reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate

Endpoint summary

Description of key information

Acute oral toxicity: One key study is available to assess the acute oral toxicity of the reaction mass of calcium bis(orthophosphate and calcium hydrogenorthophosphate. The key study (Sanders A 2010) has been conducted according to the relevant guidelines (EU and US) and is considered to be reliable for the purpose of classification and labelling. The acute oral LD50 in rats was estimated to be >2000 mg/kg bw. A number of additional studies are provided to support the conclusion that the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate and analogous calcium and magnesium phosphates are not considered to be systemically toxic and are therefore not acutely toxic via the oral route.

Acute inhalation toxicity: In accordance with Annex VIII, section 8.5.2, column 2 of Regulation (EC) No. 1907/2006, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate is a solid with a low vapour pressure. The particle size distribution data concludes that < 3% of particles have a particle size of <100 µm and therefore the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate is not considered to present an inhalation risk and as such testing via the inhalation route is not scientifically justified.

Acute dermal toxicity: The dermal LD50 value is derived using a weight of evidence approach. Taking into account all the available studies on the analogous calcium and magnesium orthophosphates which are considered to be of similar systemic toxicity, the weight of evidence indicates that the dermal LD50 is greater than the classification limit of 2000 mg/kg bw/day.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22 July - 13 July 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection: 15 September 2009, Date of signature: 26 November 2009

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation:
- Fasting period before study: overnight fast immediately before dosing and for approximately three to four hours after dosing
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made ½, 1, 2, and 4 hours after dosing and subsequently once daily for fourteen days. Morbidity and mortality checks were made twice daily.
- Necropsy of survivors performed: yes
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
:

Preliminary study:

Using available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose. In the absence of toxicity at a dose level of 2000 mg/kg, an additional group of 4 animals were treated with 2000 mg/kg.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System(EU) - Unclassified).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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:

no guideline followed

Principles of method if other than guideline:

The diluted compound was applied in increasing doses at increments of 0.2 fractional log intervals to the closely clipped, intact skin of New Zealand white male and female rabbits. The treated areas were covered with plastic strips and the animals held in wooden stocks for periods up to twenty-four hours, after which time they were assigned to individual cages. Observations were made for toxic signs and the viscera of the test animals were examined macroscopically.

GLP compliance:

no

Remarks:

study predates GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data pertinent to environmental conditions.
The animals were albinos.

Type of coverage:

occlusive

Vehicle:

corn oil

Details on dermal exposure:

TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: plastic strips

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 13.026g, 19.056g, 20.644g
- Concentration (if solution): 40.0% suspension
- Constant volume or concentration used: no
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): no data
- Lot/batch no. (if required): no data
- Purity: no data

Duration of exposure:

24 h

Doses:

5010 mg/kg bw; 7940 mg/kg bw;

No. of animals per sex per dose:

5010 mg/kg bw - 1 female
7940 mg/kg bw - 1 female, 1 male

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: surviving animals were sacrificed 14 days after dosing.
- Frequency of observations and weighing: Bodyweight was recorded 5 days after dosing. There is no other data for observations.
- Necropsy of survivors performed: yes
- Other examinations performed: observations were made for toxic signs and the viscera were examined macroscopically.

Statistics:

not applicable

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

other: minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Mortality:

There were no mortalities at the doses tested

Clinical signs:

other: Toxic signs included reduced appetite and activity for two to three days.

Gross pathology:

The viscera appeared normal by macroscopic examination.

Other findings:

no data

The Acute Skin Absorption Minimal Lethal Dose of dicalcium phosphate dihydrate for rabbits

Sample applied as a 40.0% suspension in corn oil - 24 hour exposure

Animal No. – Sex	Weight Kg.	Dose mg/kg	Weight change 5 days later kg	Fate
1 – female	2.6	5010	-0.1	survived
2 – male	2.4	7940	0.0	survived
3 – female	2.6	7940	-0.1	survived

The Acute Skin Absorption Minimal Lethal Dose for male and female rabbits was found to be greater than 7940 mg/kg bw.

Interpretation of results:

GHS criteria not met

Conclusions:

The test material was classified, according to the author, as practically nontoxic to rabbits. The Acute Skin Absorption Minimal Lethal Dose was >7940 mg/kg bw.
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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

Reason / purpose for cross-reference:

read-across source

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

other: minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Mortality:

There were no mortalities at the doses tested

Clinical signs:

other: Toxic signs included reduced appetite and activity for two to three days.

Gross pathology:

The viscera appeared normal by macroscopic examination.

The Acute Skin Absorption Minimal Lethal Dose of dicalcium phosphate dihydrate for rabbits

Sample applied as a 40.0% suspension in corn oil - 24 hour exposure

Animal No. – Sex	Weight Kg.	Dose mg/kg	Weight change 5 days later kg	Fate
1 – female	2.6	5010	-0.1	survived
2 – male	2.4	7940	0.0	survived
3 – female	2.6	7940	-0.1	survived

The Acute Skin Absorption Minimal Lethal Dose for male and female rabbits was found to be greater than 7940 mg/kg bw.

Interpretation of results:

GHS criteria not met

Conclusions:

The test material was classified, according to the author, as practically nontoxic to rabbits. The Acute Skin Absorption Minimal Lethal Dose was >7940 mg/kg bw.
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

29th June 1973

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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:

no guideline followed

Principles of method if other than guideline:

The diluted compound was applied at two dose levels to the intact skin of New Zealand White male and female rabbits. The animals were secured during the 24 hour exposure period, after which they were assigned to individual cages. Clinical observations were made and the surviving animals were sacrificed and autopsied on day 14 post dosing.

GLP compliance:

no

Remarks:

study predates GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data pertinent to conditions.
The animals were albinos

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: plastic strips covered the test area

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 12.2434 g, 17.468 g, and 19.85 g
- Concentration (if solution): 40% aqueous solution
- Constant volume or concentration used: yes, a 40% solution suspension was prepared
- For solids, paste formed: no


VEHICLE
- Amount(s) applied (volume or weight with unit): 40% aqueous solution
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: no data

Duration of exposure:

24 h

Doses:

one animal at 5010 mg/kg bw, two animals at 7940 mg/kg bw

No. of animals per sex per dose:

three animals were used.
5010 mg/kg - 1 male
7940 mg/kg - 1 female, 1 male

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: The animals were sacrificed at day 14 post dosing.
- Frequency of observations and weighing: No data for observations, changes in the bodyweight of the animals are recorded at day 5 only.
- Necropsy of survivors performed: yes
- Other examinations performed: The animals were monitored for signs of toxicity and the viscera were examined macroscopically.

Statistics:

not applicable

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

other: acute skin absorption, minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Mortality:

There were no mortalities.

Clinical signs:

other: There was no weakness or other outward signs of systemic toxicity.

Gross pathology:

The viscera appeared normal by macroscopic injection.

Other findings:

no data.

The acute skin absorption minimal lethal dose of monocalcium phosphate monohydrate for rabbits

Sample as applied as a 40.0% aqueous solution suspension - 24 hour exposure

Animal No. – Sex	Weight (kg)	Dose (mg/kg)	Weight change 5 days later (kg)	Fate
1 – male	2.4	5010	0.0	survived
2 – female	2.2	7940	0.0	survived
3 – male	2.5	7940	0.0	survived

According to the author's system of classification the compound was practically nontoxic by skin absorption in male and female rabbits.

Interpretation of results:

GHS criteria not met

Conclusions:

According to the author's system of classification the compound was practically nontoxic by skin absorption in male and female rabbits.

Reference 4

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

29th June 1973

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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

Reason / purpose for cross-reference:

read-across source

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

other: acute skin absorption, minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Mortality:

There were no mortalities.

Clinical signs:

other: There was no weakness or other outward signs of systemic toxicity.

Gross pathology:

The viscera appeared normal by macroscopic injection.

Other findings:

no data.

The acute skin absorption minimal lethal dose of monocalcium phosphate monohydrate for rabbits

Sample as applied as a 40.0% aqueous solution suspension - 24 hour exposure

Animal No. – Sex	Weight (kg)	Dose (mg/kg)	Weight change 5 days later (kg)	Fate
1 – male	2.4	5010	0.0	survived
2 – female	2.2	7940	0.0	survived
3 – male	2.5	7940	0.0	survived

According to the author's system of classification the compound was practically nontoxic by skin absorption in male and female rabbits.

Interpretation of results:

GHS criteria not met

Conclusions:

According to the author's system of classification the compound was practically nontoxic by skin absorption in male and female rabbits.

Reference 5

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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:

no guideline followed

Principles of method if other than guideline:

The test material was applied, as a 40.0% aqueous suspension, to the skin of New Zealand albino rabbits for a period of 24 hours. Four animals were applicated at 3 different dosing groups. Observations were made over a 14 day period for signs of toxicity, at the end of this period the viscera were examined macroscopically.

GLP compliance:

no

Remarks:

study predates GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: strain: New Zealand

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data pertinent to environmental conditions.
The animals were albinos.

Type of coverage:

not specified

Vehicle:

water

Details on dermal exposure:

TEST SITE
no data

REMOVAL OF TEST SUBSTANCE
no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 6320 mg - 17,468 mg (amount depended on dosing group)
- Concentration (if solution): 40.0% aqueous solution
- Constant volume or concentration used: no
- For solids, paste formed: suspension formed

VEHICLE
The vehicle was water

Duration of exposure:

24 h

Doses:

3160 mg/kg bw
5010 mg/kg bw
7940 mg/kg bw

No. of animals per sex per dose:

3160 mg/kg bw 1 female
5010 mg/kg bw 1 male
7940 mg/kg bw 1 female, 1 male

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: observations were made for signs of intoxication and the viscera were examined macroscopically.

Statistics:

not applicable

Preliminary study:

no data

Sex:

male/female

Dose descriptor:

other: Minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Remarks on result:

other: conditions: applied as a 40.0% aqueous solution

Mortality:

None of the animals died during the 14 days observation period.

Clinical signs:

other: There were no signs of intoxiciation

Gross pathology:

The viscera appeared normal by macroscopic examination

Other findings:

no data

Acute dermal toxicity, the minimal lethal dose in rabbits.

Sample: applied as a 40.0% aqueous solution

Doses mg/kg	Initial weight		Mortalities/ dosed
	male	female	male	female	combined
3160	-	2.0	-	0/1	0/1
5010	2.2	-	0/1	-	0/1
7940	2.1	2.2	0/1	0/1	0/2

Interpretation of results:

GHS criteria not met

Conclusions:

The test material, applied as a 40.0% aqueous solution, had a Minimal Lethal Dose of > 7940 mg/kg bw in male and female rabbits. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) calcium hydrogenorthophosphate is not considered to be classified for acute toxicity via the dermal route.

This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 6

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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

Reason / purpose for cross-reference:

read-across source

Preliminary study:

no data

Sex:

male/female

Dose descriptor:

other: Minimal lethal dose

Effect level:

> 7 940 mg/kg bw

Remarks on result:

other: conditions: applied as a 40.0% aqueous solution

Mortality:

None of the animals died during the 14 days observation period.

Clinical signs:

other: There were no signs of intoxiciation

Gross pathology:

The viscera appeared normal by macroscopic examination

Other findings:

no data

Acute dermal toxicity, the minimal lethal dose in rabbits.

Sample: applied as a 40.0% aqueous solution

Doses mg/kg	Initial weight		Mortalities/ dosed
	male	female	male	female	combined
3160	-	2.0	-	0/1	0/1
5010	2.2	-	0/1	-	0/1
7940	2.1	2.2	0/1	0/1	0/2

Interpretation of results:

GHS criteria not met

Conclusions:

The test material, applied as a 40.0% aqueous solution, had a Minimal Lethal Dose of > 7940 mg/kg bw in male and female rabbits. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) calcium hydrogenorthophosphate is not considered to be classified for acute toxicity via the dermal route.

This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 7

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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+ or Mg2+ 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). 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.

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:

no guideline followed

Principles of method if other than guideline:

The test material was applied as a 50.0% aqueous suspension at two dose levels to three New Zealand Albino rabbits. The animals were exposed for 24 hours and the observation period ran for 7 days post dosing. The animals were monitored for signs of intoxication and the viscera of the animals were examined macroscopically.

GLP compliance:

no

Remarks:

study predates GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

other: strain: New Zealand, animals were albinos

Sex:

male/female

Type of coverage:

not specified

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: no data
- % coverage: no data
- Type of wrap if used: no data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 13.026g in the 5010 mg/kg dose group; and 17.468g in the 7940 mg/kg dose group
- Concentration (if solution): 50.0%
- Constant volume or concentration used: constant concentration
- For solids, paste formed: a 50.0% aqueous solution was formed.

VEHICLE
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): not applicable
- Lot/batch no. (if required): no data
- Purity: no data

Duration of exposure:

24 h

Doses:

5010 mg/kg bw;
7940 mg/kg bw

No. of animals per sex per dose:

In the 5010 mg/kg group: 1 male
In the 7940 mg/kg group: 1 female, 1 male

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: signs of intoxication, the viscera were examined macroscopically

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 7 940 mg/kg bw

Mortality:

none of the animals died

Clinical signs:

other: There was reduced appetite and activity (one to two days)

Gross pathology:

the viscera appeared normal

Other findings:

no data

The Acute Dermal Toxicity LD50 for rabbits

Sample applied as a 50.0% aqueous suspension

Dosage mg/kg	Initial weight		Mortalities/ Dosed			Time of Mortality
5010	2.6	---	0/1	---	0/1	---
7940	2.2	2.2	0/1	0/1	0/2	---

Interpretation of results:

GHS criteria not met

Conclusions:

The Acute Dermal Toxicity LD50 for rabbits was > 7940 mg/kg bw. This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 8

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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+ or Mg2+ 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). 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.

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

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 7 940 mg/kg bw

Mortality:

none of the animals died

Clinical signs:

other: There was reduced appetite and activity (one to two days)

Gross pathology:

the viscera appeared normal

Other findings:

no data

The Acute Dermal Toxicity LD50 for rabbits

Sample applied as a 50.0% aqueous suspension

Dosage mg/kg	Initial weight		Mortalities/ Dosed			Time of Mortality
5010	2.6	---	0/1	---	0/1	---
7940	2.2	2.2	0/1	0/1	0/2	---

Interpretation of results:

GHS criteria not met

Conclusions:

The Acute Dermal Toxicity LD50 for rabbits was > 7940 mg/kg bw. This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 9

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

02/02/1982 to 29-05-1984

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: RTL-A-12: EPA US Guidelines; Hazard Evaluation: Humans and Domestic animals, Fed. Reg. 43:163, 37336-37402 (1978)

Deviations:

no

GLP compliance:

no

Remarks:

This study was conducted in compliance with RTL Quality Assurance Practices, RTL Standard Operating Procedures, and Good Laboratory Practices.

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

other: Stauffland albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Phillips Rabbitry, Soquel, CA.
- Age at study initiation: no data
- Weight at study initiation: 1.647 to 2.352 kg
- Fasting period before study: yes, overnight.
- Housing: Temperature controlled rooms, two to a cage in suspended steel cages (24" x 16.5" x 14").
- Diet (e.g. ad libitum): 'Special mixture, Gunter Bros., Morgan Hill, CA' provided ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-70°F
- no other data on conditions.


IN-LIFE DATES: From: Day 0 To: Day 14

Type of coverage:

occlusive

Vehicle:

other: the test material was moistened with physiological saline.

Details on dermal exposure:

The test material was applied to closely clipped abdominal skin beneath a protective binder. The skin was abraded on half of the animals and left intact on the others. The abrasions will be sufficiently deep to penetrate the stratum corneum, but not the dermis. A single application of the compound will be applied to the dose site.
After a 24-hour period, the binder material and test material were removed. The dose site will be wiped (not washed) to remove any remaining substance. The skin was then rewrapped in a guaze binder, three days later the binder was removed.

Duration of exposure:

24 hour

Doses:

2000mg/kg

No. of animals per sex per dose:

4 animals/sex/dose of the test material
2 animals/sex/control

Control animals:

yes

Details on study design:

- Duration of observation period following administration: Atleast 14 days
- Frequency of observations and weighing: Rabbits will be weighed on days 0 (prior to treatment), 7, 14 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and mortality will be recorded frequently the first day, and early morning and later afternoon thereafter. These animals will be observed once a day during weekends and holidays. All clinical signs will be recorded as for their onset, duration and severity.

Statistics:

no data

Preliminary study:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no mortalities.

Clinical signs:

other: All rabbits appeared normal throughout the 14 day test. There were no apparent local dermal effects following a 24 hour exposure.

Gross pathology:

All animals appeared normal at autopsy

Other findings:

not applicable

no data

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal toxicity LD50 was > 2000mg/kg bw. No adverse effects were observed throughout the study period. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) pentacalcium hydroxide tris(orthophosphate) is not considered to be classified for acute toxicity via the dermal route.

This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 10

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

02/02/1982 to 29-05-1984

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

Reason / purpose for cross-reference:

read-across source

Preliminary study:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no mortalities.

Clinical signs:

other: All rabbits appeared normal throughout the 14 day test. There were no apparent local dermal effects following a 24 hour exposure.

Gross pathology:

All animals appeared normal at autopsy

Other findings:

not applicable

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal toxicity LD50 was > 2000mg/kg bw. No adverse effects were observed throughout the study period. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) pentacalcium hydroxide tris(orthophosphate) is not considered to be classified for acute toxicity via the dermal route.

This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 11

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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+ or Mg2+ 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). 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.

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:

no guideline followed

Principles of method if other than guideline:

No details on methodology included within study report.

GLP compliance:

not specified

Test type:

other: No data

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

not specified

Vehicle:

not specified

Details on dermal exposure:

No data

Duration of exposure:

No data

Doses:

4640 mg/kg

No. of animals per sex per dose:

4 animals per dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

No data

Preliminary study:

Not applicable

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 4 640 mg/kg bw

Mortality:

No unscheduled deaths were recorded during the study

Clinical signs:

other: No signs of toxicity were noted. Moderate erythema and oedema were recorded.

Gross pathology:

No data (not examined)

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 for magnesium phosphate in rabbits was determined to be > 4640 mg/kg. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) magnesium bis(dihydrogenorthophosphate) is not considered to be classified for acute toxicity via the oral route.
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 12

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient 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+ or Mg2+ 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). 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.

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

Reason / purpose for cross-reference:

read-across source

Preliminary study:

Not applicable

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 4 640 mg/kg bw

Mortality:

No unscheduled deaths were recorded during the study

Clinical signs:

other: No signs of toxicity were noted. Moderate erythema and oedema were recorded.

Gross pathology:

No data (not examined)

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 for magnesium phosphate in rabbits was determined to be > 4640 mg/kg. In accordance with Regulation (EC) No. 1282/2008 (EU CLP) magnesium bis(dihydrogenorthophosphate) is not considered to be classified for acute toxicity via the oral route.
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 13

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

20/8/1984 - 7/11/1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

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:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

details on bodyweight observations during and at the end of the test period were not reported

Principles of method if other than guideline:

Study states protocols were consitent with or exceeded the requirements of EPA and OECD guidelines at the time of the study.

GLP compliance:

not specified

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

other: Stauffland albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Phillips Rabbitry, Soquel, California
- Weight at study initiation: 1.642 - 2.146 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: abdominal skin
- % coverage: no data
- Type of wrap if used: gauze binder


REMOVAL OF TEST SUBSTANCE
- Washing (if done): no



TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- For solids, paste formed: no

Duration of exposure:

72 hr

Doses:

0, 2000 mg/kg

No. of animals per sex per dose:

5 male and 5 female

Control animals:

other: sham-treated

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: :no data
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

A single dermal dose of 2000 mg/kg bw produced no mortalities in a mixed group of albino rabbits (5 male and 5 female).

Clinical signs:

other: All rabbits in the test group and the sham-exposed control group appeared normal throughout the 14-day test.

Gross pathology:

10 rabbits from the test material exposed group and 4 rabbits from the sham-exposed group were necropsied on day 14 and appeared normal.

Other findings:

- Other observations: local effects: Local dermal effects in the test material group included darkened dose sites, severe erythema, mild edema and the skin at the abrasion marks was separated and filled with reddish fluid and pus-like material. There were no apparent local dermal effects following a 24 hour sham-treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

Calcium bis(dihydrogenorthophosphate) was found to have a dermal LD50 of >2000 mg/kg bw, therefore, calcium bis(dihydrogenorthophosphate) is not considered to be classified according to Regulation (EC) No. 1272/2008 (EU CLP).
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Reference 14

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

20/8/1984 - 7/11/1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

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 source

Reason / purpose for cross-reference:

read-across: supporting information

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

A single dermal dose of 2000 mg/kg bw produced no mortalities in a mixed group of albino rabbits (5 male and 5 female).

Clinical signs:

other: All rabbits in the test group and the sham-exposed control group appeared normal throughout the 14-day test.

Gross pathology:

10 rabbits from the test material exposed group and 4 rabbits from the sham-exposed group were necropsied on day 14 and appeared normal.

Other findings:

- Other observations: local effects: Local dermal effects in the test material group included darkened dose sites, severe erythema, mild edema and the skin at the abrasion marks was separated and filled with reddish fluid and pus-like material. There were no apparent local dermal effects following a 24 hour sham-treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

Calcium bis(dihydrogenorthophosphate) was found to have a dermal LD50 of >2000 mg/kg bw, therefore, calcium bis(dihydrogenorthophosphate) is not considered to be classified according to Regulation (EC) No. 1272/2008 (EU CLP).
This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for tricalcium bis(orthophosphate).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

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(dihydrogenorthophosphate), 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.

As the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate is a mixture of two calcium orthophosphates it is appropriate to include this substance in the above group. In addition the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate has been shown to exhibit the same systemic toxicity profile as the other calcium and magnesium orthophosphates detailed above and on this basis read across is justified.

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 divalent 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 classification or non-classification

Acute toxicity, oral: The acute oral LD₅₀is estimated to be > 2000 mg/kg bw and therefore in accordance with Regulation (EC) No. 1272/2008 (EU CLP) no classification is proposed.

Acute toxicity, inhalation: As the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate is not considered to pose an inhalation risk not testing has been performed. However, on the basis of the results obtained in acute oral and acute dermal studies and the results of an acute inhalation study on the main component of the reaction mass (calcium bis(dihydrogenorthophosphate), which is submitted as supporting data, no classification is proposed for acute toxicity via the inhalation route in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

Acute toxicity, dermal: The dermal LD50 of the reaction mass of calcium bis(dihydrogenorthophosphate) and calcium hydrogenorthophosphate is estimated to be > 2000 mg/kg bw and is therefore not classified according to Regulation (EC) No. 1272/2008 (EU CLP).