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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:
2010-04-07 to 2010-05-11.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and to current guideline.
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
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Female Wistar (HsdRccHan:WIST) strain rats were supplied by Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Age at study initiation: Eight to twelve weeks.
- Weight at study initiation: 153 - 189 g. 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 and for approximately three to four hours after dosing.
- Housing: The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes.
- Diet : Free access to food (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK) was allowed throughout the study.
- Water : Free access to mains drinking water was allowed throughout the study.
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature set to achieve limits of 19 to 25°C.
- Humidity (%): Relative humidity set to achieve limits of 30 to 70%.
- Air changes (per hr): At least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): Lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 280.4 mg/ml and 42.1 mg/ml


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual): For the purpose of the study the test material was freshly prepared, as required, as a solution in distilled water.
The test material was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.


- Rationale for the selection of the starting dose: Using available information on the toxicity of the test material, 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) was chosen as the starting dose.
Doses:
Dose levels of 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) and 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).
No. of animals per sex per dose:
A single female was treated at a dose level of 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight).
Five females were treated at a dose level of 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).
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 up to 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 or at death.
- Necropsy of survivors performed: yes.
Statistics:
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.
Preliminary study:
Dose Level - 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight):

Individual clinical observations and mortality data are given in Table 1.

Mortality:
The animal was killed for humane reasons two hours after dosing, due to the approach of the moderate severity limit set by the UK Home Office.

Clinical Observations:
Signs of systemic toxicity noted were hunched posture, lethargy, tiptoe gait, abdominal discomfort and pilo erection.

Bodyweight:
The bodyweight on Day 0 and at death are given in Table 2.

Necropsy:
Necropsy findings are given in Table 3.
Abnormalities noted at necropsy of the animal treated at a dose level of 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were patchy pallor of the liver, pale kidneys and severe haemorrhage of the gastric mucosa.

Based on the results at a dose level of 2804 mg/kg, a dose level of 421 mg/kg bodyweight was investigated.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 mg/kg bw
Based on:
test mat.
Remarks:
anhydrous equivalent
Mortality:
Dose Level - 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight):
There were no deaths.
At 2804 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight, the single female rat tested had to be humanely killed.
Individual clinical observations and mortality data are given in Table 4.
Clinical signs:
Dose Level - 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight):
No signs of systemic toxicity were noted during the observation period.
Body weight:
Dose Level - 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight):
Individual bodyweights and bodyweight changes are given in Table 5.
All animals showed expected gains in bodyweight over the observation period.
Gross pathology:
Dose Level - 421 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight):
Individual necropsy findings are given in Table 6.
No abnormalities were noted at necropsy.

Table 1              Individual Clinical Observations and Mortality Data -2804 mg/kg

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

2804+

1-0

Female

HLWt

HLWtAd

HLPWtX*

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


+ =     Equivalent to 2000 mg active ingredient/kg bodyweight)

H=      Hunched posture

L =      Lethargy

Wt =    Tiptoe gait

Ad =    Abdominal discomfort

P =      Pilo‑erection

X* =     Animal was killed for humane reasons due to the approach of the moderate severity limit set by the UK Home Office

Table 2              Individual Bodyweights and Bodyweight Changes -2804 mg/kg

Dose Level

mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight (g)
at Death

Bodyweight Gain (g)
During Week

0

7

14

1

2

2804+

1-0 Female

153

-

-

151

-

-


+ =     Equivalent to 2000 mg active ingredient/kg bodyweight)

- = animal dead

Table 3              Necropsy Findings - 2804 mg/kg

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2804+

1-0 Female

Humanely Killed Day 0

Liver: patchy pallor

Kidneys: pale

Gastric mucosa: severe haemorrhage


+ =     Equivalent to 2000 mg active ingredient/kg bodyweight)

Table 4              Individual Clinical Observations and Mortality Data - 421mg/kg*

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

421*

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


* =     Equivalent to 300 mg active ingredient/kg bodyweight)

0=     No signs of systemic toxicity

Table 5              Individual Bodyweights and Bodyweight Changes - 421mg/kg*

Dose Level

mg/kg

Animal Number
and Sex

Bodyweight (g) at Day

Bodyweight Gain (g) During Week

0

7

14

1

2

421*

2-0 Female

171

184

193

10

9

3-0 Female

156

160

168

4

8

3-1 Female

184

189

200

5

11

3-2 Female

162

167

177

5

10

3-3 Female

189

193

209

4

16


* =     Equivalent to 300 mg active ingredient/kg bodyweight)

Table 6              Individual Necropsy Findings- 421mg/kg*

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

421*

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


* =     Equivalent to 300 mg active ingredient/kg bodyweight)

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat is greater than 300 mg/kg bodyweight (Globally Harmonised Classification System - Category 4). The effects seen in the single animal tested at the highest dose are most likely due to the severe local action of the test substance, rather than a true systemic effect.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Manganese dinitrate is classified as acutely toxic by the oral route. However, it is considered that the classification is based on local effects rather than systemic effects, due to the corrosive nature of the substance.

Manganese dinitrate is not classified as acutely toxic by either the inhalation or dermal routes and testing is not appropriate due to the corrosive nature of the substance.