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Administrative data

Description of key information

Oral: LD50(rat, m/f) > 2000 mg/kg bw (OECD 401 and 420, GLP)
Inhalation: LC50(rat, m/f) > 3.46 mg/L (max. achievable concentration, OECD 436, GLP)
Dermal: no study available

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:
01 - 24 May 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-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)
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, Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 147-170g
- 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: 2014C Teklad Global Rodent diet (Harlan Teklad, Oxon, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Day 0 to Day 14
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:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
2000 mg/kg bw
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 h 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
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
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

147

165

179

18

14

2-0

Female

161

187

201

26

14

2-1

Female

163

190

211

27

21

2-2

Female

166

186

202

20

16

2-3

Female

170

197

213

27

16

 

 

 

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:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
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. No mortality occurred and no signs of systemic toxicity, effects on body weigh (change) or abnormalities at necropsy were noted.

CLP: not classified
GHS: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The available data comprise studies conducted following OECD Guidelines and under GLP conditions, with no or no relevant deviations or deficiencies which may affect the validity and reliability of the study results. Therefore, the available data are sufficient to fulfil the endpoint specific standard information requirements of Regulation (EC) No 1907/2006 (REACH), and are likewise sufficient for the purpose of classification and labelling in accordance with Regulation (EC) 1272/2008 (CLP).

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:
13 Apr - 02 Jul 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
yes
Remarks:
It was noted that one atmosphere concentration sample is greater than 20% of the mean achieved atmosphere concentration. A full justification for including this sample in the test is given in the section 'any other information on the results'.
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Further details on strain: RccHanTM : WIST strain rats
- Source: Harlan Laboratories UK Ltd, Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 200-350 g
- Fasting period before study: none
- Housing: The animals were housed in groups of up to three by sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd., Cheshire, UK) and provided with environmental enrichment items: wooden chew blocks and cardboard “fun tunnels” (Datesand Ltd., Cheshire, UK).
- Diet: with the exception of the exposure period diet (Harlan 2014C Rodent Diet, Harlan Laboratories UK Ltd, Oxon, UK) was available ad libitum
- Water: with the exception of the exposure period water was available ad libitum.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: A dust atmosphere was produced from the test item using a SAG 410 Solid Aerosol Generator (TOPAS GmbH, Dresden, Germany) located adjacent to the exposure chamber. The SAG 410 was connected to a metered compressed air supply.
Compressed air was supplied by means of an oil free compressor and passed through a water trap and respiratory quality filters before it was introduced to the SAG 410.
- Exposure chamber volume: 30 litres (dimensions: 28 cm diameter x 50 cm high)
-Chamber flow rate: The chamber flow rate was maintained at 40 L/min providing 80 air changes per hour.
- Method of holding animals in test chamber: each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring. Only the nose of each animal was exposed to the test atmosphere.
- Method of conditioning air: The concentration within the chamber was controlled by adjusting the test item feed rate from the SAG 410. The extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system. The chamber was maintained under negative pressure.
- System of generating particulates/aerosols: In order to facilitate aerosolisation and reduce particle size, the test item was ground using a small amount of diethyl ether in a Retsch Planetary Ball Mill (Retsch (UK) Ltd, Leeds, UK) all of the solvent was removed via evaporation prior to use. The absorption of the test item was not determined. See 'exposure apparatus' for further details.
- Method of particle size determination: The particle size of the generated atmosphere inside the exposure chamber was determined three times during the exposure period using a Marple Personal Cascade Impactor (Westech IS Ltd, Beds., UK). This device consisted of six impactor stages (9.7, 6.7, 3.8, 1.8, 0.94 and 0.46 μm cut points) with stainless steel collection substrates and a back up glass fibre filter, housed in an aluminium sampler. The sampler was temporarily sealed in a sampling port in the animals’ breathing zone and a suitable, known volume of exposure chamber air was drawn through it using a vacuum pump.
The collection substrates and backup filter were weighed before and after sampling and the weight of test item, collected at each stage, calculated by difference.
The mean amount for each stage was used to determine the cumulative amount below each cut-off point size. In this way, the proportion (%) of aerosol less than 9.7, 6.7, 3.8, 1.8, 0.94 and 0.46 μm was calculated.
The resulting values were converted to probits and plotted against Log10 cut-point size. From this plot, the Mass Median Aerodynamic Diameter (MMAD) was determined (as the 50% point) and the geometric standard deviation was calculated. In addition the proportion (%) of aerosol less than 4 μm (considered to be the inhalable fraction) was determined.
- Temperature, humidity, pressure in air chamber: The temperature and relative humidity inside the exposure chamber were measured by an electronic thermometer/humidity meter (Hanna Instruments Ltd, Beds., UK) located in a vacant port in the animals’ breathing zone of the chamber and recorded every thirty minutes throughout the four-hour exposure period. Individual values are given in Appendix 9.
-Exposure chamber oxygen concentration: Oxygen levels within the exposure chamber were measured by an electronic oxygen analyser (Servomex (UK) Ltd, Crowborough, East Sussex) located in a port in the animals breathing zone during the four-hour exposure period. The test atmosphere was generated to contain at least 19% oxygen. Individual values are given in Appendix 10.

TEST ATMOSPHERE
- Brief description of analytical method used: Homogeneity of the test atmosphere within the chamber was not specifically determined during this study. Chambers of the same design (ADG Developments Ltd, Hitchin, Herts, UK) have been fully validated and shown to produce evenly distributed atmospheres in the animals’ breathing zone with a wide variety of test items (Green J D et al, 1984).
Prior to the start of the study, test item atmospheres were generated within the exposure chamber. During this characterisation period test item input rates, grinding techniques and generation systems were varied in order to achieve the required atmospheric conditions.
- Samples taken from breathing zone: yes
The actual chamber concentration was measured at regular intervals during the exposure period. The gravimetric method used glass fibre filters placed in a filter holder. The holder was temporarily sealed in a vacant port in the exposure chamber in the animals’ breathing zone and a suitable, known volume of exposure chamber air was drawn through the filter using a vacuum pump.
Each filter was weighed before and after sampling in order to calculate the weight of collected test item. The difference in the two weights, divided by the volume of atmosphere sampled, gave the actual chamber concentration.
The nominal chamber concentration was calculated by dividing the mass of test item used by the total volume of air passed through the chamber.
The nominal concentration is 6186% of the actual mean achieved atmosphere concentration and shows that keeping the aerosol airborne was moderately difficult.



Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
3.46 mg/L (mean maximum attainable 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: 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 up to fourteen days. Any evidence of overt toxicity was recorded at each observation.
- Bodyweight: Individual bodyweights were recorded on arrival, prior to treatment on the day of exposure and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: yes
At the end of the fourteen day observation period the animals were killed by intravenous overdose of sodium pentobarbitone. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded. The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy or local toxicity.
Statistics:
Evaluation of Data
Data evaluations included the relationship, if any, between the animals’ exposure to the test item and the incidence and severity of all abnormalities including behavioural and clinical observations, necropsy findings, bodyweight changes, mortality and any other toxicological effects.
Using the mortality data obtained, an estimate of the acute inhalation median lethal concentration (LC50) of the test item was made.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.46 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
There was no mortality.
Clinical signs:
other: Individual clinical observations are given in Appendices 4 and 5. Signs of hunched posture, pilo-erection and red/brown staining around the eyes and/or snout are commonly seen in animals for short periods on removal from the chamber following 4-Hour inhal
Body weight:
Individual bodyweights, together with bodyweight changes, are given in Appendix 6.
All males and one female animal exhibited bodyweight losses on the first day postexposure. All animals exhibited bodyweight gains during the remainder of the recovery period, with the exception of one male and one female animal which exhibited slight bodyweight losses or showed no bodyweight gain from Days 1 to 3 post-exposure. One male and one female animal also exhibited slight bodyweight losses or showed no bodyweight gain from Days 3 to 7 post-exposure.
Gross pathology:
Individual necropsy findings are given in Appendix 7.
No macroscopic abnormalities were detected amongst animals at necropsy.

It is noted that one atmosphere concentration sample is greater than 20% of the mean achieved atmosphere concentration, as this deviation to the test guideline is slight (0.04mg/L) and the fact that the generation was running at the maximum rate it is considered that this deviation was unavoidable. It is considered that re-running this group because of this deviation is inappropriate and unethical. The results obtained (in terms of animal observations) would be considered to be similar if another group was to be exposed at the same input rates, it must also be noted that the consistency of achieved atmospheres if another group was to be exposed may be even worse.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No deaths occurred in a group of six rats exposed to a mean maximum attainable atmosphere concentration of 3.46 mg/L for four hours. It was therefore considered that the acute inhalation median lethal concentration (4 hr LC50) of Aluminium dihydrogen triphosphate, in the RccHanTM: WIST strain rat, was greater than 3.46 mg/L (mean maximum attainable analytical concentration). No toxicologically relevant effects were observed for clinical signs, body weight (gain) and at gross necropsy.

CLP: not classified
GHS: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
3 460 mg/m³
Quality of whole database:
The available data comprise one study conducted following an OECD Guideline and under GLP conditions, with no or no relevant deviations or deficiencies which may affect the validity and reliability of the study results. Therefore, the available data are sufficient to fulfil the endpoint specific standard information requirements of Regulation (EC) No 1907/2006 (REACH), and are likewise sufficient for the purpose of classification and labelling in accordance with Regulation (EC) 1272/2008 (CLP).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

The acute oral toxicity of aluminium dihydrogen triphosphate was tested in rats in a study following OECD Guideline 420 and under GLP conditions (Bradshaw, 2012). A groups of 5 female Wistar rats was given the test substance (in arachis oil BP) at a single dose of 2000 mg/kg bw by oral gavage.

There were no deaths or signs of systemic toxicity up to the end of the 14-day observation period. All animals showed expected gains in bodyweight. No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was thus estimated to be greater than 2000 mg/kg bw.

In an earlier GLP-study, conducted in accordance with OECD Guideline 401, the oral LD50 in male and female rats was determined to be greater than 2000 mg/kg bw (Sunaga, 2012).

Based on the available data, the test 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 acutely toxic by the oral route.

Acute inhalation toxicity

The acute inhalation toxicity of aluminium dihydrogen triphosphate was evaluated in male and female Wistar rats by the acute toxic class (ATC) method according to OECD Guideline 436 and under GLP conditions (Griffiths, 2012). A group of three male and three female rats was exposed to a dust atmosphere. The animals were exposed for 4 h using a nose only exposure system, followed by a fourteen day observation period. The mean maximum attainable atmosphere concentration was 3.46 mg/L. The mean Mass Median Aerodynamic Diameter (MMAD) during exposure was 3.31 µm. More than 60% of the particles were <4 µm, and nearly all particles were <10 µm. The test material was therefore considered to be respirable to rats.

There were no deaths during the study. Common abnormalities noted during the study included increased respiratory rate, hunched posture, pilo-erection and wet fur. Animals recovered to appear normal from Days 6 to 7 post-exposure. All males and one female animal exhibited bodyweight losses on the first day post-exposure. All animals exhibited bodyweight gains during the remainder of the recovery period, with the exception of one male and one female animal which exhibited slight bodyweight losses or showed no bodyweight gain from Days 1 to 3 post-exposure. One male and one female animal also exhibited slight bodyweight losses or showed no bodyweight gain from Days 3 to 7 post-exposure. No macroscopic abnormalities were detected amongst animals at necropsy.

The 4-hour LC50 of the test material in male and female Wistar rats was considered to be greater than 3.46 mg/L, which was the mean maximum attainable analytical concentration under the conditions of this study.

Therefore, the test 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 acutely toxic by the inhalation route.

Acute dermal toxicity

This information is not available.

Justification for selection of acute toxicity – oral endpoint
The selected study is more reliable, as it could be assessed in its entirety and it was conducted according to a more recent test method. The results of the two available studies do not contradict each other.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available

Justification for classification or non-classification

The available data indicate that the substance does not meet the classification criteria in accordance with Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

CLP

Acute oral toxicity: not classified

Acute inhalation toxicity: not classified

Acute dermal toxicity: data lacking

GHS

Acute oral toxicity: not classified

Acute inhalation toxicity: not classified

Acute dermal toxicity: data lacking