Diammonium dihydrogenpyrophosphate

Endpoint summary

Description of key information

The data available is performed on analogous substances. This data is considered adequate and reliable to fulfil the information requirements as part of a weight of evidence. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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 proposed source chemical (is a mixture of ammonium orthophosphates and ammonium pyrophosphates and is highly soluble in water (> 10000 mg/L). In aqueous media soluble inorganic orthophosphates and pyrophosphates will dissociate to their ionic constituents; in this case ammonium and orthophosphate or pyrophosphate ions. Diammonium dihydrogenpyrophosphate will dissociate to ammonium cations and pyrophosphate anions. The pyrophosphate anions are unstable in aqueous solutions with the degree of instability varying according to pH. In distilled water they will hydrolyse slowly via abiotic mechanisms to orthophosphate. In natural waters a number of different processes can occur; abiotic hydrolysis, biotic degradation (as a result of the action of phosphatases which cleave pyrophosphates into orthophosphate subunits) and assimilation by organisms in the water. Thus, the target substance (diammonium dihydrogenpyrophosphate) and the source substance (mixture of ammonium orthophosphates and pyrophosphates) will be primarily absorbed as the same inorganic ions: ammonium and orthophosphate and are expected to behave in a similar manner under test conditions.
All (bio) transformation products of the source chemical are common to the target chemical and as such the data is considered to be adequate and reliable for use in the assessment of diammonium dihydrogenpyrophosphate for the toxicity hazard assessment.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.

4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Specific details on test material used for the study:

The identity of the test material is not reported within the study report itself, however the data is referred to in the Toxicological Risks of Selected Flame Retardant Chemicals (2000), Subcommittee on Flame-Retardant Chemicals, Committee on Toxicology, Board on Environmental Studies and Toxicology, National Research Council. ISBN: 0-309-59232-1. The substance LR-2 is an ‘ammonium polyphosphate’ and the author provides the following additional information with regards to the chemical identity of LR2: ‘Based on information provided by the manufacturer (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999), a typical species distribution of polyphosphates in LR2 is 20% orthophosphate, 40% pyrophosphate,

Preliminary study:

In the dose ranging study there were no deaths and no clinical signs or gross post mortem observations were noted.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths. Details of test results are given in Table 1.

Clinical signs:

other: No clinical signs were noted in any of the animals.

Gross pathology:

No abnormalties were detected in the post mortem observations.

Table 1: Test Results, 5000 mg/kg

Animal/sex	Mortality	Clinical signs	Post Mortem Observations
51-Male	0/5	NAD	NAD
52-Male		NAD	NAD
53-Male		NAD	NAD
54-Male		NAD	NAD
55-Male		NAD	NAD
56-Female	0/5	NAD	NAD
57-Female		NAD	NAD
58-Female		NAD	NAD
59-Female		NAD	NAD
60-Female		NAD	NAD

 

NAD = No abnormalities detected

Table 2 – Main study: Body weights, 5000mg/kg

Animal number and sex	Bodyweight (g)			Weight gain (g)
	At Dosing	After 7 days	After 14 days
51-Male	215	290	290	75
52-Male	164	229	228	64
53-Male	183	225	230	47
54-Male	190	255	265	75
55-Male	222	295	296	74
Mean	195	259	262	67
± S.D.	24	33	32	12
56-Female	148	180	200	52
57-Female	136	170	183	47
58-Female	140	176	190	50
59-Female	169	210	226	57
60-Female	147	187	193	46
Mean	148	185	198	50
± S.D.	13	15	17	4

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Executive summary:

The acute oral toxicity potential of a test material, Amgard LR2, was investigated in rats. The vehicle used for the dosing solutions was distilled water. A dose ranging study in pairs of rats indicated that the oral LD50 value is greater than 5000 mg/kg. A main study dose 1eve1 of 5000 mg/kg was selected accordingly. In the main study, no deaths occurred and no clinical signs were noted after oral administration of Amgard LR2 at a dose level of 5000 mg/kg No abnormalities were detected at post mortem. The Median Oral Lethal Dose (LD50) of Amgard LR2 is greater than 5000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The source data, performed on an analogous substance, is GLP compliant and has a Klimisch reliability of 1.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (sodium acid pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (sodium acid pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or sodium. Exposure to the non-common compound, the sodium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (sodium acid pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.

4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Duration of exposure:

h

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.58 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

See Table 1.
One female died on day 1 and one male died on day 14 post-exposure.

Clinical signs:

other: See Table 1. Clinical signs noted during the exposure included lacrimation, material on fur, oral discharge and squinting eyes. Incidence of clinical signs was highest at the removal from chamber observation. Signs gradually resolved during the study, how

Body weight:

See Table 2.
Most animals lost weight through day 4 of the study, then began to gain weight in a normal pattern. At termination all surviving animals exhibited increases in body weight over their day 0 values.

Gross pathology:

See table 3.
There were no gross internal lesions observed in any animal which survived to study termination. One male which died on day 14 had discoloured lungs with many light red nodules. This animal was also observed to have a corneal opacity in one eye.

Other findings:

No data

See attached file for Tables 1, 2 and 3.

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated not to be classifed for acute toxicity via the inhalation route.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (tetrapotassium pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (tetrapotassium pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or potassium. Exposure to the non-common compound, the potassium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (tetrapotassium pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.
4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.1 mg/L air

Exp. duration:

4 h

Mortality:

One female died on day 6 post-exposure

Clinical signs:

other: See Table 1. Incidence of clinical signs was highest at the removal from chamber observation. Clinical signs generally persisted up to day 13 post-exposure and then gradually subsided. The observation period was extended to allow for abatement of clinica

Body weight:

See Table 2 and 3.
Most animals lost weight through day 4 of the study then began to gain weight in a normal pattern. At termination all surviving animals exhibited increases in body weight over their day 0 values.

Gross pathology:

See Table 4.
There was no gross internal lesions noted in any animal which survived to study termination. The animal that died on day 6 post-exposure had all lobes and surfaces of the lungs mottled dark red and red.

Table 1 - Incidence of clinical signs – male

 

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
Abdominogenital staining	0	0	0	0	0	0	0	0	0	0	5	5	5	5	5	5
Chromodacryorrhea	0	0	0	0	0	0	0	0	5	2	2	2	2	2	2	2
Decreased feces	0	0	0	0	0	0	0	0	0	0	0	0	1	1	1	1
Dehydration	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Decreased locomotion	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Emaciated	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Lacrimation	0	5	5	5	5	5	5	5	3	2	1	1	0	0	0	0
Material on Fur	0	0	5	5	5	5	5	5	5	5	5	5	5	5	5	5
Opacity	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Oral discharge	0	0	0	3	3	3	3	3	5	1	0	0	0	0	0	0
Rales	0	0	0	0	0	0	0	0	1	1	0	0	0	0	0	0
Scab on Snout	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Squinting Eyes	0	5	5	5	5	5	5	5	3	3	2	2	2	2	2	2
Unthriftiness	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

Table 1 continued - Incidence of clinical signs - male

Observation	Day
	4		5		6		7		8		9		10		11
	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM	AM	PM
Abdominogenital staining	3	3	3	2	1	1	0	0	0	0	0	0	0	0	0	0
Chromodacryorrhea	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decreased feces	3	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dehydration	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decreased locomotion	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Emaciated	0	3	3	3	0	0	0	0	0	0	0	0	0	0	0	0
Lacrimation	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Material on Fur	5	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Opacity	0	1	1	1	1	1	2	2	2	2	2	2	2	2	2	2
Oral discharge	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rales	0	1	1	1	0	0	0	0	3	3	3	3	2	1	0	0
Scab on Snout	1	1	1	1	1	1	1	1	1	1	1	1	0	0	0	0
Squinting Eyes	2	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Unthriftiness	0	5	4	4	3	1	1	1	1	1	1	1	0	0	0	0
Death (cumulative)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated not to be classifed for acute toxicity via the inhalation route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The source data, performed on analogous substances, is GLP compliant and has a Klimisch reliability of 1.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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 proposed source chemical (is a mixture of ammonium orthophosphates and ammonium pyrophosphates and is highly soluble in water (> 10000 mg/L). In aqueous media soluble inorganic orthophosphates and pyrophosphates will dissociate to their ionic constituents; in this case ammonium and orthophosphate or pyrophosphate ions. Diammonium dihydrogenpyrophosphate will dissociate to ammonium cations and pyrophosphate anions. The pyrophosphate anions are unstable in aqueous solutions with the degree of instability varying according to pH. In distilled water they will hydrolyse slowly via abiotic mechanisms to orthophosphate. In natural waters a number of different processes can occur; abiotic hydrolysis, biotic degradation (as a result of the action of phosphatases which cleave pyrophosphates into orthophosphate subunits) and assimilation by organisms in the water. Thus, the target substance (diammonium dihydrogenpyrophosphate) and the source substance (mixture of ammonium orthophosphates and pyrophosphates) will be primarily absorbed as the same inorganic ions: ammonium and orthophosphate and are expected to behave in a similar manner under test conditions.
All (bio) transformation products of the source chemical are common to the target chemical and as such the data is considered to be adequate and reliable for use in the assessment of diammonium dihydrogenpyrophosphate for the toxicity hazard assessment.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.

4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Specific details on test material used for the study:

The identity of the test material is not reported within the study report itself, however the data is referred to in the Toxicological Risks of Selected Flame Retardant Chemicals (2000), Subcommittee on Flame-Retardant Chemicals, Committee on Toxicology, Board on Environmental Studies and Toxicology, National Research Council. ISBN: 0-309-59232-1. The substance LR-2 is an ‘ammonium polyphosphate’ and the author provides the following additional information with regards to the chemical identity of LR2: ‘Based on information provided by the manufacturer (Stewart Miller, Albright and Wilson, pers. commun., Nov. 1, 1999), a typical species distribution of polyphosphates in LR2 is 20% orthophosphate, 40% pyrophosphate,

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Mortality data is given in Table 1.
There were no deaths.

Clinical signs:

other: Individual clinical observations are given in Table 1. No signs of systemic toxicity were noted during the study.

Gross pathology:

Individual necropsy findings are given in Table 4.
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 period after dosing (days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-1 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-2 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-3 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-4 Male	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
	2-4 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0 = no signs of systemic toxicity

Table 2: Individual Dermal Reactions

Dose Level mg/kg	Animal number and sex	Effects noted during period after dosing (days)
		1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-1 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-2 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-3 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-4 Male	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
	2-1 Female	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
	2-3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-4 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0 = no signs of dermal irritation

Table 3: Individual bodyweights and weekly bodyweight gain

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 Male	226	276	321	50	45
	1-1 Male	242	289	354	47	65
	1-2 Male	224	255	306	36	51
	1-3 Male	225	256	298	31	42
	1-4 Male	225	256	298	31	42
	2-0 Female	227	242	269	15	27
	2-1 Female	228	243	271	15	28
	2-2 Female	219	234	253	15	19
	2-3 Female	206	220	244	14	24
	2-4 Female	229	245	278	16	33

 

Table 4: Individual Necropsy Findings

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	1-0 Male	Killed Day 14	No abnormalities detected
	1-1 Male	Killed Day 14	No abnormalities detected
	1-2 Male	Killed Day 14	No abnormalities detected
	1-3 Male	Killed Day 14	No abnormalities detected
	1-4 Male	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
	2-4 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Executive summary:

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC). The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directi ve 91/325/EEC).

A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

There were no deaths . No signs of systemic toxicity or skin irritation were noted during the study.

All animals showed expected gain in bodyweight during the study.

No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight . No symbol or risk phrase is required according to EC labelling regulations.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (tetrapotassium pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (tetrapotassium pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or potassium. Exposure to the non-common compound, the potassium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (tetrapotassium pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.
4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Preliminary study:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

None of the animals died during the study

Clinical signs:

other: All animals remained healthy durng the observation period.

Gross pathology:

No gross lesions were found.

Other findings:

Results for local irritation are reported in Table 2.

Table 1 - Individual bodyweights

Animal # / sex	Day 0 (kg)	Dose (g)	Amount applied (mg/cm^2)	Day 7 (kg)	Day 14 (kg)
1 / male	2.21	4.4	42.7	2.27	2.42
2 / male	2.66	5.3	51.5	2.65	2.78
3 / male	2.25	4.5	43.7	2.27	2.36
Mean ± SD	2.37 ± 0.249		46.0 ± 4.82	2.40 ± 0.219	2.52 ± 0.227
4 / female	2.55	5.1	49.5	2.69	2.85
5 / female	2.74	5.5	53.4	2.40	2.64
6 / female	2.54	5.1	49.5	2.56	2.60
Mean ± SD	2.61 ± 0.113		50.8 ± 2.25	2.55 ± 0.145	2.70 ± 0.134

Table 2 - Local irritation

Animal # / sex	Day 1	Day 3	Day 7	Day 14 (kg)
1 / male	N	N	De	De
2 / male	Er	Er	Es	Es, De
3 / male	Ed, Ne, Cb	Ed, Ne, Cb	Ts, Ne,Cb	Ne, Es, Ex, Tb, Ts
4 / female	Er	Er	Es, Tb	Es
5 / female	Er	N	N	N
6 / female	N	N	Es, Ts, Tb	Es, Ex

N - normal

De - desquamation

Er - Erythema

Ed - Edema

Ne - Necrosis

Cb - Chemcially burned

Ts - Skin thickening

Ex - Exfoliation

Tb - Tissue bleeding

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Reference 3

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (sodium acid pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (sodium acid pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or sodium. Exposure to the non-common compound, the sodium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (sodium acid pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.

4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not reported.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No clinical signs were observed during the course of the study. There were no signs of dermal irritation.

Gross pathology:

No macroscopic findings were recorded at necropsy.

Other findings:

None.

Table1              Individual Clinical Observations and Mortality Data

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Initiation of Exposure (Hours)				Effects Noted After Initiation of Exposure (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-1 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-2 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-3 Male	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-4 Male	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
	2-4 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0= No signs of systemic toxicity

See attachment for Tables 2 - 4

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Executive summary:

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

OECD Guidelines for the Testing of Chemicals No. 402 “Acute Dermal Toxicity” (adopted24 February 1987)

Method B3 Acute Toxicity (Dermal) of Commission Regulation (EC) No. 440/2008

Method. A group of ten animals (five males and five females) was given a single, 24-hour, semi‑occluded dermal application of the test material to intact skin 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.

Dermal Irritation. There were no signs of dermal irritation.

Bodyweight. All animals showed expected gains in bodyweight over the study period.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute dermal median lethal dose (LD₅₀) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Reference 4

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (tetrapotassium pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (tetrasodium pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or sodium. Exposure to the non-common compound, the sodium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (tetrasodium pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.
4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animals died during treatment or observation periods.

Clinical signs:

other: Local effects: mild erythema and dedema. Sins of toxcity: all animals appeared normal throughout.

Gross pathology:

No gross abnormalities were noted.

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Reference 5

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

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
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (tetrapotassium pyrophosphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (tetrasodium pyrophosphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble inorganic phosphate salts. In vivo both substances will be (bio)transformed into their respective ionic forms; phosphate anions (either diphosphate or orthophosphate depending on degree of metabolism) and cations; either ammonium or sodium. Exposure to the non-common compound, the sodium ion, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) Both substances contain the bio transformation product: orthophosphate. Pyrophosphate will ultimately be converted to orthophosphate in vivo. The key moiety for the assessment of diammonium dihydrogenpyrophosphate is the ammonium cation and as such the effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to or worse than the effects of the source substance (tetrasodium pyrophosphate) for the property under consideration.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.
3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.
4. DATA MATRIX
See read-across justification report attached.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 mg/kg bw

Based on:

test mat.

Mortality:

No mortality.

Clinical signs:

other: No clinical signs.

Gross pathology:

No effects.

Interpretation of results:

GHS criteria not met

Conclusions:

Diammonium dihydrogenpyrophosphate is estimated to have an estimated LD50 of >2000 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

A weight of evidence approach is applied. The source data, performed on analogous substances, are GLP compliant and have Klimisch reliabilities of 1 or 2.

Justification for classification or non-classification

All the available data supports the evidence that diammonium dihydrogenpyrophosphate is not considered to be acutely toxic in accordance with Regulation (EC) No. 1272/2008 (EU CLP).