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Toxicological information

Acute Toxicity: inhalation

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Administrative data

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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is conducted according to the appropriate guidelines (EU AND US) and under the conditions of GLP. This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint. As this study is being used for read-across the relaibiltiy has been ammended to reflect this. Read-across from sodium dihydrogenorthophosphate to trisodium orthophosphate is justified on the following basis. Both salts are monovalent inorganic phosphates, composed of a phosphate anion and an Na+ alkali metal cation. 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. This study is therefore deemed reliable for classification and labeling according to Regulation (EC) No 1272/2008 (EU CLP).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: U.S. Environmental Protection Agency Toxic Substances Health Effects Test Guidelines, October 1984 (PB82-232984) Acute Inhalation Toxicity Study
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to
Guideline:
other: FMC Acute Inhalation Toxicity Protocol Number 27
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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:
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, nasal discharge and squinting eyes. Most animals had test material present on the fur during exposure and through day 2 post-exposure. All animals were normal from day 3 observation through study termination.
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:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
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.

Read-across from sodium dihydrogenorthophosphate to trisodium orthophosphate is justified on the following basis.

Both salts are monovalent inorganic phosphates, composed of a phosphate anion and an Na+ alkali metal cation. 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.

This study is therefore deemed reliable for classification and labeling according to Regulation (EC) No 1272/2008 (EU CLP).