anatomical normality. All foetuses examined grossly for presence of external congenital abnormalities. One third of the 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. No deaths, abortions or full resorption were observed. An increase of wavy ribs in the highest tested dose was observed. This effect was not dose-related and considered not treatment related. One foetus of the lowest dose group had a hydrocephalus which is also considered as a spontaneous occurrence. The administration of up to 410 mg/kg bw of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. 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.

 

Rabbits: 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 20E06 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 (10 mL/kg bw) at 2.17, 10.10, 46.7 and 217.0 mg/kg was carried out daily on Days 6 to 18 of gestation. Observations of body weight, appearance, 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 as well as body weights of live pups were 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. In all groups except the highest dose group animals died during the study. It is also not clear why different group sizes were used which resulted in fewer than 16 rabbits with implantation sites for observation. There were 12, 12, 17, 10 and 10 for control group, 2.17, 10.10, 46.7, and 217 mg/kg bw group, respectively. Two animals died during treatment in the control group and 2.17 mg/kg bw group, 5 in the 10.10 mg/kg bw group and one in the 46 mg/kg bw group but none in the highest dose group. No reasons for these deaths were given in the study report. A decrease in the average number of corpora lutea was observed. However, due to missing dose-response and comparable number of implantation sites and number of fetuses, a treatment-related effect is not considered. No obvious effects in skeletal or visceral malformation were observed. The administration of up to 217 mg/kg bw of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. 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.

 

Since all studies for the structural analogue calcium dihydrogenorthophosphate monohydrate (CAS 10031 -30 -8) miss detailed description of effects a weight of evidence evaluation is performed. In all three studies no recurring effects were observed. Therefore, it is considered that trimagnesium bis(orthophosphate) also does not have a teratogenic potential. It is not considered to be scientifically justified to further investigate the effects of magnesium hydrogenorthophosphate on developmental toxicity and as such no classification on developmental toxicity is proposed and no further studies are deemed necessary.

Justification for classification or non-classification

The available data indicate that trimagnesium bis(orthophosphate) does not meet the classification criteria for reproductive toxicity in accordance with Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).