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Administrative data

Description of key information

Based on reliable studies with ammonium dihydrogenorthophosphate for acute oral and dermal exposure to rats, the oral LD50 is >2000 mg/kg bw and the dermal LD50 is >2000 mg/kg bw. No reliable acute inhalation study is present for the substance. A reliable acute toxicity inhalation study with read across substance diammonium hydrogenorthophosphate shows an LC50 is > 5 mg/L.  The read-across rationale can be found in the category approach document attached in Section 13 of IUCLID and is fully incorporated in the CSR.

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:
October 11 - 30, 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
the purity of MAP is unknown.
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Received from Ace Animals, Inc., Boyertown, PA on September 26 and October 10, 2000
- Age at study initiation: Young adult (8-10 weeks)
- Weight at study initiation: males 185-202 grams and females 198-206 grams
- Fasting period before study: fasted for approximately 17.5-24 hours by removing feed from their cages. During the fasting period, the rats were examined for health and weighed (initial). Six healthy rats (3 male and 3 female) were selected for test.
- Housing: The animals were 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 cage and was changed at least
three times per week.
- Diet (e.g. ad libitum): Purina Rodent Chow #5012
- Water (e.g. ad libitum): Filtered tap water was supplied ad libitum by an automatic water dispensing system.
- Acclimation period: 6 or 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
An initial dose of two thousand milligrams of the test substance per kilogram of bodyweight was administered to one healthy female rat by oral
gavage. Due to the absence of mortality in this animal a second female received the same dose level. Following the completion of dosing and 100%
survival in a total of three females, a group of three males was tested (simultaneously) at the above dose level.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing.
Bodyweights were recorded prior to administration and again on Days 7 and 14 (termination) after dosing.
Necropsies were performed on all animals at terminal sacrifice.
Statistics:
No data
Preliminary study:
no data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived
Clinical signs:
Animals appeared active and healthy throughout the study period.
Body weight:
Animals gained weight
Gross pathology:
FEMALES: All tissues/organs No gross abnormalities
MALES: All tissues/organs No gross abnormalities
Other findings:
none

none

Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to Regulation (EC) No. 1272/2008
Conclusions:
LD50 > 2000 mg/kg bw.
No signs of toxicity were observed
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study has klimisch code 2.

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:
23 March 2010 - 06 April 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation:Young adult animals were selected (approximately 10 weeks old).
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: No.
- Housing:
Before exposure:
Group housing of five animals per sex per cage in labeled Macrolon cages (type IV; height 18 cm) containing sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
After exposure:
Group housing as described above, except that a paper sheet was introduced into the cage covering the bedding and cage enrichment to prevent suffocation in case of bad health condition. At the end of the day of exposure the paper sheet was removed.
- Diet (e.g. ad libitum):Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) except during exposure to the test substance.
- Water (e.g. ad libitum):Free access to tap water except during exposure to the test substance.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8 – 21.7°C
- Humidity (%): 42 – 60%
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 23 March 2010 To: 06 April 2010
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle).
Details on inhalation exposure:
Animals were exposed to the test substance via the inhalatory route. For this purpose the animals were placed in restraining tubes, connected to the exposure chamber.
The design of the exposure chamber was based on the flow past nose-only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983). The chamber consisted of 3 animal sections with 8 animal ports each. The number of animal sections and number of open animal ports were adapted to the air flow in such a way that at each animal port the theoretical air flow was on average 1.4 L/min, which ensures an adequate oxygen supply to the test animals. The inlet of the test atmosphere was located at the top section and the outlet was located at the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal.
The placement of the individual animals in the inhalation chamber is shown in figure 2. All components of the exposure chamber, which could come in contact with the test material, were made of stainless steel, glass, rubber or plastic. To avoid exposure of the personnel and contamination of the laboratory the exposure chamber was placed in a fume hood, which was maintained at a slightly negative pressure.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
5.5 mg/L
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Diammonium hydrogenorthophosphate was administered as an aerosol by inhalation for a single but interrupted exposure lasting 4 hours and 8 minutes in total to one group of three male and three female Wistar rats. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15).
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 mg/L air
Exp. duration:
4 h
Mortality:
No mortality occurred and no clinical signs were noted during the study.
Clinical signs:
other: During and after exposure no clinical signs were noted.
Body weight:
Overall body weight gain in males and females were within the range expected for rats of this strain and age used in this type of study.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
study cannot be used for classification
Conclusions:
The inhalatory LC50, 4h value of Diammonium hydrogenorthophosphate in Wistar rats was considered to exceed 5 mg/L under the conditions in this study.
Executive summary:

Assessment of acute inhalatory toxicity with Diammonium hydrogenorthophosphate in the rat

 

The study was carried out based on the guidelines described in:

- OECD Guidelines, Section 4, Health Effects. No.403, "Acute Inhalation Toxicity", September 2009.

- Commission Regulation (EC) No 440/2008,B.2. Acute Toxicity (inhalation),L142, May 2008.

- EPA OPPTS 870.1300, Acute inhalation Toxicity. EPA 712-C-98-193, August 1998.

- JMAFF, 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.

 

Diammonium hydrogenorthophosphate was administered as an aerosol by inhalation for 4 hours to one group of five male and five female Wistar rats. Animals were subjected to daily observations and determination of body weight on Days 1, 2, 4, 8 and 15. Macroscopic examination was performed after terminal sacrifice (day 15).

 

The mean actual time-weighed concentration was 4.84 ± 0.28 mg/L. The nominal concentration was 442.92 mg/L. The generation efficiency (ratio of actual and nominal concentration) was 1.1%.

 

The Mass Median Aerodynamic Diameter (MMAD) and geometric standard deviation (gsd) were determined twice. The MMAD was 6.0mm and 5.6mm respectively and the gsd was 1.8 in both cases.

 

No mortality occurred and no clinical signs were noted during and after exposure.

 

The body weight gain shown by the animals over the study period was considered to be normal.

 

No abnormalities were found at macroscopic post mortem examination of the animals.

 

Agglomeration of aerosol particles at this high concentration tested resulted in MMAD values to exceed the recommended range of 1 - 4 µm. Additional efforts to reduce the MMAD were unsuccessful and the MMAD remained significantly larger than 4 µm (i.e. use of a micronizing jet-mill and two cyclones, lowering the concentration down to 1 mg/L). Since the gsd of 1.8 determined during the actual exposure indicated that the aerosol was polydisperse and since approximately 20% of the particles were smaller than 4 µm, it can be assumed that test substance deposition in the lower respiratory tract occurred during the exposure.

 

It was therefore considered that the outcome of this study is valid for the limit concentration of 5 mg/L.Since no mortality occurred at the limit concentration, no full study using lower concentrations was conducted.

 

The inhalatory LC50, 4hvalue of Diammonium hydrogenorthophosphate in Wistar rats was considered to exceed 5 mg/L under the conditions in this study.

 

Based on these results Diammonium hydrogenorthophosphate does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 000 mg/m³
Quality of whole database:
The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 17-31, 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Purity test substance unknown.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Received from Ace Animals, Inc., Boyertown, PA on October 10, 2000
- Age at study initiation: Young adult (8-9 weeks)
- Weight at study initiation: males 210-233 grams and females 180-190 grams at experimental start
- Housing: The animals were 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 cage and was changed at least
three times per week.
- Diet (e.g. ad libitum): Purina Rodent Chow #5012
- Water (e.g. ad libitum): Filtered tap water was supplied ad libitum by an automatic water dispensing system.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Type of coverage:
occlusive
Vehicle:
other: moistened
Details on dermal exposure:
Prior to application, the test substance was ground in a coffee mill and moistened to achieve a dry paste by preparing an 85% w/w mixture.
In order to insure adequate contact with the skin, the sample was applied as a dry paste, and administered as an 85% w/w mixture
in distilled water.

MAP was applied to the shaved intact skin on the back of each rat and covered with gauze pads.
After 24 hours the pads were removed and the test areas gently wiped with water.
Duration of exposure:
24 hours
Doses:
5000 mg/kg of bodyweight
(85% w/w mixture) Five thousand milligrams per kilogram of bodyweight of the test substance was moistened with distilled water and applied to the skin of ten healthy rats for 24 hours. Individual doses were calculated based on the initial bodyweights, taking into account the concentration
of the test mixture.
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
Prior to application, the test substance was ground in a coffee mill and moistened to achieve a dry paste by preparing an 85% w/w mixture. In order to insure adequate
contact with the skin, the sample was applied as a dry paste, and administered as an 85% w/w mixture
in distulled water.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: initial and again on days 7 and 14
- Necropsy of survivors performed: YES
- Other examinations performed: Individual bodyweights of the animals were recorded prior to test substance application (initial) and again on Days 7 and 14 (termination). The animals were observed for mortality, signs of gross toxicity, and behavioral changes at at 1 and 3 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 behavior pattern. Particular attention was directed to observation of
tremors, convulsions, salivation, diarrhea and coma.
Statistics:
No data
Preliminary study:
no data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
All animals survived
Clinical signs:
Animals appeared active and healthy throughout the test.
Body weight:
Animals gained weight
Gross pathology:
MALES: All tissues/organs No gross abnormalities
FEMALES: All tissues/organs No gross abnormalities
Other findings:
No data

none

Interpretation of results:
GHS criteria not met
Remarks:
Not classified according to Regulation (EC) No. 1272/2008
Conclusions:
No signs of toxicity were observed. LD50 > 5000 mg/kg
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
The study has klimisch code 2.

Additional information

Oral

For acute oral toxicity, ammonium hydrogenorthophosphate showed in an OECD 425 guideline study no mortality and no toxicity to rats up to 2000 mg/kg bw. Therefore, the LD50 was determined to be >2000 mg/kg bw. This was confirmed by other supporting studies.

Dermal

For acute dermal toxicity, ammonium hydrogenorthophosphate showed in an OECD 402 guideline study no mortality and no toxicity to rats up to 5000 mg/kg bw. Therefore, the LD50 was determined to be >5000 mg/kg bw. This was confirmed by other supporting studies.

Inhalation

For acute inhalation toxicity, no reliable study on the substance itself was present. However, a study with diammonium hydrogenorthophosphate particles showed in an OECD 403, EC B.2 and EPA guideline study no mortality and no toxicity to rats up to 5 mg/L. Therefore, the LC50 was determined to be >5 mg/L.


Justification for selection of acute toxicity – oral endpoint
One acute oral study on the substance is available.

Justification for selection of acute toxicity – inhalation endpoint
One acute inhalation study on the read-across substance diammonium hydrogenorthophosphate is available.

Justification for selection of acute toxicity – dermal endpoint
One acute dermal study on the substance is available.

Justification for classification or non-classification

Based on the data available, ammonium dihydrogenorthophosphate does not have to be classified for acute oral, dermal and inhalation toxicity according to Regulation (EC) No. 1272/2008 on Classification & Labelling.