Registration Dossier
Registration Dossier
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EC number: 231-837-1 | CAS number: 7758-23-8
Endpoint summary
Administrative data
Description of key information
There is no available data for calcium bis(dihydrogenorthopsphate). But reliable data is available from the structural analogue pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7) and sodium dihydrogenorthophosphate (CAS 7558 -80 -7).
Skin sensitisation (RA-A 7558 -80 -7, OECD 429, RL1): not sensitising
Skin sensitistaion (RA-A 12167 -74 -7, OECD 406, RL1): not sensitisting
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 08 July 2014 - 15 August 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- refer to analogue justification provided in IUCLID section 13
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- 1992
- Deviations:
- no
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- Pentacalcium hydroxide tris(orthophosphate) is an inorganic salt of the alkaline earth metal calcium and orthophosphate. The water solubility of pentacalcium hydroxide tris(orthophosphate) is low (6.57 mg/L). Dermal absorption is therefore anticipated to be low (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014). Based on the identity/chemical structure and physicochemical properties, testing for skin sensitisation by means of a Local Lymph Node Assay (OECD 429) is considered to be inappropriate, as it may underestimate the skin sensitising potential of the test substance, leading to a false negative result, due to a low dermal absorption and hence low exposure. For this reason, the Guinea Pig Maximization Test, which involves intradermal injection of the test substance for induction thus ensuring exposure beneath the skin surface, is considered to be the most appropriate method for assessing the skin sensitising potential of this particular substance.
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles, River, Germany
- Age at study initiation: 4-6 weeks
- Weight at study initiation: 300.9-327.1 g
- Housing: test animals were housed in groups of up to ten
- Diet: commercial feeding mixture (mühle Knull, Rostock, Germany), ad libitum
- Water: tap water (drinking quality, supplemented with 1g/L vitamin C)
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3 °C
- Humidity (%): 30-70
- Air changes (per hr): 16
- Photoperiod (hrs dark / hrs light): 12/12 - Route:
- intradermal
- Vehicle:
- water
- Concentration / amount:
- 0.5%
- Day(s)/duration:
- 7
- Adequacy of induction:
- highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
- Route:
- epicutaneous, occlusive
- Vehicle:
- water
- Concentration / amount:
- 100%
- Day(s)/duration:
- 2
- Adequacy of induction:
- non-irritant substance, but skin pre-treated with 10% SDS
- Route:
- epicutaneous, occlusive
- Vehicle:
- water
- Concentration / amount:
- 100%
- Day(s)/duration:
- 1
- Adequacy of challenge:
- highest non-irritant concentration
- No. of animals per dose:
- 5 (negative control)
10 (test groups) - Details on study design:
- RANGE FINDING TESTS:
The appropriate test material concentrations for intradermal and epicutaneous induction and epicutaneous challenge exposures were determined in preliminary test using 6 additional FCA-treated animals.
For intradermal exposure, animals were given the test material at 5, 2.5, 1 and 0.5% suspensions in water by intradermal injections (0.1 mL). Animals were examined for signs of skin irritation at 24 and 48 h post-injection according to the Magnusson Kligman grading scale.
For topical exposure, animals were treated with the test material at 100, 50 and 25% in distilled water for 24 h under occlusive conditions. Irritation responses were assessed at 24 and 48 h after patch substance removal.
Based on the results of preliminary test (see Table 1), in the main test, 0.5% test material in water and 100% test material moistened with water were selected for intradermal and topical treatment, respectively.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (intradermal and epicutaneous, respectively)
- Exposure period: single injection (intradermal) and 48 h (epicutaneous)
- Test groups:
Intradermal (3 pairs of injections, 0.1 mL):
Injection 1: 1:1 mixture (v/v) FCA/water
Injection 2: 0.5% test substance in water
Injection 3: 0.5% test substance in a 1:1 mixture (v/v) FCA/water
- Negative control group:
Intradermal (3 pairs of injections, 0.1 mL)
Injection 1: 1:1 mixture (v/v) FCA/water
Injection 2: water
Injection 3: 1:1 mixture (v/v) FCA/water
Epicutaneous:
- Test group: test substance at 100%
- Negative control: water
- Site: scapular region (intradermal + epicutaneous)
- Frequency of applications: single
- Duration: Days 0-8 (on day 6, one day prior to epicutaneous induction, the shorn skin of all animals in each group was treated with 0.5 mL of 10% sodium lauryl sulphate vaseline, in order to create a local irritation).
B. CHALLENGE EXPOSURE
- No. of exposures: 1 (challenge)
- Day(s) of challenge: 21 (challenge)
- Exposure period: 24 h
- Test groups: 100% test substance moistened with water
- Control group: 100% test substance moistened with water
- Site: flank region
- Concentrations: 100%
- Evaluation (hr after challenge): 48 and 72 h
OTHER: - Positive control substance(s):
- yes
- Remarks:
- hexyl cinnamic acid (CAS No 101-86-0, routinely evaluated every 6 month at challenge concentrations of 55% in vasseline)
- Positive control results:
- Hexyl cinnamic acid (at challenge concentration of 55% in vaseline) induced skin sensitisation reactions in 90% of the treated animals.
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction (intradermal): 0%; induction (epicutaneoues): 0%, challenge 100%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction (intradermal): 0%; induction (epicutaneoues): 0%, challenge 100%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 100%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 100%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 55%
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 55%
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test material did not induce any skin reactions in intradermally and topically induced guinea pigs after challenge treatment. Therefore, the material does not fulfil the criteria for classification according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), and is thus considered to be not skin sensitizing.
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- The study was performed between 19 October 2009 and 03 November 2009.
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- refer to analogue justification provided in IUCLID section 13
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- The Department of Health of the Government of the United Kingdom
- Type of study:
- mouse local lymph node assay (LLNA)
- Species:
- mouse
- Strain:
- other: CBA/Ca (CBA/CaOlaHsd)
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Harlan UK Limited, Bicester, Oxon, UK.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: At the start of the study the animals were eight to twelve weeks old.
- Weight at study initiation: At the start of the study the animals were in the weight range of 15 to 23g.
- Housing: The animals were individually housed in suspended solid-floor polypropylene cages furnished with softwood woodflakes.
- Diet: ad libitum (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)
- Water: ad libitum tap water
- Acclimation period: at least five days
- Indication of any skin lesions:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12 - Vehicle:
- propylene glycol
- Concentration:
- Each group was exposed to concentrations of 10%, 5% or 2.5% w/w (in propylene glycol)
- No. of animals per dose:
- Groups of four mice were treated
- Details on study design:
- RANGE FINDING TESTS:
Using available information regarding the systemic toxicity/irritancy potential of the test material, a preliminary screening test was performed using one mouse. The mouse was treated by daily application of 25 µl of the undiluted test material to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mouse was observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Any signs of toxicity or excessive local irritation noted during this period were recorded. The bodyweight was recorded on Day 1 (prior to dosing) and on Day 6.
- Lymph node proliferation response:
Clinical observations, bodyweight and mortality data are give in the results section (table 1).
No signs of systemic toxicity were noted.
Based on this information the dose levels selected for the main test were 2.5% , 5% and 10% w/w in propylene glycol.
MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
-animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card
- Name of test method:
Local Lymph Node Assay in the Mouse. The assay has undergone extensive inter-laboratory validation and has been shown to reliably detect test materials that are moderate to strong sensitisers.
- Criteria used to consider a positive response:
The proliferation response of lymph node cells was expressed as the number of radioactive disintegrations per minute per lymph node(dpm/node) and as the ratio of 3HTdR incorporation in lymph node cells of test nodes relative to that recorded for the control nodes (stimulation Index).
The test material will be regarded as a sensitiser if at least one concentration of the test material results in a threefold or greater increase in 3HTdR incorporation compared to control values. Any test material failing to produce a threefold or greater increase in 3HTdR incorporation will be classified as a "non-sensitier".
TREATMENT PREPARATION AND ADMINISTRATION:
For the purpose of the study, the test material was used undiluted and also freshly prepared in propylene glycol. This vehicle was chosen as it produced the most suitable formulation at the required concentration. The concentrations used are given above.
Determination, by analysis, of the concentration, homogeneity and stability of the test material preparations was not appropriate because it was not specified in the Study Plan and is not a requirement of the Test Guidelines.
Test Material Administration
Groups of four mice were treated with the test material at concentrations of 10%,5% or 2.5% w/win propylene glycol. The preliminary screening test suggested that the test material would not produce systemic toxicity or excessive local irritation at the highest suitable concentration. The mice were treated by daily application of 25 µl of the appropriate concentration of the test material to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The test material formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.
3H-Methyl Thymidine Administration:
Five days following the first topical application of the test material (Day 6) all mice were injected via the tail vein with 250 µl of phosphate buffered saline (PBS) containing 3H-methyl thymidine (3HTdR: 80 µCi/ml, specific activity 2.0 Ci/mmol, GE Healthcare UK Ltd) giving a total of 20 µCi to each mouse. - Positive control substance(s):
- other: Phenylacetaldehyde (90%)
- Positive control results:
- One group of five animals was treated with 50 µl (25 µl per ear) of Phenylacetaldehyde (90%) as a solution in propylene glycol at a concentration of 2.5% v/v. A further group of five animals was treated with propylene glycol alone.
The Stimulation Index expressed as the mean radioactive incorporation for the treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration % v/v in acetone/olive oil 4:1 Stimulation Index (SI) Result
15 10.91 Positive
Alpha-Hexylcinnamaldehyde, Tech 85% was considered to be a sensitiser under the conditions of the test.
EXAMPLE - Parameter:
- SI
- Value:
- 1.31
- Test group / Remarks:
- 2.5% test substance
- Parameter:
- SI
- Value:
- 1.01
- Test group / Remarks:
- 5% test substance
- Parameter:
- SI
- Value:
- 1.05
- Test group / Remarks:
- 10% test substance
- Parameter:
- SI
- Value:
- 8
- Test group / Remarks:
- positive control - 90% Phenylacetaldehyde
- Cellular proliferation data / Observations:
- CLINICAL OBSERVATIONS: No signs of systemic toxicity
BODY WEIGHTS: normal - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test material was considered to be a non-sensitiser under the conditions of the test. The study is considered to be reliable and acceptable for use as a key study.
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- 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
- Positive control results:
- Hexyl cinnamic acid (at challenge concentration of 55% in vaseline) induced skin sensitisation reactions in 90% of the treated animals.
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction (intradermal): 0%; induction (epicutaneoues): 0%, challenge 100%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction (intradermal): 0%; induction (epicutaneoues): 0%, challenge 100%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 100%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 100%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- no visible clinical symptoms over the period of observation
- Remarks on result:
- no indication of skin sensitisation
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 55%
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 55%
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test material did not induce any skin reactions in intradermally and topically induced guinea pigs after challenge treatment. Therefore, the material does not fulfil the criteria for classification according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), and is thus considered to be not skin sensitizing.
- Executive summary:
No skin senistisation properties are considered from the source study by Gruemmer, 2014 (GPMT). As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the partition coefficient that are higher than the typical experimental error of the test method.
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- 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
- Positive control results:
- One group of five animals was treated with 50 µl (25 µl per ear) of Phenylacetaldehyde (90%) as a solution in propylene glycol at a concentration of 2.5% v/v. A further group of five animals was treated with propylene glycol alone.
The Stimulation Index expressed as the mean radioactive incorporation for the treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration % v/v in acetone/olive oil 4:1 Stimulation Index (SI) Result
15 10.91 Positive
Alpha-Hexylcinnamaldehyde, Tech 85% was considered to be a sensitiser under the conditions of the test.
EXAMPLE - Parameter:
- SI
- Value:
- 1.31
- Test group / Remarks:
- 2.5% test substance
- Parameter:
- SI
- Value:
- 1.01
- Test group / Remarks:
- 5% test substance
- Parameter:
- SI
- Value:
- 1.05
- Test group / Remarks:
- 10% test substance
- Parameter:
- SI
- Value:
- 8
- Test group / Remarks:
- positive control - 90% Phenylacetaldehyde
- Cellular proliferation data / Observations:
- CLINICAL OBSERVATIONS: No signs of systemic toxicity
BODY WEIGHTS: normal - Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test material was considered to be a non-sensitiser under the conditions of the test.
- Executive summary:
No skin senistisation properties are considered from the source study by Bradshaw, 2010 (LLNA). As explained in the justification for type of information, the differences in molecular structure between the target and the source are unlikely to lead to differences in the partition coefficient that are higher than the typical experimental error of the test method.
Referenceopen allclose all
Animal weights
Table 3: Individual animal weights (g) at start / test end (test group)
Animal |
Test start |
Test end |
Body weight change |
1 |
305.3 |
387.4 |
82.1 |
2 |
313.5 |
379.8 |
66.3 |
3 |
318.7 |
414.7 |
96.0 |
4 |
309.3 |
388.8 |
79.5 |
5 |
301.2 |
399.9 |
98.7 |
6 |
315.7 |
385.2 |
69.5 |
7 |
304.1 |
399.4 |
95.3 |
8 |
321.0 |
422.8 |
101.8 |
9 |
309.8 |
375.7 |
65.9 |
10 |
309.3 |
411.5 |
102.2 |
Individual weight of control group
Table 4: Individual animal weights (g) at test start and at test end (control group)
Animal |
Test start |
Test end |
Body weight change |
K1 |
309.4 |
383.0 |
73.6 |
K2 |
300.9 |
376.1 |
75.2 |
K3 |
324.0 |
396.1 |
72.1 |
K4 |
327.1 |
408.5 |
81.4 |
K5 |
326.4 |
398.7 |
72.3 |
Table 5: Skin reactions of test animals after treatment with the test material
Animal |
Numerical grading after |
|
24 h |
48 h |
|
1 |
0 |
0 |
2 |
0 |
0 |
3 |
0 |
0 |
4 |
0 |
0 |
5 |
0 |
0 |
6 |
0 |
0 |
7 |
0 |
0 |
8 |
0 |
0 |
9 |
0 |
0 |
10 |
0 |
0 |
Table 6: Skin reactions of control animals after treatment with the test material
Animal |
Numerical grading after |
|
24h |
48h |
|
K1 |
0 |
0 |
K2 |
0 |
0 |
K3 |
0 |
0 |
K4 |
0 |
0 |
K5 |
0 |
0 |
Table 7: Skin reactions of animals after challenge treatment with HCA 55 % in vaseline
Animal |
Numerical grading after |
|
24 h |
48 h |
|
1 |
1 |
1 |
2 |
0 |
0 |
3 |
1-2 |
1-2 |
4 |
1 |
1 |
5 |
1-2 |
2 |
6 |
1 |
1 |
7 |
1-2 |
1-2 |
8 |
0-1 |
1 |
9 |
1-2 |
1 |
10 |
1 |
1 |
Preliminary Screening Test
Clinical observations, bodyweight and mortality data are given in Table 1.
No signs of systemic toxicity were noted.
Based on this information the dose levels selected for the main test were 10%, 5% and 2.5% w/w in propylene glycol.
Main Test
Estimation of the Proliferative Response of Lymph Node Cells
The radioactive disintegrations per minute per lymph node and the stimulation index are given in Table 2.
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%w/w) in |
Stimulation Index |
Result |
2.5 |
1.31 |
Negative |
5 |
1.01 |
Negative |
10 |
1.05 |
Negative |
Clinical Observations and Mortality Data
Individual clinical observations and mortality data for test and control animals are given in Table 3.
There were no deaths. No signs of systemic toxicity were noted in the test or control animals during the test.
Bodyweight
Individual bodyweights and bodyweight changes for test and control animals are given in Table 4.
Bodyweight changes of the test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period.
Table1 Clinical Observations, Bodyweight and Mortality Data – Preliminary Screening Test
Concentration (%w/w) in |
Animal Number |
Bodyweight (g) |
Day |
|||||||||
1 |
2 |
3 |
4 |
5 |
6 |
|||||||
Day 1 |
Day 6 |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
10 |
S-1 |
19 |
19 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0= No signs of systemic toxicity
Table2 Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index
Concentration |
dpm |
dpm/Nodea |
Stimulation Indexb |
Result |
Vehicle |
5155.29 |
644.41 |
na |
na |
2.5 |
6770.88 |
846.36 |
1.31 |
Negative |
5 |
5203.17 |
650.40 |
1.01 |
Negative |
10 |
5413.31 |
676.66 |
1.05 |
Negative |
Table3 Individual Clinical Observations and Mortality Data
Concentration |
Animal Number |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
Day 5 |
Day 6 |
|||
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
Vehicle |
1-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2.5 |
2-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
5 |
3-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
10 |
4-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
4-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
4-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
4-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0= No signs of systemic toxicity
Table4 Individual Bodyweights and Bodyweight Changes
Concentration |
Animal Number |
Bodyweight (g) |
Bodyweight Change (g) |
|
Day 1 |
Day 6 |
|||
Vehicle |
1-1 |
19 |
21 |
2 |
1-2 |
18 |
18 |
0 |
|
1-3 |
21 |
20 |
-1 |
|
1-4 |
19 |
19 |
0 |
|
2.5 |
2-1 |
21 |
21 |
0 |
2-2 |
17 |
18 |
1 |
|
2-3 |
19 |
20 |
1 |
|
2-4 |
18 |
18 |
0 |
|
5 |
3-1 |
18 |
20 |
2 |
3-2 |
17 |
19 |
2 |
|
3-3 |
18 |
18 |
0 |
|
3-4 |
20 |
20 |
0 |
|
10 |
4-1 |
18 |
18 |
0 |
4-2 |
19 |
20 |
1 |
|
4-3 |
19 |
19 |
0 |
|
4-4 |
21 |
21 |
0 |
|
Animal weights
Table 3: Individual animal weights (g) at start / test end (test group)
Animal |
Test start |
Test end |
Body weight change |
1 |
305.3 |
387.4 |
82.1 |
2 |
313.5 |
379.8 |
66.3 |
3 |
318.7 |
414.7 |
96.0 |
4 |
309.3 |
388.8 |
79.5 |
5 |
301.2 |
399.9 |
98.7 |
6 |
315.7 |
385.2 |
69.5 |
7 |
304.1 |
399.4 |
95.3 |
8 |
321.0 |
422.8 |
101.8 |
9 |
309.8 |
375.7 |
65.9 |
10 |
309.3 |
411.5 |
102.2 |
Individual weight of control group
Table 4: Individual animal weights (g) at test start and at test end (control group)
Animal |
Test start |
Test end |
Body weight change |
K1 |
309.4 |
383.0 |
73.6 |
K2 |
300.9 |
376.1 |
75.2 |
K3 |
324.0 |
396.1 |
72.1 |
K4 |
327.1 |
408.5 |
81.4 |
K5 |
326.4 |
398.7 |
72.3 |
Table 5: Skin reactions of test animals after treatment with the test material
Animal |
Numerical grading after |
|
24 h |
48 h |
|
1 |
0 |
0 |
2 |
0 |
0 |
3 |
0 |
0 |
4 |
0 |
0 |
5 |
0 |
0 |
6 |
0 |
0 |
7 |
0 |
0 |
8 |
0 |
0 |
9 |
0 |
0 |
10 |
0 |
0 |
Table 6: Skin reactions of control animals after treatment with the test material
Animal |
Numerical grading after |
|
24h |
48h |
|
K1 |
0 |
0 |
K2 |
0 |
0 |
K3 |
0 |
0 |
K4 |
0 |
0 |
K5 |
0 |
0 |
Table 7: Skin reactions of animals after challenge treatment with HCA 55 % in vaseline
Animal |
Numerical grading after |
|
24 h |
48 h |
|
1 |
1 |
1 |
2 |
0 |
0 |
3 |
1-2 |
1-2 |
4 |
1 |
1 |
5 |
1-2 |
2 |
6 |
1 |
1 |
7 |
1-2 |
1-2 |
8 |
0-1 |
1 |
9 |
1-2 |
1 |
10 |
1 |
1 |
Preliminary Screening Test
Clinical observations, bodyweight and mortality data are given in Table 1.
No signs of systemic toxicity were noted.
Based on this information the dose levels selected for the main test were 10%, 5% and 2.5% w/w in propylene glycol.
Main Test
Estimation of the Proliferative Response of Lymph Node Cells
The radioactive disintegrations per minute per lymph node and the stimulation index are given in Table 2.
The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:
Concentration (%w/w) in |
Stimulation Index |
Result |
2.5 |
1.31 |
Negative |
5 |
1.01 |
Negative |
10 |
1.05 |
Negative |
Clinical Observations and Mortality Data
Individual clinical observations and mortality data for test and control animals are given in Table 3.
There were no deaths. No signs of systemic toxicity were noted in the test or control animals during the test.
Bodyweight
Individual bodyweights and bodyweight changes for test and control animals are given in Table 4.
Bodyweight changes of the test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period.
Table1 Clinical Observations, Bodyweight and Mortality Data – Preliminary Screening Test
Concentration (%w/w) in |
Animal Number |
Bodyweight (g) |
Day |
|||||||||
1 |
2 |
3 |
4 |
5 |
6 |
|||||||
Day 1 |
Day 6 |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
10 |
S-1 |
19 |
19 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0= No signs of systemic toxicity
Table2 Disintegrations per Minute, Disintegrations per Minute/Node and Stimulation Index
Concentration |
dpm |
dpm/Nodea |
Stimulation Indexb |
Result |
Vehicle |
5155.29 |
644.41 |
na |
na |
2.5 |
6770.88 |
846.36 |
1.31 |
Negative |
5 |
5203.17 |
650.40 |
1.01 |
Negative |
10 |
5413.31 |
676.66 |
1.05 |
Negative |
Table3 Individual Clinical Observations and Mortality Data
Concentration |
Animal Number |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
Day 5 |
Day 6 |
|||
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
Pre-Dose |
Post Dose |
|||||
Vehicle |
1-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
1-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2.5 |
2-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
5 |
3-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
10 |
4-1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
4-2 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
4-3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
4-4 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0= No signs of systemic toxicity
Table4 Individual Bodyweights and Bodyweight Changes
Concentration |
Animal Number |
Bodyweight (g) |
Bodyweight Change (g) |
|
Day 1 |
Day 6 |
|||
Vehicle |
1-1 |
19 |
21 |
2 |
1-2 |
18 |
18 |
0 |
|
1-3 |
21 |
20 |
-1 |
|
1-4 |
19 |
19 |
0 |
|
2.5 |
2-1 |
21 |
21 |
0 |
2-2 |
17 |
18 |
1 |
|
2-3 |
19 |
20 |
1 |
|
2-4 |
18 |
18 |
0 |
|
5 |
3-1 |
18 |
20 |
2 |
3-2 |
17 |
19 |
2 |
|
3-3 |
18 |
18 |
0 |
|
3-4 |
20 |
20 |
0 |
|
10 |
4-1 |
18 |
18 |
0 |
4-2 |
19 |
20 |
1 |
|
4-3 |
19 |
19 |
0 |
|
4-4 |
21 |
21 |
0 |
|
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
- Additional information:
No studies are available with calcium bis(dihydrogenorthophosphate) (CAS 7758 -23 -8). Reliable data is available for sodium dihydrogenorthophosphate (CAS 7558-80-7) and pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7).
Sodium dihydrogenortophosphate and calcium bis(dihydrogenorthophosphate) are structurally similar ionic compounds with the only differences being that sodium is replaced by calcium and the ionic linking of two phosphate groups by the calcium instead of one by sodium. The phosphate groups are structurally identical between the two compounds and any sensitisation potential will be the same.
Sodium and calcium are both alkali metals from groups 1 and 2 and period 3 and 4, respectively. Dermal absorption of calcium is anticipated to be less than sodium as the increase in charge from 1+ (sodium) to 2+ (calcium) is likely to reduce the ability of the compound to cross the skin barrier, calcium and sodium have almost the same ionic radius and absorption through the skin barrier is largely governed by molecular size. An additional consideration is that both calcium and sodium are essential biological compounds and are unlikely to have any sensitisation potential. This assumption is supported by the sensitisation data for pentacalcium hydroxide tris(orthophosphate).
The difference between the three compounds will not have an impact on any sensitisation potential and therefore the negative LLNA results with sodium dihydrogenorthophosphate and the negative GPMT test with pentacalcium hydroxide tris(orthophosphate) can reliably be read across to calcium bis(hydrogenorthophosphate).
Sodium dihydrogenorthophosphate (CAS 7558-80-7)
A LLNA study according to OECD 429 was performed to assess the skin sensitisation potential of sodium dihydrogenorthophosphate in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 10% w/w, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µl (25 µl per ear) of the test material as a suspension in propylene glycol at concentrations of 10%, 5% or 2.5% w/w. A further group of four animals was treated with propylene glycol alone. The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows: SI = 1.31 with 2.5% test substance, SI = 1.01 with 5% test substance and SI = 1.05 with 10% test substance. Thus, the test material was considered to be a non-sensitiser under the conditions of the test.
Pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7)
A GPMT study according to OECD 406 was performed to assess the skin sensitisation potential of pentacalcium hydroxide tris(orthophosphate) in female Dunklin-Hartley guinea pigs following an intradermal induction with 0.5% of the test substance and an occlusive epicutaneous induction with 100% and an occlusive epicutaneous challenge with 100% test substance. These concentrations were the highest concentrations which caused mild to moderate skin irritation. 10 animals were used in the test group and 5 in the negative control group. At challenge, 0/10 positive responses were noted in the test group after 24 h or 48 h and 0/5 positive responses were noted in the control group following treatment with 100% pentacalcium hydroxide tris(orthophosphate) after 24 h or 48 h. Thus, the test material was considered to be a non-sensitiser under the conditions of the test.
In conclusion, since sodium hydrogenorthophosphate and pentacalcium hydroxide tris(orthophosphate) are reliable read across substances and both do not show skin sensitising potential, calcium bis(dihydrogenorthophsphate) is considered to be also not sensitising.
Further in vivo testing is deemed to be scientifically unjustified.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Classification is not proposed on the basis of read-across from analogous substances (sodium dihydrogenorthophosphate and pentacalcium hydroxide tris(orthophosphate).
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