Registration Dossier

Administrative data

Description of key information

Oral (OECD 420, RL1), rat LD50 > 2000 mg/kg bw (limit test)

There is no reliable data availabe regarding acute dermal toxicity for magnesium hydrogenorthophosphate. Read across data with calcium bis (dihydrogenorthophosphate) CAS 7758 -23 -8 is used and considered reliable.

Dermal (similar to OECD 402, CAS 7758 -23 -8, RL2), rabbit, LD50 > 2000 mg/kg bw (limit test)

There is no data regarding acute toxicity via inhalation route available for magnesium hydrogenorthophosphate. Read across data with calcium bis (dihydrogenorthophosphate) CAS 7758 -23 -8 is used and considered reliable.

Inhalation (OECD 403, CAS 7758 -23 -8, RL1), rat LC50 > 2.6 mg/L air (limit test)

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:
The study was performed between 11 March 2010 and 06 April 2010.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Remarks:
HsdRccHan®™:WIST®™
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: mean 177 g
- Fasting period before study: overnight
- Housing: n groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes
- Diet: ad libitium - 2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Using available information on the toxicity of the test material, 2009 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) was chosen as
the starting dose.

Dose Level(mg/kg) Concentration(mg/ml) Dose Volume(ml/kg) Number of Rats
Female
2009* 200.9 10 1

In the absence of toxicity at a dose level of 2009 mg/kg, an additional group of animals was treated as follows:

Dose Level(mg/kg) Concentration(mg/ml) Dose Volume(ml/kg) Number of Rats
Female
2009* 200.9 10 4

A total of five animals were therefore treated at a dose level of 2009 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) in the study.
All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was
calculated according to its fasted bodyweight at the time of dosing.


Doses:
2009 mg/kg (equivalent to 2000 mg active ingredient /kg bodyweight)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

- Necropsy of survivors performed: Yes

- Other examinations performed: clinical signs, body weigh
Preliminary study:
A sighting test at a dose level of 2009 mg/kg (equivalent to 2000 mg active ingredient /kg bodyweight) was performed.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted.
Body weight:
All animals showed expected gains in bodyweight over the observation period.
Individual bodyweights and bodyweight changes are given in Table 2.
Gross pathology:
No abnormalities were noted at necropsy.
Individual necropsy findings are given in Table 3.

Table1              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

2009*

1-0

Female

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

*= Equivalent to 2000 mg active ingredient/kg bodyweight

0= No signs of systemic toxicity


Table2              Individual Bodyweights and Bodyweight Changes

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Gain (g) During Week

0

7

14

1

2

2009*

1-0 Female

169

176

188

7

12

2-0 Female

165

178

189

13

11

2-1 Female

169

182

190

13

8

2-2 Female

187

198

207

11

9

2-3 Female

195

210

216

15

6

*= Equivalent to 2000 mg active ingredient/kg bodyweight

 

Table3              Individual Necropsy Findings

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2009*

1-0 Female

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

*= Equivalent to 2000 mg active ingredient/kg bodyweight

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (Not classified - EU CLP).
Magnesium hydrogenorthophosphate is not considered to be classified according to Regulation (EC) No. 1272/2008 (EU CLP). Study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint. Study is sufficient for classification and labelling purposes, in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
Executive summary:

Introduction. 

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

OECD Guidelines for Testing of Chemicals No.420 "Acute Oral Toxicity - Fixed Dose Method" (Adopted 17th December 2001)

Method B1  bis Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008

Method. 

Following a sighting test at a dose level of 2009 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight), an additional four fasted female animals were given a single oral dose of test material, as asuspensionindistilled water, at a dose level of 2009 mg/kg bodyweight (equivalent to 2000 mg active ingredient/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.

Bodyweight. 

All animals showed expected gains in bodyweight.

Necropsy. 

No abnormalities were noted at necropsy.

Conclusion. The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2009 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight) (Not classified - EU CLP)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The study is conducted under the conditions of GLP and in accordance with an appropriate guideline (OECD 420).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see analogue justification attached to chapter 13
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.6 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Mortality:
All animals survived the scheduled observation period.
Clinical signs:
Slight to moderate ruffled fur was noted in all animals on test day 1, one hour after the end of the exposure and persisted slightly until test day 2 in nine animals. From test day 3 onwards, all animals were free from clinical signs until their scheduled necropsy.
Body weight:
From test day 1 to test day 2, marginal to slight body weight loss was noted in all animals. Thereafter all animals gained weight until scheduled necropsy.
Gross pathology:
There were no macroscopic findings.
Other findings:
Not applicable.

The nominal aerosol concentration was 7.5 mg/L air.

Interpretation of results:
GHS criteria not met
Conclusions:
The LC50 of magnesium hydrogenorthophosphate as obtained in this study was estimated to be greater than 2.6 mg/L air (gravimetrically determined mean aerosol concentration). This was the highest technically achievable test concentration. There was no indication of relevant sex-related differences in toxicity of the test item.

In accordance with Regulation (EC) No. 1272/2008 (EU CLP) magnesium hydrogenorthophosphate is not considered to be classified as acutely toxic via the inhalation route.
Executive summary:

The LC50 was estimated to be greater than 2.6 mg/L air for magnesium hydrogenorthophosphate as found in the source study performed with calcium bis(dihydrogenorthophosphate). As explained in the justification for type of information, the differences in molecular structure between magnesium hydrogenorthophosphate and calcium bis(dihydrogenorthophosphate) are unlikely to lead to differences in the LC50 for inhalation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
2 600 mg/m³
Quality of whole database:
The available information comprises an adequate and reliable study from a reference substance similar in structure and intrinsic properties. Read-across is justified based on structural similarities of calcium- and magnesiumphosphate compounds and their similarities in PC/ECO/TOX properties (refer to read across justification for further details). The selected study is thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
A single dermal dose of 2000 mg/kg bw produced no mortalities in a mixed group of albino rabbits (5 male and 5 female).
Clinical signs:
All rabbits in the test group and the sham-exposed control group appeared normal throughout the 14-day test.
Body weight:
No data
Gross pathology:
10 rabbits from the test material exposed group and 4 rabbits from the sham-exposed group were necropsied on day 14 and appeared normal.
Other findings:
- Other observations: local effects: Local dermal effects in the test material group included darkened dose sites, severe erythema, mild edema and the skin at the abrasion marks was separated and filled with reddish fluid and pus-like material. There were no apparent local dermal effects following a 24 hour sham-treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of magnesium hydrogenorthophosphate obtained from this study was estimated to be greater than 2000 mg/kg bw. This was the highest dose tested. There was no indication of toxic signs up to this dose.
Executive summary:

The dermal LD50 > 2000 mg/kg bw was estimated from the dermal LD50 of the source substance calcium bis(dihydrogenorthophosphate). As explained in the justification for type of information, the differences in molecular structure between magnesium hydrogenorthophosphate and calcium bis(dihydrogenorthophosphate) are unlikely to lead to differences in the LD50.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study from a reference substance similar in structure and intrinsic properties. Read-across is justified based on structural similarities of calcium- and magnesiumphosphate compounds and their similarities in PC/ECO/TOX properties (refer to read across justification for further details). The selected study is thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Additional information

Oral:

A GLP acute oral toxicity study with magnesium hydrogenorthophosphate 3 -hydrate according to OECD 420 was performed (Harlan, 2010). Following a sighting test at a dose level of 2009 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight), an additional four fasted female animals were given a single oral dose of test material, as a suspension in distilled water, at a dose level of 2009 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight). Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths, no signs of systemic toxicity and no abnormalities noted at necropsy. All animals showed expected gains in bodyweight. In conclusion, the acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2009 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight).

 

Inhalation:

No study is available with magnesium hydrogenorthophosphate (CAS 7757 -86 -0). Reliable data is available for calcium bis(dihydrogenorthophosphate) (CAS 7758 -23 -8).

Calcium bis(dihydrogenorthophosphate) and trimagnesium bis(orthophosphate) are structurally similar ionic compounds with the only differences being that calcium is replaced with magnesium. The phosphate groups are structurally identical between the two compounds and any acute toxicity potential will be the same. Magnesium and calcium are both alkali metals from group 2 and periods 3 and 4 of the periodic table, respectively and have only one oxidation state (+2). Magnesium and calcium are among the most abundant elements and are the important essential nutrients for higher plants, algae, animals and human. Both elements are similar in chemical nature and show the related metabolism and similar environmental behaviour. The differences between the two compounds will not have an impact on any acute toxicity potential and therefore, the result from the acute inhalation toxicity study can reliably be read across to trimagnesium bis(orthophosphate).

In an inhalation toxicity study (according to OECD 403, Harlan, 2010), groups of 11 week old Wistar rats (5/sex) were exposed by inhalation route (nose only) to the test substance as a dust and observed for 14 days. The maximal achievable dose was 2.6 mg/L. The rats were exposed for 4 hours. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. All animals survived the scheduled observation period. Slight to moderate ruffled fur was noted in all animals after the end of the exposure and was still present in most animals up to test day 2. Thereafter, all animals were free from clinical signs. Transient body weight loss was noted in all animals from test day 1 to test day 2. Normal body weight development was observed thereafter. No macroscopical findings were present at necropsy.

In conclusion, the LC50 of calcium bis(dihydrogenorthophosphate) and thus of magnesium hydrogenorthophosphate obtained in this study was estimated to be greater than 2.6 mg/L air (gravimetrically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

 

Dermal:

No reliable study is available with magnesium hydrogenorthophosphate (CAS 7757 -86 -0). Reliable data is available for calcium bis(dihydrogenorthophosphate) (CAS 7758 -23 -8).

In an acute dermal toxicity study (similar to OECD 402) with calcium bis(dihydrogenorthophosphate), groups of fasted young Stauffland albino rabbits (5/sex) were dermally exposed to the undiluted test substance for 72 hours at 2000 mg/kg bw. and observed for 14 days. The skin was abraded before treatment and test substance was hold in place by an occlusive dressing. This procedure represents a worst case scenario since the exposure duration was 72 hours instead of 24 hours and occlusive dressing and abrasion of the skin was performed. No mortality or unusual clinical signs occurred during this study. At autopsy, no abnormalities were observed. Local dermal effects in the test material group included darkened dose sites, severe erythema, mild edema and the skin at the abrasion marks was separated and filled with reddish fluid and pus-like material. In conclusion, under the conditions of this study, the LD50 of calcium bis(dihydrogenorthophosphate) and thus of magnesium hydrogenorthophosphate was considered to be >2000 mg/kg bw.

In conclusion, since calcium bis(dihydrogenorthophosphate) is a reliable read across substance and no acute inhalation or dermal toxicity are observed, magnesium hydrogenorthophsphate is considered to be also not acute toxic via dermal and inhalation route.


Justification for classification or non-classification

In accordance with Regulation (EC) No.1272/2008 (EU CLP) trimagnesium bis(orthophosphate) is not considered to be classified for acute toxicity via any route. The data provided for this endpoint are considered to be conclusive and no further investigation is required.