Reaction mass of disodium [2,2'-(imino-kappaN)dibutanedioato-kappa2O1,O4(4-)]manganese(2-) and sodium sulphate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-12-20 to 2007-01-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Statement of GLP Compliance No. G 024 (Slovak National Accreditation Service); Statement of GLP Compliance No. 4/2006/DPL.

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of disodium [2,2'-(imino-kappaN)dibutanedioato-kappa2O1,O4(4-)]manganese(2-) and sodium sulphate

EC Number:

939-867-3

Cas Number:

666748-58-9

Molecular formula:

MnC8H7NO8Na2

IUPAC Name:

Reaction mass of disodium [2,2'-(imino-kappaN)dibutanedioato-kappa2O1,O4(4-)]manganese(2-) and sodium sulphate

Constituent 2

Reference substance name:

Manganese chelate of sodium salt N-[1,2 dicarboxyethyl] D,L aspartic acid

IUPAC Name:

Manganese chelate of sodium salt N-[1,2 dicarboxyethyl] D,L aspartic acid

Constituent 3

Reference substance name:

Mn(II)IDHA

IUPAC Name:

Mn(II)IDHA

Test material form:

other: water solution

Details on test material:

- Name of test material (as cited in study report): Mn(II)IDHA
- Substance type: chelate
- Physical state: solid (odourless, white microgranules)
- Analytical purity:
- Impurities (identity and concentrations):
- Purity test date:
- Lot/batch No.:
- Expiration date: 14.09.209
Data concerning the identification, purity and durability of the analysed material are the responsibility of the Mandator.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: conventional farm of laboratory animals run by the Institute of Occupational Medicine in Łódź, Poland.
- Age at study initiation: Pilot study: 9 week; Main experiment: 11 weeks
- Weight at study initiation: Pilot study: 166 g; Main experiment: average body weight of 190.5 g.
- Fasting period before study: yes. The day before the experiment was due to commence, some 18 hours before administration of the analysed material, the animals were deprived of feed, being left with only water. Feed was made available again 3 hours after administration of the analysed substance.
- Housing: plastic cages with metal wire covers, with the following dimensions (length x width x height): 58 x 37 x 21 cm.
During the experiment, the animals were kept in cages individually (initial study) and in groups of four (study proper). The litter comprised dedusted wood shavings, sterilised with ultraviolet radiation. Each cage was fitted with a signboard containing the study code, the dose applied, the date of commencement and planned termination of the experiment, as well as the sex and individual numbers of animals.
- Diet (e.g. ad libitum): ad libitum (standard granulated "Murigran" laboratory feed, manufactured by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL of Motycz)
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-71
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
The analysed substance was administered to the rats on the following days: 20.12.2006. (1 female – initial experiment, dose of 2,000 mg/kg of body mass) and 04.01.2007. (4 females – experiment proper, dose of 2,000 mg/kg of body mass). The experiment was terminated on the following days: 03.01.2007 (1 female – initial experiment, dose of 2,000 mg/kg of body mass) and 18.01.2007 (4 females – experiment proper, dose of 2,000 mg/kg of body mass), respectively.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 1 mL of the water solution of the analysed substance contained: 400 mg of the substance (dose of 2,000 mg/kg b.w.);
- Amount of vehicle (if gavage): 0.5 mL per 100 g of the body weight.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

Initial experiment: one animal
Main strudy: four animals

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: An assessment of the general condition of the animals, i.e. observation of all animals in terms of incidence and mortality, was performed twice daily throughout the 14-day duration of the experiment. Detailed clinical observations were performed on the day of administration of the analysed substance (day 0), 10, 30 and 60 minutes after administration, and subsequently every hour over a period of 5 hours from the time of administration. On successive days of the 14-day period of the experiment – once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Results and discussion

Preliminary study:

Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation.
Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to four successive females (experiment proper), no symptoms of toxicity were observed during the 14-day period of observation for three of the animals. The females survived the 14-day observation period.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: based on mortality, clinical signs and findings at necropsy at 2000 mg/kg bw

Mortality:

All females survived the 14-day observation period.

Clinical signs:

other: Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. Following the single administrati

Gross pathology:

No pathological changes were found during the macroscopic study in the analysed animals.

Any other information on results incl. tables

Table 1. Mn (II) IDHA Acute oral toxicity study conducted on rats – clinical symptoms – summary breakdown 

Dose(mg/kg b.w.)	Day following administration	Number of live animals	Rat no.
			1*	2	3	4	5
2,000	0 1 2 3 4 5 6 7 8 9 10 11 12 13 14	5 5 5 5 5 5 5 5 5 5 5 5 5 5 5	BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ	BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ	BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ	BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ	BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ

* female from the initial experiment

BZ = without change

Table 2. Mn (II) IDHA Acute oral toxicity study conducted on rats - animal body mass (g)

Dose mg/kg b.w.	Rat no.	Day of experiment			Difference 14 – 0
		0	7	14
2,000	1* 2 3 4 5	166 183 198 188 193	215 210 227 206 228	236 219 229 216 232	70 36 31 28 39

* females from the initial experiment

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

On the grounds of the study, it may be stated that the median lethal dose (LD50) of Mn (II) IDHA is greater than 2000 mg/kg b.w.

Executive summary:

A study was conducted to test oral toxicity potential of Mn (II) IDHA in rats. Following the single administration of the analysed substance in a dose of 2,000 mg/kg b.w. to a single female, no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation. Following the single administration of the analysed substance in a dose of 2,000 mg/kg bw to four successive females, no symptoms of toxicity were observed during the 14-day period of observation. The females survived the 14-day observation period. All the animals were put down following the 14-day period of observation and subsequently underwent autopsies and macroscopic studies. No pathological changes were found during the macroscopic study in the studied animals.