Potassium dihydrogenorthophosphate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

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

Both the Na+ and the K+ cation have a similar biological function and therefore orthophosphate salts of these types are not considered to differ in their systemic toxicity profile; differences arise in their local effects profile due to the increasing or decreasing acidity/alkalinity and buffering capacities of the substances. This has been shown not to have an effect on systemic toxicity. In addition, both salts have been shown to be of similar low toxicity in acute oral studies. These studies are supported by a number of acute oral studies on similar compounds which all show potassium and sodium orthophosphates to possess low systemic toxicity via the oral route (See section 7.2.1.) and therefore comparisons can be drawn to allow read-across for the acute inhalation endpoint.

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’.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: U.S. Environmental Protection Agency Toxic Substances Health Effects Test Guidelines, October 1984 (PB82-232984) Acute Inhalation Toxicity Study

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Test guideline 5

Qualifier:

according to guideline

Guideline:

other: FMC Acute Inhalation Toxicity Protocol Number 27

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Sodium dihydrogenorthophosphate

EC Number:

231-449-2

EC Name:

Sodium dihydrogenorthophosphate

Cas Number:

7558-80-7

Molecular formula:

H3O4P.Na

Details on test material:

- Name of test material: Monosodium phosphate
- Molecular formula: NaH2PO4
- Physical state: White powder
- Storage condition of test material: Room temperature
- Reference No.: B485AR001
- FMC-T#: 1039
- Date received: 1993-05-03

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY.
- Age at study initiation: young adult
- Weight at study initiation: males: 274 ± 9.1; females 217 ± 7.3
- Fasting period before study: not reported
- Housing: Individually housed in stainless steel suspended rat cages. Desorb bedding was used in the litter pans.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: a minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 69 - 73ºF
- Humidity (%): 41 - 70 %
- Photoperiod (hrs dark / hrs light): 12 h dark/ 12 h light

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rochester type exposure chamber
- Exposure chamber volume: 150 L
- Method of holding animals in test chamber: test animals were assigned to and housed in individual compartments of a wire mesh cage bank (all on the same horizontal level) during the exposure. The cage position assignment ensured equal distribution of both sexes throughout the cage bank.
- Source and rate of air: breathing grade compressed air
- System of generating particulates/aerosols: a BGI Wright dust feeder II was used to generate the test atmosphere. The test material was desiccated and packed into large dust cups. Breathing grade compressed air was metered to the Wright dust feeder through 1/4 inch teflon tubing by a Matheson® 605 rotameter with metal float. Rotameter back pressure was controlled using a Matheson®3104-C regulator. The dust feeder back pressure was controlled using a Marshalltown® back pressure gauge. The test material was made airborne by compressed air dispersing the material into the exposure chamber. The concentration of the test atmostphere was controlled by the delivery rate setting of the wright dust feeder.
- Method of particle size determination: the aerodynamic particle size distribution was determined by gravimetric analysis of the test material collected on the impactor stages and subsequent determination of the MMAD, geometric SD and other particule size parameters by logarithmic-probability plotting.
- Temperature, humidity, pressure in air chamber: Chamber and room air temperature and relative humidity were monitored continuously during the exposure with FMC wet/dry bulb hygrometers. Measurements were recorded at 30 min intervals.
At the end of the exposure, the chamber was cleared for 30 min by drawing room air through it at the same flow rate (31.9 L/min) prior to removing the animals.

TEST ATMOSPHERE
- Brief description of analytical method used: chamber air samples were taken on Gelman® Type A/E 47 mm glass fibre filters held in cassettes at approximately 1 h intervals during exposure to determine the airborne concentration of test material. The airborne concentration of the test material was determined gravimetrically by drawing a known amount of chamber air through the filter. The concentration was calculated by dividing filter weight gain by the sample volume. The samples were taken from the centre of the chamber directly over the animal exposure caging.
Atmospheric monitoring:
The chamber homogeneity determination showed that the test atmosphere was homogeneously distributed throughout the test chamber (cv = 7.10 %).
The dust feeder was operated at what was considered a maximum setting which would allow reliable operation. At this setting the delivery rate required the dust feeder to be manually assisted during the exposure. The chamber airflow was operated at as low flow rate which would allow timely chamber equilibrium and maintain a slight negative pressure in the chamber. The difference between gravimetric and nominal concentration was attributed to sedimentation of larger particles and / or adhesion of the test material to surfaces in the exposure chamber.


- Samples taken from breathing zone: yes
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMADs ranged from 5.87 to 6.82 μm with geometric standard deviations ranging from 2.55 to 2.92. The fraction of particles less than or equal to 1 μm in mass aerodynamic diameter, based on the log probability graphs, ranged from 0 to 3.6 %. The fraction of particles less than or equal to 10 μm in mass aerodynamic diameter, based on the log probability graphs, ranged from 65.9 to 69.1 %. These results indicated the test material was respirable in size to the rat. The MMAD represents the smallest size that could be acheived in this study. The material had a static electric charge when generated causing the particles to agglomerate and / or adhere to surfaces inside the chamber.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

chamber air samples were taken on Gelman® Type A/E 47 mm glass fibre filters held in cassettes at approximately 1 h intervals during exposure to determine the airborne concentration of test material

Duration of exposure:

4 h

Concentrations:

Nominal concentration: 37.35 mg/L
Mean analytical data ±SD (Gravimetric concentration): 0.83 ± 0.065 mg/L

No. of animals per sex per dose:

5/sex/dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed for signs of toxicity and mortality at 15 min intervals during the first h of exposure , hourly for the remainder of the exposure, upon removal from the chamber, at 1 h post-exposure, twice daily thereafter for 13 days and once on day 14.
- Necropsy of survivors performed: yes, all animals were sacrificed and submitetd to gross necroscopy.
- Other examinations performed: body weights were recorded on days 0, 1, 2, 4, 7 and 14.

Statistics:

None reported

Results and discussion

Preliminary study:

No data

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.83 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

There were no deaths during the study.

Clinical signs:

other: The incidence of clinical signs were highest at the removal from chamber observations. Clinical signs noted during the exposure included lacrimation and squinting eyes. Clinical signs noted following the exposure incuded chromodacryorrhea, lacrimation, n

Body weight:

Most animals lost weight through day 1 of the study and then began to gain weight in a normal pattern. At termination all animals had exhibited increases in body weight over their day 0 values.

Gross pathology:

There were no gross internal lesions observed in any animal necropsy.

Other findings:

no data

Any other information on results incl. tables

Table 4. The concentration presented should be considered the maximum available:

Exposure Date	Mean Analytical Data ± SD (mg/L)	Nominal Concentration (mg/L)	Mortality
	Gravimetric Concentration		# Dead / # Exposed
			Male	Female
1993-08-06	0.83 ± 0.065	37.35	0 / 5	0 / 5

Table 5. Mean body weights (g) ± SD:

	Study day
	0	1	2	4	7	14
Males	274 ± 9.1	270 ± 10.4	277 ± 11.1	293 ± 10.3	313 ± 10.6	348 ± 13.4
Females	217 ±7.3	218 ± 5.9	215 ± 6.1	222 ± 6.8	228 ± 9.9	238 ± 10.2

Table 6. Incidence of clinical signs: Male

Observation	Time after treatment
	Day 0										Day 1		Day 2		Day 3
	Hour
	PT	0.25	0.50	0.75	1	2	3	4	R	1PE	AM	PM	AM	PM	AM	PM
Chromodacryorrhea	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Lacrimation	0	3	3	3	3	3	3	3	5	2	0	0	0	0	0	0
Material on fur	0	0	0	5	5	5	5	5	5	5	5	5	5	5	0	0
Nasal discharge	0	0	0	0	0	0	0	0	2	1	0	0	0	0	0	0
Squinting eyes	0	5	5	5	5	5	5	5	1	0	0	0	0	0	0	0
Death (cumulative)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Continued:

Observation	Day
	4		5		6		7		8		9		10		11		12		13		14
	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM
Chromodacryorrhea	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Lacrimation	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Material on fur	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nasal discharge	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Squinting eyes	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Death (cumulative)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

PE - Post exposure

PT - Prior to exposure

R - Removal from chamber

Incidence of clinical signs: Female

Observation	Day 0										Day 1		Day 2		Day 3
	Hour
	PT	0.25	0.50	0.75	1	2	3	4	R	1PE	AM	PM	AM	PM	AM	PM
Lacrimation	0	2	3	3	3	3	2	0	5	3	0	0	0	0	0	0
Material on fur	0	0	0	5	5	5	5	5	5	5	5	5	3	3	0	0
Nasal discharge	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Squinting eyes	0	5	5	5	5	5	5	2	1	0	0	0	0	0	0	0
Death (cumulative)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Continued:

Observation	Day
	4		5		6		7		8		9		10		11		12		13		14
	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM
Lacrimation	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Material on fur	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nasal discharge	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Squinting eyes	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Death (cumulative)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

PE - Post exposure

PT - Prior to exposure

R - Removal from chamber

Table 7. Individual body weights:

Animal #	Day 0 (g)	Day 1 (g)	Day 2 (g)	Day 4 (g)	Day 7 (g)	Day 14 (g)
Male
AC8941M	262	260	266	280	299	330
AC8942M	277	268	277	292	311	351
AC8943M	281	683	293	307	327	365
AC8944M	282	279	283	298	319	354
AC8945M	266	261	268	287	309	340
Mean	274	270	277	293	313	348
SD	± 9.1	± 10.4	± 11.1	± 10.3	± 10.6	± 13.4
Female
AC8951F	209	212	212	216	223	228
AC8952F	227	223	222	231	242	251
AC8953F	221	223	216	223	225	238
AC8954F	217	220	220	224	232	245
AC8955F	211	211	207	214	216	228
Mean	217	218	215	222	228	238
SD	± 7.3	± 5.9	± 6.1	± 6.8	± 9.9	± 10.2

AC - rat

M - Male

F - Female

Table 8. Individual necropsy findings:

Animal	Type, Time of Death	Term Body Weight (g)	Body Weight Change (g)	Internal Findings
Male
AC8941M	S (14)	330	+ 68	No gross lesions
AC8942M	S (14)	351	+ 74	No gross lesions
AC8943M	S (14)	365	+ 84	No gross lesions
AC8944M	S (14)	354	+ 72	No gross lesions
AC8945M	S (14)	340	+ 74	No gross lesions
Female
AC8951F	S (14)	228	+ 19	No gross lesions
AC8952F	S (14)	251	+ 24	No gross lesions
AC8953F	S (14)	238	+ 17	No gross lesions
AC8954F	S (14)	245	+ 28	No gross lesions
AC8955F	S (14)	228	+ 17	No gross lesions

AC - Rat

M - Male

F - Female

S ( ) - Sacrificed (study day)

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the test material caused no mortality when administered for 4 h to Sprague Dawley rats at a mean, maximum attainable concentration of 0.83 mg/L. Based on this, the LC50 for monosodium phosphate is considered to be greater than 0.83 mg/L. This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint.

As the study was conducted up to the maximum attainable concentration and in accordance with Regulation (EC) No. 1272/2008 (EU CLP) sodium dihydrogenorthophosphate is not considered to be classified.