Potassium dihydrogenorthophosphate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005-09-27 to 2006-07-07

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 salts are monovalent inorganic phosphates, composed of a phosphate anion and a K+ cation.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 dermal endpoint.
Regarding the nature of the substances in question (inorganic, Molecular weight >100) the absorption through the dermal layer will be considerably less than via the gastro-intestinal tract (a route which has shown low systemic toxicity).

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

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

Study on analogous substance submitted as supporting data only.

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

up-and-down procedure

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA.
- Age at study initiation: young adults 9 - 10 weeks
- Weight at study initiation: 165 - 220 g
- Fasting period before study: overnight by removing the feed from their cages. Feed was replaced approximately 3 - 4 h after dosing.
- Housing: singly in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least 3 times per week.
- Water: ad libitum
- Acclimation period: 6 - 17 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23 ºC
- Photoperiod: 12 h light/dark cycle.


IN-LIFE DATES: From: 2005-09-27 To:2006-05-24

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2000 mg/kg administered as a 50 % w/w mixture.

DOSAGE PREPARATION: a tissue homogeniser was used ot facilitate the preparation of a homogenous mixture. Preliminary solubility tests indicated that mixtures in excess of 50 % were too viscous to be administered properly.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 females only

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: individual body weights were recorded prior to test substance administration and again on Days 7 and 14 (termination) following dosing. Animals were observed for mortality, signs of gorss toxicity and behavioural changes during the first several hours post-dosing and at least once daily thereafter for 14 days after dosing. Observations included gross evaluation of skin an fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systmes, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea and coma.
- Necropsy of survivors performed: necropsies were performed on all animals. Tissues and organs of hte thoracic and abdominal cavities were examined.

Statistics:

No data

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no mortalities

Clinical signs:

other: All animals appeared active and healthy during the study.

Gross pathology:

No gross abnormalities were noted for any of the animals when necropsied.

Other findings:

No data

Table 2. Individual body weights and doses

Animal No.	Sex	Dose level (mg/kg)	Body weight (g)			Dose^1 (mL)
			Initial	Day 7	Day 14
9096	F	2000	192	219	250	0.55
9137	F	2000	177	201	243	0.51
9262	F	2000	165	189	240	0.47
9289	F	2000	173	192	240	0.50
9335	F	2000	220	233	256	0.63

¹: the test substance was administered as a 50 % w/w mixture in distilled waster. Specific gravity - 1.393 g/mL.

Table 3. Individual cage-side observations

Animal No.	Findings	Day of occurrence
All animals	Active and healthy	0 - 14

Table 4. Individual necropsy observations

Animal No.	Tissues	Findings
All animals	All tissues and organs	No gross abnormalities

Interpretation of results:

GHS criteria not met

Conclusions:

Under the condiitons of the study, the acute oral LD50 pf PeKacid was greater than 2000 mg/kg of body weight in female rats. According to Regulation (EC) No 1272/2008 (EU CLP) potassium pentahydrogen bis(phosphate) (also known as PeKacid) is not considered to be classified.

This study supports the conclusion that sodium and potassium orthophosphates exhibit low systemic toxicity and therefore the study is included to support the read-across argumentation for acute systemic toxicity for the endpoint; 8.5.2 Acute Dermal Toxicity and 8.5.3 Acute Inhalation Toxicity.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

not specified

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

not specified

GLP compliance:

yes

Test type:

fixed dose procedure

Test material

Test material information

Constituent 1

Reference substance name:

Potassium pentahydrogen bis(phosphate)

EC Number:

238-961-5

EC Name:

Potassium pentahydrogen bis(phosphate)

Cas Number:

14887-42-4

Molecular formula:

H5KO8P2

IUPAC Name:

potassium pentahydrogen bis(phosphate)

Details on test material:

- Name of test material: PeKacid
- Lot No.: 0001
- Description: White crystalline powder
- Laboratory reference no.: 060214-3H
- Storeage: At room temperature
- Composition: The product is an inorganic phosphate salt. See methods table.
- pH 1 % water 2.2
- Solubility: Soluble in water (fully soluble)
- Stability: Test substance was expected to be stable for the duration of testing
- Expiration date: 2007-12-31

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA.
- Age at study initiation: 9 - 10 weeks (young adult)
- Weight at study initiation: Males 298 - 320 g; females 206 - 220 g.
- Housing: Singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent guide for the care and use of laboratory animals DHEW (NIH). Litter paper was placed beneath the case and was changed at least three times per week.
- Diet: Purina rodent chow #5012
- Water: Filtered tap water supplied ad libitum by automatic water dispenser.
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23 ºC
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal area and trunk.
- % coverage: Approximately 10 % (2 inches by 3 inches)
- Type of wrap if used: A gauze pad and 3 inch Durapore tape.

REMOVAL OF TEST SUBSTANCE
- Washing: Test site was gently cleansed of any residual test substance.
- Time after start of exposure: After 24 h.

TEST MATERIAL
- Amount applied: 2000 mg/kg bw. Individual doese were calculated based on the initial body weights and concentration of the test mixture.
- Concentration: 90 % w/w
- For solids, paste formed: Yes the test substance was moistened with distiled water to acheive a dry paste.

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

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: body weights of the animals were recorded prior to test substance application (initial) and again on Days 7 and 14 (termination). Cage side observations for mortality, signs of gross toxicity and behavioural changes during the first several hours after application and at least once daily thereafter for 14 days. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea and coma.
- Necropsy of survivors performed: Yes gross necropsies were performed on all animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Statistics:

No data

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: The test substance was applied as a 90 % w/w mixture in distilled water.

Mortality:

All animals survived.

Clinical signs:

other: All animals appeared healthy and active during the study. There were no signs of gross toxicity, dermal irritation, adverse pharmacologic effects or abnormal behaviour.

Gross pathology:

No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Other findings:

No data

Any other information on results incl. tables

Table 2. Individual body weights and doses:

Animal No.	Sex	Body weight			Dose*
		Initial	Day 7	Day 14
9342	M	307	363	400	0.68
9343	M	320	348	388	0.71
9344	M	312	338	376	0.69
9345	M	298	345	390	0.66
9346	M	307	369	416	0.68
9347	F	212	227	239	0.47
9348	F	215	239	248	0.48
9349	F	214	243	253	0.48
9350	F	220	236	254	0.49
9351	F	206	242	261	0.46

* The test substance was applied as a 90 % w/w mixture in distilled water.

Table 3. Individual cage-side observations:

Animal No.	Findings	Day of occurrence
Males
9342 – 9346	Active and healthy	0 - 14
Females
9347 - 9351	Active and healthy	0 - 14

Table 4. Individual necroscopy observations:

Animal No.	Tissue	Findings
Males
9342 – 9346	All tissues and organs	No gross abnormalities
Females
9347 - 9351	All tissues and organs	No gross abnormalities

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study, the single dose acute dermal LD50 of PeKacid is greater than 2000 mg/kg bw in male and female rats.
This study is conducted according to the appropriate guidelines (EU AND US) and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint.
In addition, this study is suitable to fulfill the requirements for classification and labelling according to Regulation (EC) No 1272/2008 (EU CLP).