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EC number: 231-105-1 | CAS number: 7439-96-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Remarks:
- based on test type
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Not to GLP, follows basic scientific principles. Level of manganese ingested by the two exposed groups varied considerably within the dosing groups.
- Remarks:
- Study conducted on read-across material
- Justification for type of information:
- This study has been used to address the reproductive toxicity data requirements of manganese metal on the basis that a negative result for a soluble inorganic manganese compound is a worst case and therefore should demonstrate the lack of any developmental toxicity potential if compared to the bioavailable concentration of Mn.
Cross-reference
- Reason / purpose for cross-reference:
- other: Read-across target
Reference
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study conducted on read-across material
- Justification for type of information:
- This study has been used to address the reproductive toxicity data requirements of manganese metal on the basis that a negative result for a soluble inorganic manganese compound is a worst case and therefore should demonstrate the lack of any developmental toxicity potential if compared to the bioavailable concentration of Mn.
- Reason / purpose for cross-reference:
- read-across source
- Dose descriptor:
- conc. level: 3 mg/mL
- Generation:
- F1
- Effect level:
- >= 325 - <= 678 other: mg/kg
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: Air righting reflex delayed (Developmental parameter) in low protein group
- Dose descriptor:
- conc. level: 3 mg/mL
- Generation:
- F1
- Effect level:
- >= 354 - <= 715 other: mg/kg
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: Air righting reflex delayed (Developmental parameter) in normal protein group.
- Reproductive effects observed:
- not specified
Data source
Reference
- Reference Type:
- publication
- Title:
- Effect of low protein diet on manganese neurotoxicity: I. Developmental and biochemical changes
- Author:
- Ali MM, Murthy RC, Saxena DK, Srivastava RS and Chandra SV
- Year:
- 1 983
- Bibliographic source:
- Neurobehavioural toxicology and teratology, 5: 377-383
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The effects of a low protein diet (19% casein) and manganese exposure (Mn2+, 3 mg/mL drinking water) in rats was studied. The effect on growing (F0-90 days), rehabilitated (F0 low-normal protein- 28 days) and F1 generation pups was studied.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- managanese dichloride
- IUPAC Name:
- managanese dichloride
- Details on test material:
- - Name of test material (as cited in study report): Manganese chloride
- Analytical purity: Not reported
Constituent 1
Test animals
- Species:
- rat
- Strain:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: ITRC colony bred
- Weight at study initiation: 40-45 g
- Housing: Acrylic cages
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±2°C
- Photoperiod (hrs dark / hrs light): 12 hr light:dark cycle
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- VEHICLE
- Choice of vehicle : Drinking water
- Concentration in vehicle: 3 mg/mL
- Amount of vehicle : Drinking water containing Mn was available ad libitum
DIET
Rats were divided randomly into two dietary groups: one group received a synthetic diet containing 21% casein and the other received a low protein diet containing 10% casein. Half of the rats in each dietary group were given drinking water containing MnCl2 at 3 mg/mL.
In addition some male rats on the low protein diet were given a normal protein diet for 28 days, the Mn exposure schedule remained the same. At the end of 28-day rehabilitation animals were sacrificed. - Details on mating procedure:
- - M/F ratio per cage: 75 male to 50 female rats
- After successful mating each pregnant female was caged. Rats were isolated and kept singly in plastic cages and allowed to deliver normally. - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not applicable
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- daily
- Details on study schedule:
- Not reported
Doses / concentrations
- Remarks:
- Doses / Concentrations:
3 mg/mL water
Basis:
nominal in water
- No. of animals per sex per dose:
- 21% casein (group 1): 37 male and 27 female
10% casein (group 2: 37 male and 27 female - Control animals:
- other: Yes, normal protein diet without Mn exposure
- Details on study design:
- Estimation of manganese consumption (for individual animals):
((Mn2+ concentration mg/mL x water consumed over 24 hours mL)/ Body weight g) x 1000 - Positive control:
- Not reported
Examinations
- Parental animals: Observations and examinations:
- Growth pattern, diet consumption, water consumption, brain weight, brain Mn content, body weight assessed.
- Oestrous cyclicity (parental animals):
- Not reported
- Sperm parameters (parental animals):
- Not reported
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter redistributed within the groups to dams who had delivered on the same day.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: litter size, eye opening, startle index, air rightening index, viability index and lactation index.
GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.] - Postmortem examinations (parental animals):
- ORGAN WEIGHTS
The effect of the protein diet and manganese administration on brain weight was examined. - Postmortem examinations (offspring):
- ORGAN WEIGHTS
The effect of the protein diet and manganese administration on brain weight was examined. - Statistics:
- All results, excluding developmental changes, were analysed by Student's t-test. For the developmental changes, a one way analysis of variance was applied to determine the significance of the difference of the means between the groups. The technique was applied after ascertaining the homogenicity of variance and normality assumptions of the data. The effect of Mn2+ in the low and normal protein fed rats were compared with their respective controls and in addition, the effect of low protein diet was assessed by comparing the low and normal protein fed control groups. Differences at p < 0.05 were considered significant.
- Reproductive indices:
- Not reported
- Offspring viability indices:
- Not reported
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- not specified
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not examined
Details on results (P0)
Rats maintained on a low protein diet had a marked growth retardation compared to those on the normal protein diet. Mn2+ exposure in either dietary groups had no significant effect on the body weight growth pattern. No effects were noted on dietary consumption. The animals in the dietary rehabilitation group gained weight rapidly over the 28 days of rehabilitation (31-35%). The normal protein fed rats had a weight gain of only 8-10% during this period.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Water consumption in controls maintained on either diet was not found to differ (range 30-60 mL/day/rat over the entire experimental period). In Mn2+ exposed groups the diet exerted no effect on water consumption, however the volume of water consumed was much less compared to the controls (6-42 mL/day/rat). In the rehabilitated groups (control and Mn2+ exposed groups was less (18-34 mL/rat/day) compared to control groups (40-60 mL/rat/day).
ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects were noted on the brain weights in any treatment groups or the rehabilitation group.
BIOCHEMICAL PARAMETERS (PARENTAL ANIMALS): (Brain and plasma protein and brain Mn2+ content).
No effects were noted in the brain protein level in either diet or dosing group, this was also true for the rehabilitation group. However plasma levels were found to be reduced in the lower protein diet regimen. No effects were found to correlate with Mn2+ exposure. Plasma protein levels were found to be increased in rehabilitated groups, in the control as well as the Mn2+ groups, over the rehabilitation levels, recovering to those fed the normal protein diet. Mn+2 was again found to have no effect. Administration of manganese was found to increase the Mn2+ content in the brain in every dosing group, including the rehabilitated group.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Details on results (F1)
The litter size of the pups born to the low protein fed dams was significantly lower than those born to the normal protein fed dams. Mn2+ exposure, in either dietary groups was found to have no significant effect on the litter size.
CLINICAL SIGNS (OFFSPRING): Developmental indices.
a). Eye opening: The age at opening both eyes was found to be significantly delayed in the pups born to protein deficient dams. Exposure to Mn2+ was found to have no significant effect. b). Auditory startle reflex: The age at which the pups first exhibited the auditory startle reflex was significantly delayed in the pups from protein deficient mothers. Mn2+ exposure in the low protein groups further delayed the appearance of this response, however it had no significant effect in the pups born to normal protein fed mothers dosed with Mn2+. c). Air righting: The age at which air righting reflex was noted was significantly delayed in the pups born to protein fed mothers. Mn2+ exposure caused further delay in the protein deficient groups. d). Viability and lactation indices: No significant effect on the viability and lactation indices in the pups of either dietary group either due to the dietary or Mn2+ exposure schedules.
TEST SUBSTANCE INTAKE (DAMS)
The dietary and Mn2+ exposure had no effect on food consumption rate of the dams during gestation and lactation. The water intake in the control and Mn2+ exposed groups on both dietary schedules was found to be slightly increased during the lactation period (control 47-75 mL and Mn2+ exposed 28-63 mL/day/rat) than during the gestation period (control 35-56 mL and experimental 20-52 mL/day/rat).
BODY WEIGHT (OFFSPRING)
The body weights of the low protein fed dams, both control and Mn2+ exposed were retarded by 37-45 % throughout the gestation and lactation periods, compared to the normal protein fed groups. F1 pups' body weights born to low protein dams were found to be retarded by 26, 16, 37, 46 and 43 % on days 0, 4, 7, 14 and 21 days of age respectively compared to those born to the normal protein fed dams.
ORGAN WEIGHTS (OFFSPRING)
The brain weight of the pups born from the low protein fed dams was found to be significantly lower than that of the offspring of the normal protein fed ones. Mn2+ exposure had no significant effect in either dietary group.
BIOCHEMICAL PARAMETERS (OFFSPRING): (Brain and plasma protein and brain Mn2+ content).
The brain protein level of the pups from the protein deficient dams was found to be considerably lower than pups to mothers fed a normal protein diet. The plasma protein levels of pups from protein deficient dams was decreased significantly and the Mn2+ exposure schedules in either dietary group were found to have no significant effect on the brain and plasma protein levels. The brain Mn2+ contents in the pups of either dietary group was found to be considerably higher than that found in the adults, the extent of the accumulation was the same in both dietary groups.
Effect levels (F1)
open allclose all
- Dose descriptor:
- conc. level: 3 mg/mL
- Generation:
- F1
- Effect level:
- >= 325 - <= 678 other: mg/kg
- Sex:
- not specified
- Basis for effect level:
- other: Air righting reflex delayed (Developmental parameter) in low protein group
- Dose descriptor:
- conc. level: 3 mg/mL
- Generation:
- F1
- Effect level:
- >= 354 - <= 715 other: mg/kg
- Sex:
- not specified
- Basis for effect level:
- other: Air righting reflex delayed (Developmental parameter) in normal protein group.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1: Effect of Concurrent Low Protein Diet and Mn2+ Exposure (90) Days in F0-Growing Rats
Group |
Body Weight |
Brain weight g |
Brain weight/ Body weight |
Protein contents |
Brain Mn2+content |
||||
g |
% Change |
Brain mg/g |
Plasma g/100 mL |
% Change |
µg/g |
% Change |
|||
Normal protein |
308.0 ± 28 |
|
1.59 ± 0.06 |
0.0051 ± 0.0002 |
147.0 ± 2.0 |
8.6 ± 0.11 |
|
0.84 ± 0.15 |
|
§Normal protein + Mn2+ |
298.0 ± 32 |
N.S.* |
1.61 ± 0.14 |
0.0054 ± 0.0004 |
150.0 ± 3.1 |
8.8 ± 0.34 |
N.S.* |
1.84 ± 0.13 |
†120* p<0.001 |
Low protein |
164.0 ± 19.5 |
-47† p<0.001 |
1.58 ± 0.08 |
0.0096 ± 0.0006 |
140.0 ± 2.9 |
6.2 ± 0.10 |
-28† p<0.001 |
0.86 ± 0.10 |
N.S.† |
¶Low protein + Mn2+ |
158.0 ± 14 |
N.S.‡ |
1.58 ± 0.12 |
0.01 ± 0.005 |
134.0 ± 9.4 |
6.0 ± 0.08 |
N.S.‡ |
1.86 ± 0.14 |
+116 p<0.001 |
Values represent mean ± S.E. of 6 rats; p values evaluated by Student’s t-test *† Compared to normal protein controls; ‡ Compared to low protein controls N.S. = Not significant Daily Mn2+intake, mg/kg: 0-30 days ¶377-473 §301-410 30-60 days ¶298-557 §240-495 60-90 days ¶305-675 §260-585 |
Table 2: Effect of Diet Rehabilitation (28 days) in F0-Rats Exposed to Concurrent Low Protein Diet and Mn2+ Exposure (90 days)
Group |
Body Weight |
Brain weight g |
Brain weight/ Body weight |
Protein contents |
Brain Mn2 + content |
||||
g |
% Change |
Brain mg/g |
Plasma g/100 mL |
% Change |
µg/g |
% Change |
|||
Normal protein |
338.0 ± 31 |
|
1.60 ± 1.10 |
0.0047 ± 0.0001 |
125.29 ± 2.99 |
8.39 ± 0.20 |
|
0.82 ± 0.09 |
|
§Normal protein + Mn2+ |
333.0 ± 31 |
N.S.* |
1.61 ± 0.09 |
0.0048 ± 0.0003 |
127.86 ± 2.96 |
8.22 ± 0.32 |
N.S.* |
2.03 ± 0.08 |
†1.48* p<0.001 |
Low protein |
266.0 ± 22 |
-21.3† p<0.05 |
1.60 ± 0.09 |
0.0060 ± 0.002 |
115.36 ± 4.17 |
8.22 ± 0.08 |
N.S.† |
0.80 ± 0.06 |
N.S.† |
¶Low protein + Mn2+ |
250.0 ± 21 |
N.S.‡ |
1.58 ± 0.07 |
0.0063 ± 0.0003 |
119.78 ± 4.47 |
8.48 ± 0.32 |
N.S.‡ |
2.03 ± 0.05 |
+155‡ p<0.001 |
Values represent mean ± S.E. of 6 rats; p values evaluated by Student’s t-test *† Compared to normal protein controls; ‡ Compared to low protein controls N.S. = Not significant Daily Mn2+intake, mg/kg: ¶725-655 §315-610 |
Table 3: Effect of Concurrent Low Protein Diet and Mn2+ Exposure on the Appearance of Certain Developmental Landmarks and Indices in F1-Pups
Group |
Litter Size |
Day of |
Viability index |
Lactation index |
||
Eye opening |
Auditory startle reflex |
Air righting reflex |
||||
Normal protein |
10.31 ± 0.73 |
15.31 ± 0.65 |
12.37 ± 0.79 |
16.25 ± 0.97 |
99.26 ± 6.2 |
95.22 ± 5.6 |
§Normal protein + Mn2+ |
9.25 ± 0.55 N.S.* |
15.58 ± 0.93 N.S.* |
13.10 ± 1.10 N.S.* |
19.74 ± 0.93 p<0.001* |
88.24 ± 4.7 N.S.* |
91.68 ± 8.2 N.S.* |
Low protein |
8.13 ± 0.15 p<0.01† |
18.27 ± 0.85 p<0.001† |
15.96 ± 0.92 p<0.001† |
20.14 ± 1.21 p<0.001† |
95.64 ± 5.2 N.S.† |
90.40 ± 7.2 N.S.† |
¶Low protein + Mn2+ |
7.65 ± 0.64 N.S.‡ |
17.9 ± 1.2 N.S.‡ |
25.61 ± 1.17 p<0.01‡ |
25.61 ± 1.17 p<0.001‡ |
82.21 ± 4.3 N.S.‡ |
89.76 ± 6.5 N.S.‡ |
Values represent mean ± S.E. of 10-14 pups (litter mate); Statistical significance evaluated by ANOVA *† Compared to normal protein controls; ‡ Compared to low protein controls N.S. = Not significant Daily Mn2+intake, mg/kg: ¶325-678 §354-715 |
Table 4: Effect of Concurrent Low Protein Diet and Mn2+ Exposure in F1-Pups (Weaned)
Group |
Body weight |
Brain weight |
Brain weight/ Body weight |
Protein contents |
Brain Mn2+ content |
||||||
g |
% Change |
g |
% Change |
Brain mg/g |
% Change |
Plasma g/100 mL |
% Change |
µg/g |
% Change |
||
Normal protein |
43.7 ± 2.3 |
|
1.40 ± 0.09 |
|
0.0320 ± 0.0009 |
120.0 ± 3.0 |
|
8.4 ± 0.2 |
|
0.87 ± 0.14 |
|
§Normal protein + Mn2+ |
41.4 ± 2.2 |
N.S.* |
1.38 ± 1.03 |
N.S.* |
0.0333 ± 0.0006 |
115.0 ± 4.0 |
N.S.* |
8.7 ± 0.4 |
N.S.* |
2.45 ± 0.10 |
+180* p<0.001 |
Low protein |
24.8 ± 1.7 |
-43.2† P<0.001 |
1.13 ± 0.05 |
119† P<0.05 |
0.0455 ± 0.002 |
105.4 ± 3.0 |
-12† p<0.05 |
5.5 ± 0.2 |
-35† p<0.001 |
0.82 ± 0.09 |
N.S.† |
¶Low protein + Mn2+ |
23.6 ± 1.9 |
N.S.‡ |
1.15 ± 0.07 |
N.S.‡ |
0.0487 ± 0.0007 |
110.5 ± 1.63 |
N.S.‡ |
5.9 ± 0.2 |
N.S.‡ |
2.28 ± 0.08 |
+177‡ p<0.001 |
Values represent mean ± S.E. of 6 pups; Statistical significance evaluated by Student’s t-test *† Compared to normal protein controls; ‡ Compared to low protein controls N.S. = Not significant Daily Mn2+ intake of dams during gestation and lactation, mg/kg: ¶325-678 §354-715 |
Applicant's summary and conclusion
- Conclusions:
- Mn exposure had no significant effect on growth pattern, brain weight or brain and plasma protein contents in either dietary group. Diet regimen had no effect on accumulation of Mn in any group but levels were higher in F1 pups. In F1 pups Mn exposure had no effect on eye opening in either group, delayed startle reflex in low protein group only but air righting reflex development delayed in both dietary groups, more marked in low protein group.
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