Calcium hydrogenorthophosphate

Endpoint summary

Description of key information

Oral (similar to OECD 401, RL2), rat: LD50 > 3968 mg/kg bw for females, LD 50 > 5000 mg/kg bw for males

Dermal (similar to OECD 402, woe, RL2 and 4), rabbit: LD50 > 7940 mg/kg bw (lowest value)

Inhalation based on read across from calcium bis(dihydrogenorthophosphate) (OECD 403, RL1), rat: LC50 > 2.6 mg/L air (limit test)

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:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test material (either reagent grade dicalcium phosphate or dicalcium phosphate made from PCI superphosphoric acid) was dissolved in water and administered in single doses (2 dose levels) to fasted rats by means of a stomach tube. The animals were observed for 14 days post-treatment.

GLP compliance:

no

Remarks:

Study pre-dates GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 190-210 g
- Fasting period before study: 24 hours

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL

Doses:

4640 mg/kg bw, 10000 mg/kg bw

No. of animals per sex per dose:

5 females/dose

Control animals:

yes

Details on study design:

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

Sex:

female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Substance tested: dicalcium phosphate reagent grade

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 7 940 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Substance tested: Dicalcium phosphate derived from PCI SPA

Mortality:

REAGENT GRADE DICALCIUM PHOSPHATE:
Dose level : 4,640 mg/kg bw
Mortality: 0/5

Dose level: 10,000 mg/kg bw
Mortality: 0/5

DICALCIUM PHOSPHATE DEERVIED FROM PCI SUPERPHOSPHORIC ACID:
Dose level : 4,640 mg/kg bw
Mortality: 0/5

Dose level: 10,000 mg/kg bw
Mortality: 4/5

Clinical signs:

other: No apparent signs of toxicity were produced from either sample when dosed at 4,640 mg/kg bw. The sample from Salt Lake (PCI SPA derived dical) produced acute depression and dyspnea at the 10,000 mg/kg dose level. Reagent grade dicalcium phosphate exhibit

Gross pathology:

The following abnormalities were observed in the animals dosed with 10,000 mg/kg of the Salt Lake sample when autopsied; stomach and upper gastro-intestinal tract erythemic with congestion of the liver, kidneys and adrenals.
Animals treated with reagent grade dicalcium phosphate at 10,000 mg/kg bw appeared grossly normal when autopsied 14 days after treatment.
Animals treated with reagent grade dicalcium phosphate and PCI dicalcium phosphate at 4,640 mg/kg bw appeared grossly normal when autopsied 14 days after treatment.

Interpretation of results:

GHS criteria not met

Conclusions:

Dicaclium phosphate Reagent grade and PCI dicalciumphosphate both gave acute oral LD50 vales of >5,000 mg/kg bw and thererfore under the conditions of this study are determined to be not acutely toxic via the oral route (according to EU CLP).

The results are sufficient in order to derive a reliable conclusion on classification and labelling in accordance with Regulation (EC) No.1272/2008 (EU CLP) and is therefore suitable for use as a key study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 968 mg/kg bw

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2-4) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.6 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

All animals survived the scheduled observation period.

Clinical signs:

other: Slight to moderate ruffled fur was noted in all animals on test day 1, one hour after the end of the exposure and persisted slightly until test day 2 in nine animals. From test day 3 onwards, all animals were free from clinical signs until their scheduled

Body weight:

From test day 1 to test day 2, marginal to slight body weight loss was noted in all animals. Thereafter all animals gained weight until scheduled necropsy.

Gross pathology:

There were no macroscopic findings.

Other findings:

Not applicable.

The nominal aerosol concentration was 7.5 mg/L air.

Interpretation of results:

GHS criteria not met

Conclusions:

The LC50 of calcium hydrogenorthophosphate obtained from this study was estimated to be greater than 2.6 mg/L air (gravimetrically determined mean aerosol concentration). This was the highest technically achievable test concentration. There was no indication of relevant sex-related differences in toxicity of the test item.

Executive summary:

The LC50 > 2.6 mg/L was estimated from the LC50 of the source substance calcium bis(dihydrogenorthophosphate). As explained in the justification for type of information, the differences in molecular structure between target and the source are unlikely to lead to differences in the LC50.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2 600 mg/m³ air

Quality of whole database:

The available information comprises an adequate and reliable study 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). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

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:

LD50

Effect level:

> 7 940 mg/kg bw

Based on:

test mat.

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 calcium hydrogenorthophosphate.

Reference 2

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

Remarks:

This study is not considered to be sufficient for classification and labelling as information on the materials and methods used in the study is not reported and therefore the study cannot be assigned as reliable for use as a key study. This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for calcium hydrogenorthophosphate.

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:

LD50

Effect level:

> 7 940 mg/kg bw

Based on:

test mat.

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 oral route.

This data is considered to meet the regulatory requirements for this endpoint as part of a weight of evidence approach for calcium hydrogenorthophosphate.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

7 940 mg/kg bw

Quality of whole database:

The available information comprises studies which each alone are regarded insufficient for assessment (Klimisch score 2-4). 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 VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

In an acute oral toxicity study (similar to OECD 401), groups of female Sprague Dawley rats (5/group) were treated with the test material. The test material (either reagent grade dicalcium phosphate or dicalcium phosphate made from PCI superphosphoric acid was dissolved in water and administered in single doses (2 dose levels) to fasted rats by means of a stomach tube. The animals were observed for 14 days post-treatment. At a dose level of 4,640 mg/kg bw no rats died until the end of the observation period. At a dose level of 10,000 mg/kg no rat died treated with reagent grade dicalcium phosphate and 4/5 rats died treated with dicalcium phosphate made from PCI superphosphoric acid. No apparent signs of toxicity were produced from either sample when dosed at 4,640 mg/kg bw. The sample of dicalcium phosphate made of PCI superphosphoric acid produced acute depression and dyspnea at the 10,000 mg/kg dose level. The following abnormalities at gross pathology were observed in the animals dosed with 10,000 mg/kg of dicalcium phosphate made of PCI superphosphoric acid: stomach and upper gastrointestinal tract erythemic with congestion of the liver, kidneys and adrenals. Animals treated with reagent grade dicalcium phosphate at 10,000 mg/kg bw appeared grossly normal when autopsied 14 days after treatment. Animals treated with reagent grade dicalcium phosphate and PCI dicalcium phosphate at 4,640 mg/kg bw appeared also grossly normal when autopsied 14 days after treatment.

The following LD50 after oral administration of reagent grade dicalcium phosphate and dicalcium phosphate made from PCI superphosphoric acid were determined: LD50 (females) > 10,000 mg/kg bw and LD 50 (females) = 7940 mg/kg bw, respectively.

This data is supported by two further acute oral toxicity studies performed in 1973 and 1974 with calcium hydrogenorthophsphate dihydrate and calcium hydrogenorthophosphate, respectively. Both studies resulted in LD50 > 5000 mg/kg bw for male and female rats.

 

Inhalation:

No study is available for calcium hydrogenorthophosphate. A study is available with the read across substance calcium bis(dihydrogenorthophosphate) (CAS 7758 -23 -8). This study is considered relevant since the calcium phosphate compounds are structural similar. These two substance dissociate into Ca2+ cations and orthophosphate anion and it is assumed that they will undergo the same pathway once entered the body.

The inhalation toxicity study (according to OECD 403) with calcium bis(dihydrogenorthophosphate) in which groups of 11 week old Wistar rats (5/sex) were exposed by inhalation route (nose only) to the test substance as a dust and observed for 14 days. The maximal achievable dose was 2.6 mg/L. The rats were exposed for 4 hours. All animals survived the scheduled observation period. Slight to moderate ruffled fur was noted in all animals after the end of the exposure and was still present in most animals up to test day 2. Thereafter, all animals were free from clinical signs. Transient body weight loss was noted in all animals from test day 1 to test day 2. Normal body weight development was observed thereafter. No macroscopical findings were present at necropsy.

In conclusion, the LC50 of calcium bis(dihydrogenorthophosphate) obtained in this study was estimated to be greater than 2.6 mg/L air (gravimetrically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item. Thus, the LC50 for calcium hydrogenorthophosphate is also estimated to be greater than 2.6 mg/L air.

Dermal:

For the test substance only studies are available which were performed before guidelines and GLP was mandatory and each alone is regarded insufficient for assessment. However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment.

Both studies are similar to OECD 402. Both studies tested the acute dermal toxicity of either calcium hydrogenorthophosphate dihydrate or calcium hydrogenorthophosphate in New Zealand White rabbits up to 7940 mg/kg bw under occlusive conditions. No animal died in any dose group. The animals showed reduced appetite and activity for two to three days after treatment with calcium hydrogenorthophosphate dihydrate. No signs of toxicity were observed after treatment with calcium hydrogenorthophsphate. The viscera appeared normal by macroscopic examination after 14 days of observation in both studies.

In conclusion, the LD50 of calcium hydrogenorthophosphate or calcium hydrogenorthophosphate dihydrate is considered to be greater than 7940 mg/kg bw.

Justification for classification or non-classification

The available data indicate that calcium hydrogenorthophosphate does not meet the classification criteria for acute oral, inhalation or dermal toxicity in accordance with Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).