Registration Dossier
Registration Dossier
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EC number: 914-172-8 | CAS number: -
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There are currently no experimental data available to assess effects on fertility for the test substance. A data waiver is set in place to justify that no further testing on reproductive toxicity is required.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Reproductive effects observed:
- not specified
Reference
Effects on developmental toxicity
Description of key information
No data are available for calcium 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
- 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) All salts are inorganic phosphates, composed of a phosphate anion and a calcium cation.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Ca2+ cation and the PO43-anion.
(3) A number of studies are provided to show that monovalent 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. All substances are ionic and will readily dissociate to their ionic forms in aqueous environments. The orthophosphate ion can undergo 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 dependent upon the associated cation and the ambient pH (if in solution). Calcium 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.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- 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
- 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 - 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
- Remarks:
- Doses / Concentrations:
4.65 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
21.6 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
100.0 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
465.0 mg/kg
Basis:
nominal in water - 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
- 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
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 465 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 465 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- necropsy findings
- number of abortions
- pre and post implantation loss
- Fetal body weight changes:
- not examined
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- 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
- Details on embryotoxic / teratogenic effects:
- No effects
- 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
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- 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.
- 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) All salts are inorganic phosphates, composed of a phosphate anion and a calcium cation.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Ca2+ cation and the PO43-anion.
(3) A number of studies are provided to show that monovalent 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. All substances are ionic and will readily dissociate to their ionic forms in aqueous environments. The orthophosphate ion can undergo 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 dependent upon the associated cation and the ambient pH (if in solution). Calcium 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.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- 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
- Remarks:
- Doses / Concentrations:
2.17 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
10.10 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
46.7 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
217.0 mg/kg
Basis:
nominal in water - 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
- 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 examined
- 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
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- not examined
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- 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
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal toxicity
- Effect level:
- > 217 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- > 217 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- number of abortions
- pre and post implantation loss
- total litter losses by resorption
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No dose related response 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
- 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.
- 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) All salts are inorganic phosphates, composed of a phosphate anion and a calcium cation.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Ca2+ cation and the PO43-anion.
(3) A number of studies are provided to show that monovalent 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. All substances are ionic and will readily dissociate to their ionic forms in aqueous environments. The orthophosphate ion can undergo 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 dependent upon the associated cation and the ambient pH (if in solution). Calcium 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.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.
4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’. - Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- 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
- Remarks:
- Doses / Concentrations:
4.1 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
19.1 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
88.5 mg/kg
Basis:
nominal in water - Remarks:
- Doses / Concentrations:
410.0 mg/kg
Basis:
nominal in water - 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
- 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
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- not examined
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- 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:
- body weight and weight gain
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- development toxicity
- Effect level:
- > 410 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- dead fetuses
- number of abortions
- pre and post implantation loss
- total litter losses by resorption
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- 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 weig
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- 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.
- 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
- 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.
Referenceopen allclose all
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 |
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.
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 |
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 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 fulfil the standard information requirements set out in Annex X, 8.7.2, of Regulation (EC) No 1907/2006.
Justification for classification or non-classification
Results of the developmental toxicity study conducted on monocalcium phosphate monohydrate:
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.
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.
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.
It is not considered to be scientifically justified to further investigate the effects of the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate on reprotoxicity, developmental or maternal toxicity and as such no classification is proposed for this endpoint and no further studies are deemed necessary.
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