Registration Dossier

Administrative data

Description of key information

One key study is available for acute oral toxicity. This study is performed under the conditions of GLP and to an appropriate OECD guideline. As such, it is considered to be adequate and reliable for use a key studies for the purpose of REACH Registration and classification and labelling in accordance with EU CLP. It is not considered necessary to provide acute dermal toxicity data on the basis of the physiochemical and toxicological properties of manganese bis(dihydrogen phosphate).

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 01 May 2012 and 31 May 2012.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted to GLP and in compliance with agreed protocols, with no deviations from standard test guidelines (OECD 420, EU Method B1 bis) and no methodological deficiencies. This study has been selected as the key study because the results are sufficient in order to derive a reliable conclusion on classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
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)
Remarks:
Date of inspection: 19-21 July 2011, Date of signature: 31 August 2011
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).
- Fasting period before study: overnight fast immediately before dosing.
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): ad libitum (2014C Teklad Global Rodent diet supplied by Harlan Teklad, Oxon, UK)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70%
- Air changes (per hr): at least 15 per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

IN-LIFE DATES: From: Day 0 to Day 14
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
For the purpose of the study the test item was freshly prepared, as required, as a solution in distilled water.
The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.
Doses:
300 mg/kg bw, 2000 mg/kg bw
No. of animals per sex per dose:
300 mg/kg bw: 1
5000 mg/kg bw 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 subsequently once 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
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.


Preliminary study:
One animal treated at 300 mg/kg bw No mortality observed. See table for clinical observations of the animal treated with 300 mg/kg.
Individual bodyweights and bodyweight changes are given in Table 2: The animal showed expected gains in bodyweight over the observation period.
Necropsy findings are given in Table 3: No abnormalities were noted at necropsy.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths in the 5 animals tested.
Clinical signs:
Individual clinical observations and mortality data are given in Table 4. No signs of systemic toxicity were noted during the observation period.
Body weight:
Individual bodyweights and bodyweight changes are given in Table 5.
All animals showed expected gains in bodyweight over the observation period.
Gross pathology:
Individual necropsy findings are given in Table 6.
No abnormalities were noted at necropsy.

Table 1. Individual clinical observations and mortality data – 300 mg/kg

 

 

Dose level mg/kg

Animal

number

and sex

Effects noted after dosing (hours)

Effects noted during periods after doing

(days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

*

0

0

0

0

 

 

 

 

 

 

 

0 = No signs of systemic toxicity

* = Due to a technician error observation not performed 

 

 

Table 2. Individual bodyweight and bodyweight changes– 300 mg/kg bw

 

Dose level mg/kg

Animal

number

and sex

Bodyweight (g) at day

 

Bodyweight gain (g) during week

 

0

7

14

1

2

300

1-0

Female

161

185

205

24

20

 

 

 

 

 

 

 

 

Table 3. Individual Necropsy Findings – 300 mg/kg

 

Dose level mg/kg

Animal

number

and sex

Time of death

Macroscopic observations

300

1-0

Female

Killed day 14

No abnormalities detected

 

 

 

 

Table 4. Individual clinical observations and mortality data.– 2000 mg/kg bw

 

Dose level mg/kg

Animal

number

and sex

Effects noted after dosing (hours)

Effects noted during periods after doing

(days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000 

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

 

 

 

Table 6. Individual bodyweight and bodyweight changes– 2000 mg/kg bw

 

Dose level mg/kg

Animal

number

and sex

Bodyweight (g) at day

 

Bodyweight gain (g) during week

 

0

7

14

1

2

2000

2-0

Female

156

174

190

18

16

3-0

Female

179

195

204

16

9

3-1

Female

173

198

220

25

22

3-2

Female

175

203

217

28

14

3-3

Female

175

193

211

18

18

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 6. Individual Necropsy Findings– 2000 mg/kg

 

Dose level mg/kg

Animal

number

and sex

Time of death

Macroscopic observations

2000

2-0

Female

Killed day 14

No abnormalities detected

3-0

Female

Killed day 14

No abnormalities detected

3-1

Female

Killed day 14

No abnormalities detected

3-2

Female

Killed day 14

No abnormalities detected

3-3

Female

Killed day 14

No abnormalities detected

 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
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 (EU CLP: Unclassified).
This study is considered to be reliable and acceptable for use as a key study in accordance with Regulation (EC) No. 1907/2006 (REACH) and for the purposes of classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
One study exists: study is conducted to GLP and in compliance with agreed protocols, with no deviations from standard test guidelines (OECD 420) and no methodological deficiencies.
The LD50 was found to be > 2000 mg/kg bw.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Section 8.5.2: Adaptation

The inhalation toxicity of manganese bis(dihydrogen phosphate) is influenced by the Mn2+ cation and as such the material is considered to be classified via the inhalation route as STOT RE2 (target organ brain) in accordance with Regulation (EC) No. 1272/2008 (EU CLP) and on the basis of neurological symptoms (neurotoxicity) observed after inhalation of manganese. Neurotoxicity is considered to be the leading health effect and as such an IOELV has been proposed and adopted by the European Commission (1). This relates primarily to cumulative exposures however the authors state that as the proposed values are not based on one single study but on a database of available data the values proposed are acceptable for use in the risk mitigation of both cumulative and peak exposures.

The values are as follows:

- Inhalable IOELV: 0.2 mg/m3

- respirable IOELV: 0.05 mg/m3

It is recommended that both values should be observed conjointly.

 

Based on the above, it is not considered to be scientifically justified to conduct an acute inhalation study for manganese bis(dihydrogen phosphate) on the basis of the available data and taking into account the requirements to minimise animal testing in accordance with Regulation (EC) No. 1907/2006 (REACH). 

(1) ‘Recommendation from the Scientific Committee on Occupational Exposure Limits for Manganese and Inorganic Manganese Compounds’. SCOEL/SUM/127 – Adopted by the European Commission, June 2011

Section 8.5.3: Adaptation

In accordance with Annex VIII, Section 8.5.3, Column 2 of Regulation (EC) No. 1907/2006 (REACH) testing by the dermal route is appropriate if :

1. Inhalation of the substance is unlikely; and

2. skin contact in production and/or use is likely; and

3. the physicochemical and toxicological suggest a potential for a significant rate of absorption through the skin.

Although skin contact is likely during production and use of manganese bis(dihydrogen phosphate) dermal absorption is not considered to be favourable for metal compounds. Considerations of molecular weight and logPow do not apply to metals as inorganic compounds require dissociation to metal cations prior to being able to penetrate the dermis. As metal ions have an inherent reactivity towards protein structures the likelihood of them penetrating the skin is reduced. As such, it is anticipated that the following default dermal absorption factors be used for metal cations*:

- From exposure to liquid / wet material: 1%

- From dry (dust) exposure: 0.1%

As systemic absorption will be considerably less via the dermal route as opposed to the oral route it can be reliably assumed that a full characterisation of the acute systemic toxicity profile of manganese bis(dihydrogen phosphate) can be derived from the acute oral study and from the information relating to the inhalation of inorganic manganese substances. Further in vivo testing would be unethical and could not be scientifically justified.

 

 

* Default factors taken from the ICMM (2007) HERAG: Health Risk Assessment Guidance for Metals


Justification for selection of acute toxicity – oral endpoint
This study has been selected as the key study because the results are sufficient in order to derive a reliable conclusion on classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

Justification for selection of acute toxicity – inhalation endpoint
No study selected as an adaptation to the standard testing regime has been submitted.

Justification for selection of acute toxicity – dermal endpoint
No study selected as an adaptation to the standard testing regime has been submitted.

Justification for classification or non-classification

Acute oral toxicity: The oral LD50has been determined to be > 2000 mg/kg bw and therefore in accordance with Regulation (EC) No. 1272/2008 (EU CLP). Manganese bis(dihydrogen phosphate) is not considered to be classified as acutely toxic via the oral route.

Acute inhalation toxicity: Available data suggests that the health risks relating to manganese exposure via the inhalation route are as a result of repeated exposure. Based on the available data and taking into account the requirements to minimise animal testing in accordance with Regulation (EC) No. 1907/2006 (REACH) it is not considered to be scientifically justified to conduct further testing and no classification is proposed.

Acute dermal toxicity: Based on considerations of the physicochemical and toxicological properties of manganese bis(dihydrogen phosphate) the substance is not considered to be classified as acutely toxic via the dermal route. Further in vivo testing is not scientifically justified.