Registration Dossier
Registration Dossier
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EC number: 236-004-6 | CAS number: 13092-66-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
1. Both substances are inorganic salts of a monovalent cation from Group 2 of the periodic table, calcium or magnesium, and phosphoric acid. Thus, they all share the Ca2+ or Mg2+ cation and the PO43- anion as common functional groups.
2. Both substances will ultimately dissociate into the common breakdown products of the Ca2+ or Mg2+ cations and the PO43- anion.
3. Calcium and magnesium orthophosphates have been shown to have a similar toxicological profile and physicochemical nature and therefore this data is considered to be adequate and reliable for use in read-across. In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier. Orthophosphates are not considered to be genotoxic and are essential micronutrients. As such the reproductive toxicity will be predominantly determined by the presence of the Mg2+ cation.
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 for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- Meets generally accepted scientific standards with acceptable restrictions. Deficiencies: Food consumption not reported Uterine weights not determined 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 The reliability has been amended in accordance with 'practical guide 6: How to report read-across and categories' which states that the maximum reliability for a read-across study is 2. JUSTIFICATION FOR READ ACROSS; calcium and magnesium orthophosphates. The following substances are considered to be similar enough to facilitate read across for systemic toxicity endpoints: Calcium bis(dihydrogenorthophosohate, EC No: 231-837-1 Calcium hydrogenorthophosphate. EC No: 231-826-1 Tricalcium bis(orthophosphate), EC No: 231-840-8 Pentacalcium hydroxide tris(orthophosphate), EC No: 235-330-6 Magnesium hydrogenorthophosphate, EC No: 231-823-5 Trimagnesium bis(orthophosphate), EC No. 231-824-0 Magnesium bis(dihydrogenorthophosphate), EC No. 236-004-6 All of the above substances have exhibited similar toxicity in acute oral and dermal studies. Read across is justified on the following basis: 1. Low systemic toxicity in acute oral studies. A number of studies are provided to show that calcium and/or magnesium inorganic orthophosphates exhibit low acute oral toxicity. These data are provided in Section 7.2.1 of this dossier. The information provided in these records is considered to be of suitable relevance and reliability to underpin the read across for the acute dermal and inhalation endpoints. 2. Substance similarities All substances are ionic and will readily dissociate to their ionic forms in aqueous environments. The orthophosphate ion can under go ionisation with loss of H+from each of the three –OH groups and therefore can occur in the -1, -2 or -3. The degree of ionisation is dependant upon the associated cation and the ambient pH (if in solution). The ionic form of the Group 1ii alkali metals is M2+.Calcium, magnesium and phosphate are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. Orthophosphate salts of these types are not considered to differ in their systemic toxicity profiles. Differences arise in their local effects profile due differences in pH and buffering capacities. This does not have an effect on systemic toxicity.
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
1. Both substances are inorganic salts of a monovalent cation from Group 2 of the periodic table, calcium or magnesium, and phosphoric acid. Thus, they all share the Ca2+ or Mg2+ cation and the PO43- anion as common functional groups.
2. Both substances will ultimately dissociate into the common breakdown products of the Ca2+ or Mg2+ cations and the PO43- anion.
3. Calcium and magnesium orthophosphates have been shown to have a similar toxicological profile and physicochemical nature and therefore this data is considered to be adequate and reliable for use in read-across. In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier. Orthophosphates are not considered to be genotoxic and are essential micronutrients. As such the reproductive toxicity will be predominantly determined by the presence of the Mg2+ cation.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- 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 (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. 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 or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 1.84 - 2.21 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 21 12
6-AN 2.5 18 9
FDA 71-81 2.17 21 12
10.10 27 17
46.7 15 10
217.0 27 10 - 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:
- > 217 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:
- > 217 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
- Conclusions:
- Under the conditions of the study, the test material 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.
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.- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.
The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
1. Both substances are inorganic salts of a monovalent cation from Group 2 of the periodic table, calcium or magnesium, and phosphoric acid. Thus, they all share the Ca2+ or Mg2+ cation and the PO43- anion as common functional groups.
2. Both substances will ultimately dissociate into the common breakdown products of the Ca2+ or Mg2+ cations and the PO43- anion.
3. Calcium and magnesium orthophosphates have been shown to have a similar toxicological profile and physicochemical nature and therefore this data is considered to be adequate and reliable for use in read-across. In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier. Orthophosphates are not considered to be genotoxic and are essential micronutrients. As such the reproductive toxicity will be predominantly determined by the presence of the Mg2+ cation.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- 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 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. 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 or test system and environmental conditions:
- TEST ANIMALS
- Source: Outbred
- Age at study initiation: No data
- Weight at study initiation: 216 - 224 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: From: 12/01/1975 To: 06/02/1975 - 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 21
Aspirin 250.0 25 21
FDA 71-81 4.1 28 22
19.1 29 21
88.5 25 19
410.0 25 22 - 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:
- > 410 mg/kg bw/day
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
The 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. - Dose descriptor:
- NOAEL
- Effect level:
- > 410 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
- Conclusions:
- Under the conditions of the study, the test material 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.
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 |
- Reason / purpose for cross-reference:
- read-across: supporting information
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 974
- Report date:
- 1973
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 4.65, 21.6, 100.0 and 465.0 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
Test material
- Reference substance name:
- calcium dihydrogenorthophosphate monohydrate
- IUPAC Name:
- calcium dihydrogenorthophosphate monohydrate
- Reference substance name:
- Calcium bis(dihydrogenorthophosphate)
- EC Number:
- 231-837-1
- EC Name:
- Calcium bis(dihydrogenorthophosphate)
- Cas Number:
- 7758-23-8
- Molecular formula:
- CaH4O8P2
- IUPAC Name:
- calcium dihydrogen phosphate
- Test material form:
- solid: crystalline
- Details on test material:
- - Name of test material (as cited in study report): FDA 71-81 (Monocalcium phosphate; monohydrate)
- Physical state: Fine white crystalline material
Constituent 1
Constituent 2
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: 29.2 - 30.6 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
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 25 22
Aspirin 150.0 25 20
FDA 71-81 4.65 25 24
21.6 26 19
100.0 23 22
465.0 25 23 - 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: 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
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:
- > 465 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:
- > 465 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 |
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 |
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 465 mg/kg bw showed no maternal or developmental toxicity. The NOAEL for both maternal and developmental toxicity is > 465 mg/kg bw.
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