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Administrative data

Description of key information

Based on the results of a feeding study (Kshirsagar 1975) in which rats were exposed to a maximum concentration of 2000 mg/kg bw/ day, it can be concluded that the LD50 for acute oral toxicity for strontium phosphate is > 2000mg/kg bw. The LD50 of the substance analogue Strontium chloride for rats and mice were reported to be 2.250 and 3100 mg/kg bw respectively (Calvery, 1942 and Woodard, G; Calvery, HO (1941)). The LD50 of the substance analogue strontium nitrate for mice is reported to be 5675 mg/kg bw (Llobet et al. 1991). The hypothesis for the analogue approach is attached in section 13.
Based on an acute inalation study performed with Strontium nitrate according to OECD guideline and GLP principles, the inhalatory LC50 of strontium nitrate in Wistar rats was considered to be >4.5 +/- 0.6 mg/l. According to the rationale attached in section 13, these data can be read across to Strontiumhydrogenphosphate.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study is not performed according to a validated guideline or GLP principles. Although basic information is limited, sufficient data are provided to derive an endpoint conclusion. The test substance is not strontium hydrogen phosphate, but strontium phosphate. The pH of phosphate is known to be higher than for the hydrogenphosphate, but as these anions are in equilibrium with each other they are expected to behave similar in aqueous solutions (HPO42- + H2O↔PO43- + H3O+ (pKa = 12.32)). A report with further details on the hypothesis for the analogue approach is attached in section 13.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Feeding study
GLP compliance:
no
Remarks:
Study performed before GLP guidelines were in place
Test type:
other: feeding study
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: animal colony of test lab
- Age at study initiation: 21 days
- Diet: Stock diet, ad libitum (composition: wheat 70%, Bengal Gram (Cicer arietinum) 20%, fish meal 5%, yeast powder 4% and oil 1%)
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- No data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- Concentration in feed: 0%, 0.5%, 1% and 2% Sr
Doses:
0, 500, 1000 and 2000 mg/kg bw (estimated by calculation)
No. of animals per sex per dose:
5-6
Control animals:
yes
Details on study design:
- Duration of administration: 2, 4 or 6 weeks (control and 2000 mg/kg bw/day groups) or 6 weeks (500 and 1000 mg/kg bw/day groups).
- Duration of observation period following administration: 14 days (recovery groups)
- Frequency of observations and weighing: observations not reported, weight gain was recorded at day 1 and end of treatment (day 14, 28 or 42 resp.)
- Necropsy of survivors performed: yes
- Other examinations performed: Alkaline and acid phosphatase activity in liver, small intestine, kidney and bone was recorded; radiography of tibia and femurs, determination of Sr-concentration in liver, small intestine and kidney tissue.
Statistics:
The statistical significance of the results was estimated by using Student's t test (where possible).
Preliminary study:
Preliminary experiments did not reveal any appreciable changs at 500 or 1000 mg/kg bw/day when dosed for 4 weeks.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Based on 30% mortality at 2000 mg/kg bw
Mortality:
Mortality up to 30% was recorded in rats of the 2000 mg/kg bw/ day group (exposed for 4-6 weeks). Time point of mortality was not reported. No mortality reported in other groups.
Clinical signs:
Paralysis was seen in rats exposed to 2000 mg/kg bw/d for 4 to 6 weeks. No adverse effects were noticed in rats in the 500 and 1000 mg/kg bw/d groups.
Body weight:
Body weight gain was reduced at 2000 mg/kg bw/d after 2 weeks exposure or more.
Body weight gain was reduced at 1000 mg/kg bw/day after 6 weeks of exposure, but not at 500 mg/kg bw/d.
Gross pathology:
Hemorrhages and widening of the epiphyseal cartilage plate were seen in rats exposed to 2000 mg/kg bw/d for 4 to 6 weeks. Considerable calcification was induced in the recovery group, but no gross skeletal damage or external signs were noted. No adverse effects were noticed in rats in the 500 and 1000 mg/kg bw/d groups.
Other findings:
Effects on alkaline phosphatase activity in the tissues are further summarized in 7.5.1, since they are not relevant for the acute endpoints.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of a feeding study in which rats were exposed repeatedly to a maximum concentration of 2000 mg/kg bw/ day, it can be concluded that the LD50 for acute oral toxicity for strontium phosphate is > 2000mg/kg bw.
Executive summary:

A feeding study was performed in which young male rats were exposed to approximately 0, 500, 1000 or 2000 mg/kg bw/day for 2, 4 or 6 weeks (control and 2000 mg/kg bw/day groups) or 6 weeks (500 and 1000 mg/kg bw/day groups). Mortality up to 30% was recorded in rats of the 2000 mg/kg bw/ day group (exposed for 4-6 weeks). No mortality was reported in other groups. Paralysis and reduction in body weight gain were seen in rats exposed to 2000 mg/kg bw/d. No clinical signs or pathological findings were noticed in rats in the 500 and 1000 mg/kg bw/d groups. Hemorrhages and widening of the epiphyseal cartilage plate were seen in rats exposed to 2000 mg/kg bw/d for 4 to 6 weeks. Based on these results, it can be concluded that the LD50 for acute oral toxicity for strontium phosphate is > 2000mg/kg bw/day. Based on the rationale attached in section 13, these data can be read-across to Strontium hydrogenphosphate. Strontium hydrogenphosphate does not need to be classified for acute toxicity by the oral route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Reliability: 2

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2010-06-14 to 2010-06-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study has been performed according to OECD and/or EC guidelines and according to GLP principles. According to ECHA's practical guide 6: "How to report read-across and categories" the maximum reliability for a study performed with a substance analogue is 2. The hypothesis for the analogue approach is attached in section 13.
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
, 2009-09-07
Deviations:
yes
Remarks:
A target concentration of 5.5 mg/l was used instead of 5 mg/L (the upper limit of the guideline was increased with 10% in order to avoid the mean actual concentration to fall below the cut off value due to experimental variation)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Approximately 11 weeks old
- Weight at study initiation: Males: 296 - 320 g; Females: 197 - 217 g
- Housing: Before exposure: Group housing of five animals per sex per cage in labelled Macrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom); After exposure: Group housing as before exposure, except that a paper sheet was introduced into the cage covering the bedding and cage enrichment to prevent suffocation in case of bad health condition. At the end of the Day of exposure the paper sheet was removed.
- Diet (ad libitum except during exposure to the test substance): Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany)
- Water (ad libitum except during exposure to the test substance): Tap water
- Acclimation period: At least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature: 21.0 ± 3.0°C (actual range: 19.8 – 21.5°C)
- Relative humidity: 40-70% (actual range: 39 - 78%)
- Air changes: Approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: water
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The design of the exposure chamber is based on the flow past nose-only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983). The chamber consisted of three animal sections with eight animal ports each. Each animal port had its own atmosphere inlet and exhaust outlet. The animals were placed in restraining tubes and connected to the animal ports (20 min. after the last animal was placed the generation of the test atmosphere was started). The number of animal sections and number of open inlets were adapted to the air flow in such a way that at each animal port the theoretical air flow was at least 1 L/min, which ensures an adequate oxygen supply to the animals. The main inlet of the test atmosphere was located at the top section and the main outlet was located at the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal. All components of the exposure chamber in contact with the test material were made of stainless steel, glass, rubber or plastic. To avoid exposure of the personnel and contamination of the laboratory the exposure chamber was placed in a fume hood, which maintained at a slight negative pressure.

- Test substance preparation: A 60 % formulation was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level

- System of generating particulates/aerosols: An aerosol was generated by nebulization of the test substance by means of a nebulizer (type 950, Hospitak Inc., Lindenhurst, NY, USA) (appendix 1, figure 1). The primary aerosol was diluted with pressurized air before it entered the exposure chamber. The mean total airflow was 12 L/min.

- Method of particle size determination: The droplet size distribution was characterized twice during the exposure period. The samples were drawn (2 L/min) from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. The samples were collected with an 8 stage Marple personal cascade impactor containing fiber glass filters (SKC 225-713, glass fiber, SKC Omega Specialty Division, Chelmsford, MA, USA) and a fiber glass back-up filter (SEC-290-F1, Westech, Upper Stondon, Bedfordshire, England). Amounts of test substance collected were measured gravimetrically. Subsequently the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined.

- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, pressure in air chamber: The temperature and relative humidity were measured with a humidity and temperature indicator (E+E Elektronik, Engerwitzdorf, Austria) and were recorded after the animals were placed in the experimental set-up and at 30 minute intervals after initiation of the exposure. The temperature of the atmosphere was between 20.4 and 20.7°C and relative humidity was between 69 and 76%.

TEST ATMOSPHERE
- Nominal concentration: The nominal concentration was calculated by dividing the amount of test substance used by the volume of pressurized air (average air flow times exposure time) entering the exposure chamber used for exposure of the animals.

- Brief description of analytical method used: The actual concentration was determined nine times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. Samples were drawn through a glass fiber filter (type APFC04700, Millipore, Billerica, MA, USA). The filters were placed in a stove at 70ºC for 3 minutes before weighing to allow the water to evaporate. The collected amount of test substance in the air sample (before and after drying the filters) was measured gravimetrically. Sample volumes were measured by means of a dry gas meter (type G 1.6, Actaris Meterfabriek B.V., Dordrecht, The Netherlands).

- Samples taken from breathing zone: yes

-Stability monitoring: The opacity of the test atmosphere was monitored by means of a real time aerosol monitoring system (Windust Pro, Casella, Amherst, NH, USA). Data obtained with this system were used to illustrate the stability of the aerosol during exposure of the animals.
Data obtained from the opacity monitor showed that the aerosol was sufficiently stable

VEHICLE - Water (Elix, Millipore S.A.S., Molsheim, France)
- Justification of choice of vehicle: The vehicle was selected based on trial formulation performed at NOTOX and on test substance data supplied by the sponsor.

TEST ATMOSPHERE (if not tabulated)
The MMAD and GSD were determined twice:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
Measurement 1: MMAD: 3.4 µm (GSD = 1.8)
Measurement 2: MMAD: 3.7 µm (GSD = 2.1)
No further information on the inhalation exposure was stated.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
See "Details on inhalation exposure" above
Duration of exposure:
4 h
Concentrations:
Nominal concentration: 10.1 mg/L
Mean actual concentration: 4.5 +/- 0.6 mg/L
The actual and nominal concentrations were corrected for water content of the formulation. The generation efficiency (ratio of actual and nominal concentration) was 10%.
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Observations and weighing: Mortality/Viability was observed twice daily. The time of death was recorded as precisely as possible. Clinical signs (mortality, behavioural signs of distress and effect on respiration) were observed three times during the exposure. Clinical signs were also observed after exposure. These observations were made at 1 and at 3 hours after exposure on the day of dosing (day1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
Body weight was measured on Days 1 (pre-administration), 2,4 8 and 15.

- Necropsy of survivors performed: Yes
The animals surviving to the end of the observation period were sacrificed by an intraperitoneal injection with Euthasol ® (AST Farma BV, Oudewater, The Netherlands). All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities were recorded. Particular attention was given to any changes in the respiratory tract.
No further information on the study design was stated.
Statistics:
No statistical analysis was performed.

Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.5 other: mg/l water (analytically verified)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Standard deviation: 0.6 mg/l
Mortality:
One male was found dead approximately 2 hours after start of exposure. No further mortality occurred.
Clinical signs:
other: Laboured respiration was observed for two males between approximately 1.5 and 3.5 hours after start of exposure, including the male that was found dead. Hunched posture, lethargy, rales, gasping, piloerection, chromodacryorrhoea and/or ptosis were observ
Body weight:
Body weight gain of surviving males and females was within the range expected for rats of this strain and age used in this type of study.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Other findings:
No data
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
An acute inalation study was performed with Strontium nitrate according to OECD guideline and GLP principles. The inhalatory LC50 of strontium nitrate in Wistar rats was considered to be 4.5 +/- 0.6 mg/l. Based on the rationale attached in section 13, these data can be read across to Strontiumhydrogenphosphate. Strontium hydrogenphosphate is therefore not classified according to the criteria specified by Directive 67/548/EEC and subsequent regulations.
Executive summary:

An acute inalation study with Wistar rats was performed with Strontium nitrate according to OECD guideline and GLP principles. One male was found dead approximately 2 hours after start of exposure, no further mortality occurred. Laboured respiration was observed for two males between approximately 1.5 and 3.5 hours after start of exposure, including the male that was found dead. Hunched posture, lethargy, rales, gasping, piloerection, chromodacryorrhoea and/or ptosis were observed among three males mainly between Days 1 and 6 after exposure. Rales were also observed during the second week of the observation period. No unexpected alterations in body weight gain were observed in the surviving animals and no macroscopic effects were observed at necrospy.

The inhalatory LC50 of strontium nitrate was considered to be 4.5 +/- 0.6 mg/l. Based on the rationale attached in section 13, these data can be read across to Strontium hydrogenphosphate. Strontiumhydrogen phosphate is therefore not classified according to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as acute toxic by the inhalation route.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
4 500 mg/m³
Quality of whole database:
This study has been performed according to OECD and/or EC guidelines and according to GLP principles. According to ECHA's practical guide 6: "How to report read-across and categories" the maximum reliability for as study performed with a substance analogue is 2.T he hypothesis for the analogue approach is attached in section 13.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A feeding study (Kshirsagar 1975) was performed in which young male rats were exposed to approximately 0, 500, 1000 or 2000 mg/kg bw/day for 2, 4 or 6 weeks (control and 2000 mg/kg bw/day groups) or 6 weeks (500 and 1000 mg/kg bw/day groups). Recovery groups were included for all exposure groups (2 weeks recovery after 6 weeks exposure) and for the highest exposure group (2 weeks recovery after 2 and 4 weeks exposure). Mortality up to 30% was recorded in rats of the 2000 mg/kg bw/ day group (exposed for 4-6 weeks). No mortality was reported in other groups. Paralysis and reduction in body weight gain were seen in rats exposed to 2000 mg/kg bw/d. No clinical signs or pathological findings were noticed in rats in the 500 and 1000 mg/kg bw/d groups. Hemorrhages and widening of the epiphyseal cartilage plate were seen in rats exposed to 2000 mg/kg bw/d for 4 to 6 weeks. Based on these results, it can be concluded that the LD50 for acute oral toxicity for strontium phosphate is > 2000mg/kg bw/day. Based on this result, the substance does not need to be classified for acute toxicity by the oral route.

In the two supporting studies, the LD50's for the substance analogues strontium nitrate and strontium chloride is mentioned without experimental data. The LD50's are all above 2000 mg/kg bw, thus there are no inconsistencies and all data support the endpoint conclusion for oral toxicity.

An acute inalation study with Wistar rats was performed with strontium nitrate according to OECD guideline and GLP principles. One male was found dead approximately 2 hours after start of exposure, no further mortality occurred. Laboured respiration was observed for two males between approximately 1.5 and 3.5 hours after start of exposure, including the male that was found dead. Hunched posture, lethargy, rales, gasping, piloerection, chromodacryorrhoea and/or ptosis were observed among three males mainly between Days 1 and 6 after exposure. Rales were also observed during the second week of the observation period. No unexpected alterations in body weight gain were observed in the surviving animals and no macroscopic effects were observed at necrospy.

The inhalatory LC50 of strontium nitrate was considered to be >4.5 +/- 0.6 mg/l.

Based on the rationale attached in section 13, these data can be read across to strontiumhydrogenphosphate.


Justification for selection of acute toxicity – oral endpoint
Three publications are available: Kshirsagar (1975) is used as key study (Klimisch factor 2). The LD50's of substance analogues strontium chloride and strontium nitrate are mentioned in Calvery (1942) and Llobet et al (1991) (both Klimisch factor 4, used as supporting data). The hypothesis for the analogue approach is attached in section 13. Although the study is not performed according to a validated guideline or GLP principles, sufficient information is given to derive a conclusion for this endpoint. The test substance is not strontium hydrogen phosphate, but strontiuum phosphate. The pH of phosphate is known to be higher than for the hydrogenphosphate, but as these anions are in equilibrium with each other they are expected to behave similar in aqueous solutions (HPO42- + H2O↔PO43- + H3O+ (pKa = 12.32)), justifying the use of this study as key study.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available, performed with substance analogue Strontium nitrate.

Justification for classification or non-classification

Based on the available data, Strontium hydrogenphosphate is not classified for acute oral or inhalation toxicity according to the criteria specified by the CLP Regulation.