Phosphonic acid, calcium salt (2:1)

Endpoint summary

Description of key information

LD50 Acute Oral rat > 1683 mg Ca(H₂PO₃)₂ /kg bw

LD50 Acute Dermal rat > 4206 mg Ca(H₂PO₃)₂ /kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013, January

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Age and weight range :6 to 7 weeks old, 150 to 174 grams(at order) Supplier :Charles River Italia S.p.A., Calco (Lecco), ItalyBreeder :Charles River Italia S.p.A., Calco (Lecco), ItalyDate of arrival :17 January 2013Weight range at arrival:170 to 200 gramsAcclimatisation period:At least 5 daysVeterinary health check:After arrivalCagingNo. of animals/cage:Up to 3 during the study; up to 5 during acclimatisationHousing :Polysulphone solid bottomed cages measuring 59.5x38x20 cm with nesting materialCage tray control:Daily inspected and changed as necessary (at least 3 times/week)Water and dietWater :Drinking water supplied to each cage via a water bottleWater supply :Ad libitumDiet :4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)Diet supply :Ad libitum throughout the study except for dosing procedure indicated in section 4.2.2Records of analyses of water and diet are kept on file at RTC. Components present in the drinking water or diet are not at a level likely to interfere with the purpose or conduct of the study.Housing conditions (parameters set)Room lighting :Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours Air changes :Approximately 15 to 20 air changes per hour Temperature range:22°C ± 2°C Relative humidity range:55% ± 15% Actual conditions were monitored and recorded and records retained. No relevant deviations occurred.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

As requested by the Sponsor, since similar substances were judged to be non toxic at that dose level, and for regulatory requirements related to the potential registration of the test item in some countries, the animals were treated at a maximum dose level of 5000 mg/kg. As indicated in OECD guideline no. 423, a first sub-group of one female animal was initially dosed at 5000 mg/kg (Step 1). Since mortality occurred in this animal, a lower dose level of 2000 mg/kg was investigated. Then, a first sub-group of 3 female animals was dosed at a level of 2000 mg/kg (Step 2). Mortality did not occur. A second sub-group, similarly composed, was then dosed at the same dose level (Step 3). No mortality occurred.No further doses were investigated since the objective of the study had been achieved.

Doses:

During the study, the test item was suspended as follows:Vehicle:Purified waterConcentration:500 and 200 mg/mLConcentrations were calculated and expressed in terms of test item corrected for purity (50%).Frequency of treatment:Once only, on the day of dosing (Day 1).Fasting procedure:Overnight prior to dosing (Day –1) up to 4 hours after dosing.Dose calculation:Dose volume of 10 mL/kg of body weight for each animal.

No. of animals per sex per dose:

3 female for 5000 mg/kg5 female for 2000 mg/Kg

Control animals:

no

Preliminary study:

Mortality occurred on Day 2 in the first animal initially dosed at 5000 mg/kg (Step 1). Clinical signs observed prior to death (on the day of dosing) were piloerection and reduced activity.

Sex:

female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were noted in the first sub-group of three animals dosed at 2000 mg/kg (Step 2). No mortality occurred and no clinical signs were seen in the second sub-group of three females (Step 3) treated at the same dose level

Gross pathology:

The necropsy examination performed in the decedent animal treated at 5000 mg/kg (Step 1) and, at the end of the observation period in the animals dosed at 2000 mg/kg (Steps 2 and 3), did not reveal external or internal alterations

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

No reason for classification according to EU criteria

Conclusions:

LD0 > 2000 mg/kg bwLD50 > 2000 mg/kg bw

Executive summary:

The acute toxicity of KH₂PO₃/K₂HPO₃ was investigated following a single oral administration to the Sprague Dawley rat followed by a 14-day observation period.

A sub-group of 1 female animal was initially dosed at 5000 mg/kg (Step 1). Mortality occurred on Day 2 following dosing. Clinical signs observed prior to death were limited to piloerection and reduced activity.

No mortality occurred and no clinical signs were seen in the 2 sub-groups of animals subsequently dosed at 2000 mg/kg (Steps 2 and 3).

Body weight changes recorded during the study were within the expected range for this strain and age of animals.

No abnormalities were observed at necropsy examination performed in the early decedent animal or in those sacrificed at the end of the observation period.

These results indicate that the test item KH₂PO₃/K₂HPO₃ induced mortality in the rat following oral administration of a single dose at a level of 5000 mg/kg. No mortality or other signs of toxicity were observed following dosing at 2000 mg/kg. These results suggest the acute toxicity estimate (ATE) to be greater than 2000 but lower than 5000 mg/kg body weight.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

In the assessment of calcium dihydrogenphosphite (Ca(H2PO3)2, CAS 13780-04-6), a read-across approach is followed based on the information available for potassium phosphonate (KH2PO3/K2HPO3 EC 915-179-9). This read-across strategy is based on the hypothesis that the phosphite anion is the driver for the ecotoxicological and toxicological effects of both salts.The read-across hypothesis is justified by the immediate dissociation of calcium dihydrogenphosphate and potassium phosphonate upon dissolution in aqueous media. Both phosphite salts are highly soluble (>200 g/L) and are only present in their dissociated form in solution, i.e. the calcium or potassium cation and the phosphite anion. The transformation of the salts into the ions is rapid and complete in relevant environmental and physiological media and therefore no systemic exposure to the salts as such occurs. Exposure to the non-common cations (Ca2+ and K+) does not influence the prediction of the (eco)-toxicity because both elements are abundantly present in natural environments and emissions from these salts do not significantly increase the exposure concentration for calcium and potassium. Moreover, calcium and potassium are major essential element for living organisms.Further information is included as attachment in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Preliminary study:

Mortality occurred on Day 2 in the first animal initially dosed at 5000 mg KH2PO3 /kg bw, corresponding to 4206 mg Ca(H2PO3)2 /kg bw at equimolar H2PO3- concentrations (Step 1). Clinical signs observed prior to death (on the day of dosing) were piloerection and reduced activity.

Sex:

female

Dose descriptor:

LD0

Effect level:

> 1 349 - < 3 372 mg/kg bw

Based on:

act. ingr.

Remarks:

dihydrogen phosphite anion

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 349 mg/kg bw

Based on:

act. ingr.

Remarks:

dihydrogen phosphite anion

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

> 1 683 - < 4 206 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 683 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were noted in the first sub-group of three animals dosed at 2000 mg KH2PO3 /kg bw, corresponding to 1683 mg Ca(H2PO3)2 /kg bw at equimolar H2PO3- concentrations (Step 2). No mortality occurred and no clinical signs were seen in the second sub-group of three females (Step 3) treated at the same dose level.

Gross pathology:

The necropsy examination performed in the decedent animal treated at 5000 mg KH2PO3 /kg bw, corresponding to 4206 mg Ca(H2PO3)2 /kg bw at equimolar H2PO3- concentrations (Step 1) and, at the end of the observation period in the animals dosed at 2000 mg KH2PO3 /kg bw, corresponding to 1683 mg Ca(H2PO3)2 /kg bw at equimolar H2PO3- concentrations (Steps 2 and 3), did not reveal external or internal alterations

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

No reason for classification according to EU criteria

Conclusions:

LD0 > 1683 and <4206 mg Ca(H2PO3)2 /kg bwLD50 > 1683 mg Ca(H2PO3)2 /kg bw

Executive summary:

The acute toxicity of KH₂PO₃/K₂HPO₃ was investigated following a single oral administration to the Sprague Dawley rat followed by a 14-day observation period.

A sub-group of 1 female animal was initially dosed at 5000 mg/kg bw (Step 1). Mortality occurred on Day 2 following dosing. Clinical signs observed prior to death were limited to piloerection and reduced activity.

No mortality occurred and no clinical signs were seen in the 2 sub-groups of animals subsequently dosed at 2000 mg/kg bw (Steps 2 and 3).

Body weight changes recorded during the study were within the expected range for this strain and age of animals.

No abnormalities were observed at necropsy examination performed in the early decedent animal or in those sacrificed at the end of the observation period.

These results indicate that KH₂PO₃/K₂HPO₃ induced mortality in the rat following oral administration of a single dose at a level of 5000 mg/kg bw. No mortality or other signs of toxicity were observed following dosing at 2000 mg/kg bw. Values were recalculated for Ca(H₂PO₃)₂ based on the assumption that the phosphite anion is the active ingredient reposonsible for the effects. Results for Ca(H₂PO₃)₂ suggests the acute toxicity estimate (ATE) to be greater than 1683 but lower than 4206 mg Ca(H₂PO₃)₂ /kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

1 683 mg/kg bw

Quality of whole database:

The original study is a Klimish 1 guideline study.

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:

key study

Study period:

2013, January

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age and weight range :6 to 8 weeks old, 176 to 200 grams(at order)Supplier :Charles River Italia S.p.A., Calco (Lecco), ItalyBreeder :Charles River Italia S.p.A., Calco (Lecco), ItalyDate of arrival :17 January 2013Weight range at arrival:201 to 206 grams Acclimatisation period:At least 5 daysVeterinary health check:After arrivalCagingNo. of animals/cage:Individually caged (both during acclimatisation and study)Housing :Clear polysulphone H-Temp solid bottomed cages measuring 35.5x23.5x19 cm (during acclimatisation) an d 42.5x26.6x18.5 cm (during the study) with nesting material provided into suitable bedding bagsCage control :Daily inspected and changed as necessary (at least 3 times/week)Water and dietWater :Drinking water supplied to each cage via a water bottleWater supply :Ad libitumDiet :4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)Diet supply :Ad libitum throughout the study Records of analyses of water and diet are kept on file at RTC. Components present in the drinking water or diet are not at a level likely to interfere with the purpose or conduct of the study.Housing conditions (parameters set)Room lighting: :Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours Air changes: :Approximately 15 to 20 air changes per hourTemperature range::22°C ± 2°C Relative humidity range::55% ± 15%Actual conditions were monitored, recorded and records retained. No relevant deviations occurred

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

Frequency of treatment:Once only, on the day of dosing (Day 1).Treatment area preparation:On the day before dosing (Day –1).A single area was clipped free of hair (by an electric clipper equipped with a suitable blade) on the dorsal surfaces of the trunk of each animal, (approximately 10% of body surface).Care was taken to avoid damage to the skin.Dose calculation:Aliquots were weighed according to the body weight of each animal measured prior to dosing and corrected for purity (50%).

Duration of exposure:

Exposure time :24 hoursWashing procedure:After exposure, the adhesive bandage and gauze patch were removed. The treatment area was cleaned by gentle swabbing of the skin with cotton wool soaked with lukewarm water.

Doses:

5000 mg/Kg bw

No. of animals per sex per dose:

A single group of 5 male and 5 female animals was dosed at a level of 5000 mg/kg

Details on study design:

In life observationsMortality and morbidity:Twice daily.Clinical signs :-Day of dosing (on dosing, approximately 1, 2 and 4 hours after dosing). -Daily thereafter (14 days).Body weight :Allocation (Day -1), Days 1, 8 and 15.Terminal studiesTermination :Day 15.Euthanasia method:Carbon dioxide narcosis.Necropsy procedure:Necropsy was carried out on all animals (gross necropsy examination for both external and internal abnormalities, with particular attention to the treatment site).

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were observed in male or female animals following treatment

Gross pathology:

No abnormalities were found at necropsy examination performed on all animals at termination of the study

Interpretation of results:

GHS criteria not met

Conclusions:

LD0 > 5000 mg/kg bw LD50 > 5000 mg/kg bw

Executive summary:

The acute toxicityof KH₂PO₃/K₂HPO₃was investigated following dermal administration of a single dose to the rat at 5000 mg/kg.

No mortality occurred following dosing and no signs of toxicity were observed.

These results indicate that the test item, KH₂PO₃/K₂HPO₃, has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 5000 mg/kg. The lack of mortality demonstrates the LD50 to be greater than 5000 mg/kg.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

In the assessment of calcium dihydrogenphosphite (Ca(H2PO3)2, CAS 13780-04-6), a read-across approach is followed based on the information available for potassium phosphonate (KH2PO3/K2HPO3 EC 915-179-9). This read-across strategy is based on the hypothesis that the phosphite anion is the driver for the ecotoxicological and toxicological effects of both salts.The read-across hypothesis is justified by the immediate dissociation of calcium dihydrogenphosphate and potassium phosphonate upon dissolution in aqueous media. Both phosphite salts are highly soluble (>200 g/L) and are only present in their dissociated form in solution, i.e. the calcium or potassium cation and the phosphite anion. The transformation of the salts into the ions is rapid and complete in relevant environmental and physiological media and therefore no systemic exposure to the salts as such occurs. Exposure to the non-common cations (Ca2+ and K+) does not influence the prediction of the (eco)-toxicity because both elements are abundantly present in natural environments and emissions from these salts do not significantly increase the exposure concentration for calcium and potassium. Moreover, calcium and potassium are major essential element for living organisms.Further information is included as attachment in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 3 372 mg/kg bw

Based on:

act. ingr.

Remarks:

dihydrogen phosphite anion

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 373 mg/kg bw

Based on:

act. ingr.

Remarks:

dihydrogen phosphite anion

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 4 206 mg/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 206 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred and no clinical signs were observed in male or female animals following treatment

Gross pathology:

No abnormalities were found at necropsy examination performed on all animals at termination of the study

Interpretation of results:

GHS criteria not met

Conclusions:

LD0 > 4206 mg Ca(H2PO3)2 /kg bw LD50 > 4206 mg Ca(H2PO3)2 /kg bw

Executive summary:

The acute toxicityof KH₂PO₃/K₂HPO₃ was investigated following dermal administration of a single dose to the rat at 5000 mg/kg bw.

No mortality occurred following dosing and no signs of toxicity were observed.

These results indicate that KH₂PO₃/K₂HPO₃ has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 5000 mg/kg bw. The lack of mortality demonstrates the LD50 to be greater than 5000 mg/kg. Values were recalculated for Ca(H₂PO₃)₂ based on the assumption that the phosphite anion is the active ingredient reposonsible for the effects. The corrected LD50 for Ca(H₂PO₃)₂ is greater than 4206 mg Ca(H₂PO₃)₂ /kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 206 mg/kg bw

Quality of whole database:

The original study is a Klimish 1 guideline study.

Additional information

Acute toxicity studies per oral and dermal exposure have been performed on the multiconstituent substance "Reaction mass of dipotassium phosphonate and Phosphonic acid, potassium salt (1:1)" (Salvador, 2013) and the results of those studies are also applicable to the monoconstituent "mono Potassium phosphonate", which is a component and also the favourite species in the gastric environment.

Results for mono Potassium phosphonate were recalculated to calcium dihydrogen phosphite (Ca(H₂PO₃)₂) based on the assumption that the phosphite anion is the active ingredient reposonsible for the effects. No effect has been predicted respectively at 1683 and 4206 mg Ca(H₂PO₃)₂ /kg bw for oral and dermal exposure.

Justification for classification or non-classification

Oral acute toxicity

The substance is not classified for oral toxicity because it doesn't meet the classification criteria of the CLP regulation n. 1272/2008:

Oral (mg/kg bodyweight)

Category 1: ATE ≤ 5

Category 2: 5 < ATE≤ 50

Category 3: 50 < ATE≤ 300

Category 4: 300 < ATE≤ 2 000

Results for Ca(H₂PO₃)₂ suggest the acute toxicity estimate (ATE) to be greater than 1683 but lower than 4206 mg/kg body weight.

Inhalation acute toxicity

According to the Annex VIII of the REACH Regulation n. 1907/2006, inhalation route is not considered appropriate, based also on vapour pressure and the test can be waived.

Dermal acute toxicity

The substance is not classified for dermal toxicity because it doesn't meet the classification criteria of the CLP regulation n. 1272/2008:

Dermal (mg/kg bodyweight)

Category 1: ATE ≤ 50

Category 2: 50 < ATE≤ 2000

No effect has been predicted for Ca(H₂PO₃)₂ at 4206 mg/kg bw.