Registration Dossier

Administrative data

Description of key information

Key studies are available for acute oral and acute inhalation toxicity. These studies are performed under the conditions of GLP and to an appropriate OECD guideline. As such, these studies are considered to be adequate and reliable for use a key study for the purpose of REACH Registration and classification and labelling in accordance with EU CLP. It is not considered necessary to provide acute dermal toxicity data on the basis of the physiochemical and toxicological properties of aluminium orthophosphate.

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:
The study was performed between 13 April 2010 and 05 May 2010.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Date of inspection: 15th Spetember 2009, Date of signature: 26th November 2009
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 166-188 g. The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).
- Fasting period before study: overnight fast immediately before dosing.
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): ad libitum (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): at least 15 per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

IN-LIFE DATES: From: 13 April 2010 To: 05 May 2010

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
For the purpose of the study the test material was freshly prepared, as required, as a suspension in distilled water at a dose level of 2000 mg/kg /concentration of 200 mg/mL
- Amount of vehicle (if gavage): Not stated
- Justification for choice of vehicle: Not stated
- Lot/batch no. (if required): Not stated
- Purity: Not stated

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: Not applicable

CLASS METHOD (if applicable)
Not applicable

- Rationale for the selection of the starting dose:
Using available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose.
Doses:
Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test material, as a suspension in distilled water, at a dose level of 2000 mg/kg bodyweight.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made ½, 1, 2, and 4 hours after dosing and subsequently once daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: yes
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Preliminary study:
A sighting test at a dose level of 2000 mg/kg was performed.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not given in study report
Mortality:
There were no deaths in the 5 animals tested.
Clinical signs:
Individual clinical observations and mortality data are given in Table 1. No signs of systemic toxicity were noted.
Body weight:
Individual bodyweights and bodyweight changes are given in Table 2.
All animals showed expected gains in bodyweight over the observation period.
Gross pathology:
Individual necropsy findings are given in Table 3.
No abnormalities were noted at necropsy.

Table 1. Individual clinical observations and mortality data.

 

 

Dose level mg/kg

Animal

number

and sex

Effects noted after dosing (hours)

Effects noted during periods after doing

(days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000 

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

 

 

 

Table 2. Individual bodyweight and bodyweight changes

 

Dose level mg/kg

Animal

number

and sex

Bodyweight (g) at day

 

Bodyweight gain (g) during week

 

0

7

14

1

2

2000

1-0

Female

166

170

183

3

13

2-0

Female

188

204

216

16

12

2-1

Female

175

193

203

18

10

2-2

Female

171

185

193

14

8

2-3

Female

161

176

189

15

13

 

 

 

Table 3. Individual Necropsy Findings

 

Dose level mg/kg

Animal

number

and sex

Time of death

Macroscopic observations

2000

1-0

Female

Killed day 14

No abnormalities detected

2-0

Female

Killed day 14

No abnormalities detected

2-1

Female

Killed day 14

No abnormalities detected

2-2

Female

Killed day 14

No abnormalities detected

2-3

Female

Killed day 14

No abnormalities detected

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System: Unclassified).
This study is considered to be reliable and acceptable for use as a key study in accordance with Regulation (EC) No. 1907/2006 (REACH) and for the purposes of classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of the following:

 OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (adopted 17 December 2001)

 Method B1 bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

Method.

Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test material, as a suspension in distilled water, at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality.

There were no deaths.

Clinical Observations.

There were no signs of systemic toxicity.

Bodyweight.

All animals showed expected gains in bodyweight.

Necropsy.

No abnormalities were noted at necropsy.

Conclusion.

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Globally Harmonised Classification System Unclassified).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
LD50 >2000 mg/kg bw
The study is conducted under the conditions of GLP and in accordance with an appropriate guideline (OECD 420). This study has been assigned a Klimisch reliability of 1.

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:
21st May 2010 - 10th August 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category

The source substance and the target substance are considered to be similar enough to facilitate read-across for the following reasons:
(1) Both substances are inorganic salts containing a trivalent aluminium cation and phosphoric acid. Thus, they all share the Al3+ cation and the PO43- anion as common functional groups. Therefore the toxicity of the above substances will be predominantly determined by the presence of the Al3+ cation.
(2) Both substances will ultimately dissociate into the common breakdown products of the Al3+ cations and the PO43- anion.
(3) In general, independently of the cation under consideration, the water solubility of phosphates decreases with increasing degree of phosphate condensation (orthophosphate > diphosphate > triphosphate > polyphosphate).
In accordance with the provisions set out in Annex XI, Section 1.5, the results of the studies used for assessment and read-across are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method; cover an exposure duration comparable to or longer than the corresponding test method; and adequate and reliable documentation of the applied method is provided in the technical dossier. Orthophosphates are not considered to be genotoxic and are essential micronutrients. As such the acute inhalation toxicity of the target substance will be predominantly determined by the presence of the Al3+ cation. This approach is considered to be reliable and justified and no further testing for aluminium orthophosphate is required.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Values for relative humidity above the range occasionally occurred, usually following room cleaning, and were considered not to have any influence on the study.
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
yes
Remarks:
Values for relative humidity above the range occasionally occurred, usually following room cleaning, and were considered not to have any influence on the study.
GLP compliance:
yes (incl. QA statement)
Remarks:
Date of Inspection: 5th to 9th and 26th to 30th November 2007 Date of signature: 30th April 2008
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Source: Harlan Laboratories B.V., Kreuzelweg 53, 5961 NM Horst / Netherlands
- Age at study initiation: Males: 9 weeks, Females: 9 weeks
- Weight at study initiation: Males: 273.8 to 304.9 g, Females: 175.4 to 187.2 g
- Fasting period before study: Not applicable
- Housing: Animals were housed in groups of 5 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel" J. Rettenmaier & Söhne GmbH & Co KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK).
- Diet (e.g. ad libitum): Animals had ad libitum access to a pelleted standard Harlan Teklad 2914C rat maintenance diet (Provimi Kliba AG, 4303 Kaiseraugst, Switzerland) batch no. 82/09 except during the period when the animals were restrained in exposure tubes. Results of the analyses for contaminants and their limits of acceptability are archived at Harlan Laboratories Ltd.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum in water bottles, except during the period when they were restrained in exposure tubes. Results of representative analyses for contaminants are archived at Harlan Laboratories Ltd.
- Acclimation period: For ten days under laboratory conditions, after clinical health examination. Only animals without any visible signs of illness were used for the study. A further observation of clinical signs was performed on the day of exposure, before exposure start.


ENVIRONMENTAL CONDITIONS
Optimal Hygienic Conditions (OHC) inside a barrier system. Air-conditioned with 10 - 15 air changes per hour, continuously monitored environment with a temperature range of 22 ± 3 °C, a relative humidity range of 30 - 70% and a 12 hour fluorescent light / 12 hour dark cycle. Values for relative humidity above the range occasionally occurred, usually following room cleaning, and were considered not to have any influence on the study. These data are not reported but retained at Harlan Laboratories Ltd. A radio program was played during most of the light period.

IN-LIFE DATES: From: Day 1 To: Day 14
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Remarks:
flow-past
Vehicle:
clean air
Mass median aerodynamic diameter (MMAD):
2.56 µm
Geometric standard deviation (GSD):
2.38
Remark on MMAD/GSD:
Mean Mass Median Aerodynamic Diameter (µm) 2.56, 2.79 and 2.72
Inhalable Fraction (% <4 µm) 69.6%, 65.8% and 67.1%
Geometric Standard Deviation 2.38, 2.43 and 2.38
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: A CR3020 rotating brush aerosol generator connected to a micronizing jet mill. The aerosol generated was then discharged into the flow-past, nose-only exposure chamber through a 63Ni charge neutralizer.
- Exposure chamber volume: Not applicable (nose-only, flow-past inhalation exposure chamber)
- Method of holding animals in test chamber: The animals were confined separately in restraint tubes which were positioned radially around the flow-past, nose-only exposure chamber. Only the nose of each animal was exposed to the test atmosphere.
- Source of air: Compressed air was supplied by means of an oil free compressor and passed respiratory quality filters before it was introduced into the exposure system.
- Method of conditioning air: Respiratory quality filters
- System of generating particulates/aerosols: A dust aerosol was generated from the test item using a CR3020 rotating brush aerosol generator connected to a micronizing jet mill. The aerosol generated was then discharged into the exposure chamber through a 63Ni charge neutralizer.
- Method of particle size determination: Mercer Impactor (Model 02-130, In-Tox. Products Inc., Albuquerque, New Mexico, U.S.A.).
- Treatment of exhaust air: Filtered
- Temperature, humidity, pressure in air chamber: The oxygen concentration, temperature and relative humidity of the test atmosphere were measured continuously during the exposure on test aerosol samples taken at a representative exposure port using a calibrated device. The results were recorded manually and are reported at 30 minute intervals from the start of exposure.

TEST ATMOSPHERE

- Brief description of analytical method used: Gravimetric determinations of aerosol concentration were performed four times during exposure. The samples were collected on a Millipore®durapore filter, Type HVLP loaded in a 47 mm inline stainless steel filter sampling device. The filters were weighed before and immediately after sampling using a calibrated balance. The test aerosol concentration was calculated from the amount of test item present on the filter and the sample volume.

- Samples taken from breathing zone: Yes

VEHICLE
No vehicle used.
Analytical verification of test atmosphere concentrations:
no
Remarks:
Gravimetric only
Duration of exposure:
4 h
Concentrations:
Mean Achieved (mg/L) 5.1
The nominal aerosol concentration was 10.6 mg/L air.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration:
14 days

- Frequency of observations and weighing:
All animals were observed for clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to treatment on the day of exposure and on Days 2, 4, 8 and 15 or at death.

- Necropsy of survivors performed:
yes

- Other examinations performed:
None
Statistics:
No statistical analysis was performed as only one group was allocated to the study.
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: CL not given
Mortality:
All animals survived the scheduled observation period.
Clinical signs:
other: Hunched posture, salivation, ruffled fur, labored breathing and breathing noises were noted in all animals after the end of exposure. Only ruffled fur, labored breathing and breathing noises were recorded on test day 2 and persisted up to test day 10. In
Body weight:
From test day 1 to test day 2, slight to moderate body weight loss was noted in all animals. From test day 2 to test day 4, reduced body weight gain was noted in four males and two females. Thereafter normal body weight development was recorded in all animals.
Gross pathology:
There were no macroscopic findings.
Other findings:
Not applicable.

The nominal aerosol concentration was 10.6 mg/L air.

Interpretation of results:
GHS criteria not met
Conclusions:
The LC50 of MONOBASIC ALUMINIUM PHOSPHATE (FFB 716) obtained in this study was estimated to be greater than 5.1 mg/L air (gravimetrically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

This study is conducted according to an appropriate guideline and under the conditions of GLP, the study is therefore considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement as a key study for this endpoint.
Executive summary:

A group of five male and five female albino rats [RccHanTM:WIST(SPF)] was exposed by nose-only, flow-past inhalation for four hours to the test item atagravimetricallydetermined mean concentration of 5.1 mg/L air.All animals were observed for clinical signs and mortality during the inhalation exposure and the subsequent 14-dayobservation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 2, 4, 8 and 15 before necropsy. On test day 15 all animals were sacrificed and necropsied.

The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats.

 

All animals survived the scheduled observation period.

 

Principal clinical signs consisted of hunched posture, ruffled fur, labored breathing, breathing noises and salivation in all animals after exposure. No symptoms were recorded during the observation period from test day 11 onwards.

 

From test day 1 to test day 2, transient body weight loss was noted in all animals. From test day 2 to test day 4 reduced body weight gain was recorded in most males and some females. Normal body weight development was observed thereafter.

 

No treatment-related macroscopic findings were recorded.

 

In conclusion, the LC50of MONOBASIC ALUMINIUM PHOSPHATE (FFB 716)obtained in this study was estimated to be greater than 5.1 mg/L air(gravimetrically determined mean aerosol concentration).There was no indication of relevant sex-related differences in toxicity of the test item.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 100 mg/m³
Quality of whole database:
LC50 > 5100 mg/m3
The study is conducted under the conditions of GLP and in accordance with an appropriate guideline (OECD 403).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No data available.

Additional information

Read-across justification: Acute inhalation

Both substances are structurally similar inorganic orthophosphates containing phosphate anions and aluminium cations. Neither substance is classified for acute toxicity via the oral route. In addition, when solubilised aluminium tris(dihydrogen orthophosphate) will form aluminium orthophosphate and as such it is not considered to be justified to perform acute inhalation studies on both substances. 

Adaptation to the standard testing regime; dermal toxicity:

According to Annex VIII, Section 8.5.3, Column 2 of Regulation No 1907/2006, testing by the dermal route is not appropriate when the physicochemical and toxicological properties suggest that the rate of absorption through the skin will not occur at a significant rate.

 

- The molecular weight of the substance is 125, this makes dermal absorption unfavourable*. It is therefore considered unlikely that aluminium orthophosphate will become readily available for systemic absorption via the dermal route. In addition, as aluminium orthophosphate is ionic the phosphate and aluminium ions may be available for dermal absorption. The phosphate is, depending on the pH, highly to very highly ionised which reduces drastically the potential to penetrate the lipid rich environment of the striatum corneum. Therefore, dermal uptake of phosphate will probably be minimal. For the same reasoning, dermal uptake of aluminium ions is expected to be low. Aluminium chlorohydrate used as active ingredient of antiperspirant has been evaluated for dermal update and it is suggested that 4 μg of aluminium is absorbed from a single use on both underarms (WHO FOOD ADDITIVES SERIES: 58, Safety evaluation of certain food additives and contaminants. World Health Organization, 2007, IPCS — International Program on Chemical Safety, p. 186, ISBN 978 92 4 166058 7, ISSN 0300-0923, http://www.inchem.org/documents/jecfa/jecmono/v58je01.pdf).

- Further to this, studies conducted to assess the potential for acute oral and inhalation toxicity concluded that aluminium orthophosphate and an analogous substance (aluminium tris(dihydrogen phosphate)) are not classified in accordance with Regulation (EC) No. 1272/2008 (EU CLP). As it is considered likely that absorption via the oral or inhalation routes will be greater than total systemic absorption via the dermal route, it has been concluded that aluminium orthophosphate will also not be classified for acute dermal toxicity. As such, further in vivo testing is considered scientifically unjustified.

 

*According to the guidance on information requirements and chemical safety assessment; Chapter R.7c: Endpoint specific guidance

Justification for classification or non-classification

Acute oral toxicity: The oral LD50has been determined to be > 2000 mg/kg bw and therefore in accordance with Regulation (EC) No. 1272/2008 (EU CLP) aluminium orthophosphate is not considered to be classified as acutely toxic via the oral route.

Acute inhalation toxicity: The LC50value for the inhalation of the analogous substance aluminium tris(dihydrogen orthophosphate) was found to be > 5.1 mg/L and therefore, via the use of a read-across approach, aluminium orthophosphate is not considered to be classified in accordance with Regulation (EC) No. 1272/2008 (EU CLP) and no further testing is recommended.

 

Acute dermal toxicity: Based on considerations of the physicochemical and toxicological properties of aluminium orthophosphate, the substance is not considered to be classified as acutely toxic via the dermal route. Further in vivo testing is not scientifically justified.