Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Oral (similar to OECD 401, RL2), rat: LD50 > 5000 mg/kg bw (limit test)

Inhalation (OECD 436, RL2), rat: 2 h 50 min exposure: LC50 > 2.35 mg/L (limit test)

Dermal (similar to OECD 402, RL2), rabbit: LD50 > 2000 mg/kg bw (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:
02/02/1982 to 29-05-1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study not conducted to current guideline, however study is scientifically sound and acceptable for assessment.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.
Qualifier:
according to guideline
Guideline:
other: EPA US Guidelines: Hazard Evaluation: Human and Domestic Animals, Fed. Reg. 43:163, 37336-37402 (1978)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1981
Deviations:
no
GLP compliance:
no
Remarks:
study was conducted in compliance with RTL quality assurance practices, RTL Standard Operating Procedures, and Good Laboratory Practices.
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: no data
- Weight at study initiation: The males ranged between 173-219 grams and the females were between 146-173 grams.
- Fasting period before study: Yes; no food 16-18 hours prior to treatment.
- Housing: five per cage in suspended mesh-bottom plastic cages (19" x 10.5" x 8")
- Diet: Purina Rat Chow provided ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: 66-72°F (18.9 - 22.2°C)
- no other data on conditions.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

DOSAGE PREPARATION: The test material was suspended in corn oil after it was passed through a #300 mesh screen.
Doses:
5000 mg/kg bw
Control rats received an equivalent dose of corn-oil only.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
- Duration of observation period following administration: The animals were observed for at least 14 days post treatment for mortality and signs of toxicity.
- Necropsy of survivors performed: Necropsies were performed on any animals that died and on all survivors.
- Observations for clinical signs and mortality will be recorded frequently the first day, and early morning and late afternoon thereafter. These animals will be observed once a day during weekends and holidays. All clinical signs will be recorded as to their onset, duration, and severity. The rats will be weighed on days 0 (prior to treatment), 7, 14, or at death.

Statistics:
no applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
None of the animals died during the treatment or post exposure periods.
Clinical signs:
Normal behaviour was reported throughout the study for all animals. The only adverse clinical sign observed in male rats was piloerection (until day 2). In female rats adverse clinical signs included depression, piloerection, and diarrhea. All female rats appeared normal by day 1.
Body weight:
There were no adverse effects on bodyweight gain. See Tabes 1-4.
Gross pathology:
Autopsy revealed no abnormalities.

Table 1. Changes in body weight recorded for the female control group

Animal No.*

Volume dosed

Time dosed

Daily bodyweight (grams) on day:

0

7

14

1

4.2

11:00

214

310

358

2

3.9

196

271

310

3

3.7

187

270

321

4

4.0

198

279

321

5

4.1

203

291

342

6

3.8

190

273

324

7

3.7

183

270

333

8

3.6

179

251

311

9

3.5

173

251

302

10

3.6

179

266

319

*Animals 1-5 were in cage A and animals 6-10 were in cage B.

Table 2. Changes in body weight recorded for the male group receiving the test material.

Animal No.*

Volume dosed

Time dosed

Daily bodyweight (grams) on day:

0

7

14

1

2.0

11:37

195

269

328

2

2.0

196

269

298

3

1.9

188

275

321

4

2.0

204

293

351

5

2.0

200

277

320

6

2.2

219

307

351

7

2.1

209

292

337

8

2.0

202

290

313

9

2.0

199

271

334

10

2.0

197

294

342

*Animals 1-5 were in cage A and animals 6-10 were in cage B.

Table 3. Changes in bodyweight recorded for the female control group

Animal No.*

Volume dosed

Time dosed

Daily bodyweight (grams) on day:

0

7

14

1

2.9

10:55

146

213

196

2

3.3

166

212

213

3

3.4

171

211

220

4

3.2

163

197

226

5

3.2

159

188

213

6

3.2

161

202

232

7

3.4

168

187

236

8

3.3

165

201

229

9

3.1

156

210

229

10

3.2

158

217

220

*Animals 1-5 were in cage A and animals 6-10 were in cage B.

Table 4. Changes in body weight recorded for the female group receiving the test material.

Animal No.*

Volume dosed

Time dosed

Daily bodyweight (grams) on day:

0

7

14

1

3.4

11:30

169

209

231

2

3.2

164

200

217

3

3.2

163

200

231

4

3.0

152

190

207

5

3.1

157

197

202

6

3.4

173

210

230

7

3.2

163

196

216

8

3.2

161

202

217

9

3.2

161

198

222

10

3.1

154

189

206

*Animals 1-5 were in cage A and animals 6-10 were in cage B.

Interpretation of results:
GHS criteria not met
Conclusions:
The test material was found to have an LD50 > 5000 mg/kg bw. Piloerection was reported for one rat after administration, bodyweights were comparable between the control groups and those groups dosed with the test material. At autopsy the animals appeared normal.
In accordance with Regulation (EC) No. 1282/2008 (EU CLP) pentacalcium hydroxide tris(orthophosphate) has not to be classified for acute toxicity via the oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study, 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:
experimental study
Adequacy of study:
key study
Study period:
11 - 27 May 2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Due to agglomeration of the test substance the aerosol generator was blocked repeatedly and, consequently, it was only possible to expose the rats for a total of 2 h and 50 min. The animals were in the exposure tubes for a total of 6 h and 54 min until the exposure was ended.
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
adopted Sep 2007
Deviations:
yes
Remarks:
Due to agglomeration of the test substance the aerosol generator was blocked repeatedly and it was only possible to expose the rats for a total of 2 h and 50 min. The animals were in the exposure tubes for a total of 6 h and 54 min.
GLP compliance:
yes (incl. QA statement)
Remarks:
Comunidad de Madrid, Consejera de Sanidad, Dirección General de Ordenación e Inspecctión, Spain
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley (Crl:sd)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Barcelona, Spain
- Age at study initiation: 12 weeks
- Weight at study initiation: 442.3 - 463.5 g (males); 233.7 - 264.3 g (females)
- Fasting period before study: no
- Housing: animals were housed 4/cage/sex before study start and 3/cage/sex after study start. Enrichment material (nesting material, tubes and chewing blocks) was provided.
- Diet: Global Diet 2914C (Harlan Teklad, Oxon, UK), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 33 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 14.1 - 25.8
- Humidity (%): 23 - 68
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 13 May 2015 To: 27 May 2015
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
3.08 µm
Geometric standard deviation (GSD):
3.87 - 5.77
Remark on MMAD/GSD:
Geometric Standard Deviation (GSD) on the two PSD determinations (PSD #2 and PSD #3) were 3.87 and 5.77 respectively, which are above the target range (1.5 to 3). Nevertheless, these values were considered to be acceptable taking into account that more than 76% and 50% of particles were below upper limit of 4µm in PSD #2 and PSD #3 respectively. Hence, the particle size distributions obtained were considered to be respirable to rats and these incidents are considered to have no impact on the quality / integrity of the study
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: EC-FPC-232 anodised aluminium exposure chamber
- Exposure chamber volume: approximately 3 L in individual nose-only, flow-past chamber
- Method of holding animals in test chamber: separately in glass restraint tubes
- Source and rate of air: filtered air at 1 L/min
- System of generating particulates/aerosols: the test subtance was desiccated for 18 h to facilitate the generation of a respirable aerosol. The dust aerosol was generated from the desiccated test substance using a Rotating Brush Generator (PALAS RBG 2000) and the dust was diluted with filtered air from a compressor and lead in glass tubes from the generator to the exposure chamber
- Method of particle size determination: mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined at the target concentration and calculated on the basis of the results from the impactor using Microsoft Excel software.
- Temperature, humidity, pressure in air chamber: 21. 4 ± 0.55 °C, 16.9 ± 0.76%

TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentration was determined using gravimetric analysis at least once per hour during each hour of exposure.

VEHICLE
- Composition of vehicle (if applicable): air

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: determined gravimetrically 3 times during the exposure period (see Table 1 under 'any other information on materials and methods incl. tables').
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD: 3.08 µm; GSD: 3.87 and 5.77 (results from PSD#2 and #3 are considered to be acceptable as the majority of the particles were below the upper limit of 4 µm)

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration: the starting dose of approximately 2 mg/L air was selected based on the available data and as this was the highest technically achievable dose during technical trials.

OTHER:
The test substance pentacalcium hydroxide tris(orthophosphate) is prone to agglomeration and aerosolisation could not be performed in its natural form. Therefore, the test substance was provided by the data owner as a commercial product whose specific manufacture process yields more spherical particles (without affecting the chemical identity), which were predicted to have a better aerosolisation than products from other manufacture processes.
Technical trials were performed without animals and conducted before the animal phase of the corresponding dose group(s) to establish the conditions for aerosol generation. These trial included determination of the target concentration and/or technical limit. Several tests were performed to establish the highest stable aerosol concentration achievable that could be maintained for at least 4 h. Aerosol concentration was initially aimed to 5 mg/L air since the test item was expected to be non-toxic. A stable aerosol concentration of approximately 2 mg/L air could be achieved with a PALAS RBG 2000 generator. Higher concentrations were not attempted since they would have required piston speed configurations that could damage the generator. Aerosol concentration was determined by gravimetric analysis.
Despite the attempts to aerosolize the test substance for the total duration of 4 h, blockages started to occur after the first hour of exposure and all attempts to complete the 4 hours exposure were unsuccessful. The study director decided to stop the aerosol generation after 6 hours and 54 minutes. The total cumulative exposure of animals to pentacalcium hydroxide tris(orthophosphate) (CAS No.: 12167-74-7, EC No.: 235-330-6) was 2 hours and 50 minutes.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
170 min
Remarks on duration:
Due to agglomeration of the test substance the aerosol generator was blocked repeatedly, therefore it was only possible to expose the rats for a total of 2 h and 50 min. The animals were in the exposure tubes for a total of 6 h and 54 min.
Concentrations:
2.35 mg/L (analytical concentration)
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: animals were observed for mortality and morbidity daily; clinical signs were recorded hourly during exposure (only grossly abnormal signs), immediately and 1 h after exposure, and once daily thereafter for the rest of the study period; the body weight was recorded on Day 1 prior to treatment, on Day 2, 4, 8, and on Day 15 prior to sacrifice.
- Necropsy of survivors performed: yes, with particular attention being paid to changes in the respiratory tract.
Statistics:
No statistical analysis was performed.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.35 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
170 min
Remarks on result:
other: Due to agglomeration of the test substance the aerosol generator was blocked repeatedly, therefore it was only possible to expose the rats for a total of 2 h and 50 min.
Mortality:
No mortality occurred during the study period.
Clinical signs:
other: 2/3 males had wet fur after 2 h exposure, while 3/3 males and 3/3 females had wet fur immediately after exposure ended and 1 h post-dosing. 1/3 males had dirty fur 2 h after exposure ended. Chromorrhinorrhea was observed in 3/3 males and chromodacryorrea
Body weight:
A slight decrease in mean body weight (< 5%) was observed from Day 1 to Day 2 in 6/6 rats. On Day 4, 6/6 rats had gained weight, relative to Day 2, although the individual body weight in 2/3 males and 1/3 females was lower than the body weight recorded on Day 1. By Day 8, all rats had gained body weights that were higher than that recorded on Day 1.
Gross pathology:
In 1/3 males, 2 red foci were observed in the right lung. It is not clear if this effect is treatment-related. No other macroscopic findings were reported in any animal.

Table 2: Results

Target concentration

[mg/L air]

Mortality

Clinical signs

 

N

N

Males

2.35 mg/L

0/3

3/3

Females

2.35 mg/L

0/3

3/3

*N= Number of animals/ number of animals used

Interpretation of results:
GHS criteria not met
Conclusions:
No mortality occurred during the study period and the LC50 of pentacalcium hydroxide tris(orthophosphate) was considered to be > 2.35 mg/L in air (analytical). This was the highest technically achievable test concentration. Due to agglomeration of the test substance the aerosol generator was blocked repeatedly and, consequently, it was only possible to expose the rats for a total of 2 h and 50 min. The animals were held in the individual restraint tubes for a total of 6 h and 54 min until the exposure phase was ended, as opposed to the standard 4-h exposure period. Therefore, both for technical reasons and for animal welfare reasons it was justified to end the exposure phase. During the exposure period and the 14-day observation period the study was performed according to OECD guideline 436, with the exception of the total exposure period of the animals, for technical and animal welfare reasons.
Taking into account the lack of mortality at 2.35 mg/L, the highest technically achievable test concentration, and the lack of clearly toxicologically relevant effects on body weight or macroscopic findings, the study is considered to be In accordance with Regulation (EC) No. 1272/2008. The test substance is considered to be not classified as acutely toxic via the inhalation route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
2 350 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02/02/1982 to 29-05-1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Non GLP, carried out according to recognised (older) guideline, results fully documented. Considered appropriate for use based on data available and animal welfare concerns.
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
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1981
Deviations:
yes
Remarks:
test on abraded skin and occlusive dressing
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:
standard acute method
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: 'Special mixture, Gunter Bros., Morgan Hill, CA' provided ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature: 65-70°F (18.3 - 21.1°C)
- no other data on conditions.

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:
2000 mg/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: At least 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:
not applicable
Preliminary study:
no data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no mortalities.
Clinical signs:
All rabbits appeared normal throughout the 14 day test. There were no apparent local dermal effects following a 24 hour exposure.
Body weight:
No reported effects
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) has not to be classified for acute toxicity via the dermal route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral:

In an acute oral toxicity study (similar to OECD 401), groups of fasted young Sprague Dawley rats (10/sex) were given a single oral dose of

pentacalcium hydroxide tris(orthophosphate) in corn oil at 5000 mg/kg bw and observed for 14 days. No mortality occurred and normal body weight gain were found in this study. Only piloerection was seen, being a common symptom in acute tests. At autopsy, no abnormalities were observed. Under the conditions of the study, the LD50 was considered to be > 5000 mg/kg bw.

Inhalation:

In an inhalation toxicity study (according to OECD 436), groups of fasted 12 week old Sprague Dawley rats (3/sex) were exposed by inhalation route (nose only) to pentacalcium hydroxide tris(orthophosphate) as an aerosol and observed for 14 days. The intended dose and duration of exposure was 2 mg/L and 4 hours, respectively. However, blockages in the generator due to agglomeration of the test item occured frequently, leading to intermittent exposure and ultimately to the impossibility to complete an exposure period of 4 hours. Total cumulative exposure was 2 hours and 50 minutes, during a total time of 6 hours and 54 minutes.A mean aerosol concentration of 2.35 mg/L was achieved. Dirty/wet fur was recorded in all animals immediately and 1 hour after exposure. In addition, chromorrhinorrhea was recored in all males immediately after expsoue, and chromodacryorrhea was recorded immediately postdose in 2 out of 3 males. All these clinical signs were transient and were not longer present at day 2 of study, with the exception of one male whose dirty fur disappeared on day 3 of study. No clinical signs were observed from day 3 of study to the end of the observation period. These clinical signs were considered to be mainly stress related to the nose-only exposure but a contribution of the treatment with the test item cannot be completely excluded. An initial slight decrease in body weight was observed in all animals from day 1 to day 2. Thereafter, a normal body weight gain was observed in all animals. No mortality and no relevant signs of toxicity during necrospy were observed after intermittent exposure. Under the conditions of the study, the LC50 was considered to be >2.35 mg/L. Taking into account the lack of mortality at 2.35 mg/L, the highest technically achievable test concentration, and the lack of clearly toxicologically relevant effects on body weight or macroscopic findings, the study is considered to be in accordance with Regulation (EC) No. 1272/2008 and suitable.

Dermal:

In an acute dermal toxicity study (similar to OECD 402), groups of fasted young Stauffland albino rabbits (4/sex) were dermally exposed to the undiluted pentacalcium hydroxide tris(orthophosphate) tor 24 hours at 2000 mg/kg bw and observed for 14 days. The skin was abraded before treatment and test substance was hold in place by an occlusive dressing. This procedure represents a worst case scenario. No mortality or unusual clincial signs occurred and normal body weight gain were found in this study. At autopsy, no abnormalities were observed. Under the conditions of this study, the LD50 was considered to be >2000 mg/kg bw.

Justification for classification or non-classification

The available data on acute oral toxicity with pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7) do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.

The available data on acute inhalation toxicity with pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7) do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.

The available data on acute dermal toxicity with pentacalcium hydroxide tris(orthophosphate) (CAS 12167 -74 -7) do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.