Reaction mass of iron chelate of sodium salt N-[1,2 dicarboxyethyl] D,L aspartic acid and sodium chloride

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 2007-01-23

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:

666828-40-6

Cas Number:

666828-40-6

IUPAC Name:

666828-40-6

Constituent 2

Reference substance name:

Fe(III)IDHA

IUPAC Name:

Fe(III)IDHA

Test material form:

other: microgranules

Details on test material:

- Name of test material (as cited in study report): Fe (III) IDHA
- Substance type: chelate
- Physical state: solid (odourless, green microgranules)

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute of Occupational Medicine in Łódź, Poland
- Age and weight at study initiation: Pilot study: 10 week (dose of 2,000 mg/kg bw). Main experiment: 11 weeks (average body weight of 188.5 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: The animals were kept in 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 (main study).
- 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), 04.01.2007 (4 females – experiment proper, dose of 2000 mg/kg of body mass). The experiment was terminated on the following days: 03.01.2007. (1 female – initial experiment, dose of 2000 mg/kg of body mass), 23.01.2007. (4 females – experiment proper, dose of 2000 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 of body mass).
- Amount of vehicle (if gavage): 0.5 mL per 100 g of the body weight.

- Rationale for the selection of the starting dose: During the initial experiment, one female received a dose of 2,000 mg/kg of body mass of the analysed substance. During the 14 day observation period were not observed the symptoms of toxicity. The female survived the 14-day observation period.
On the basis of the initial experiment, during the experiment proper the analysed substance was administered to four successive females in a dose of 2000 mg/kg of body mass.

Doses:

Initial experiment: 2000 mg/kg bw;
Main strudy: 2000 mg/kg bw

No. of animals per sex per dose:

Initial experiment: 2000 mg/kg bw - one animal;
Main strudy: 2000 mg/kg bw - 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 at the dose of 2,000 mg/kg of body weight to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. The animal survived the 14-day period of observation.

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:

No mortality occured during the 14-day observation period.

Clinical signs:

other: After a single administration of test substance to one female at a dose of 2000 mg / kg b.w. (preliminary experience), during the 14-day period of observation there was no diagnosed with symptoms of toxicity. The female survived the 14-day observation per

Gross pathology:

Macroscopic studies did not find any pathological changes in the test animals.

Any other information on results incl. tables

Table 1. Clinical signs.

Dose (mg/kg bw)	Day following administra tion	Number of live animals			Rat No
			1 *	2	3	4	5
	0	5	BZ	BZ	BZ	BZ	BZ
	1	5	BZ	BZ	BZ	BZ	BZ
	2	5	BZ	BZ	BZ	BZ	BZ
	3	5	BZ	BZ	BZ	BZ	BZ
2000	4	5	BZ	BZ	BZ	BZ	BZ
	5	5	BZ	BZ	BZ	BZ	BZ
	6	5	BZ	BZ	BZ	BZ	BZ
	7	5	BZ	BZ	BZ	BZ	BZ
	8	5	BZ	BZ	BZ	BZ	BZ
	9	5	BZ	BZ	BZ	BZ	BZ
	10	5	BZ	BZ	BZ	BZ	BZ
	11	5	BZ	BZ	BZ	BZ	BZ
	12	5	BZ	BZ	BZ	BZ	BZ
	13	5	BZ	BZ	BZ	BZ	BZ
	14	5	BZ	BZ	BZ	BZ	BZ

* females from the initial experiment

BZ = without change

Table 2. Body weights

Dose mg/kg of body mass	Rat no.	Day of experiment			Difference 14 – 0
		0	7	14
2000	1* 2 3 4 5	198 179 174 189 174	233 206 225 211 222	241 225 232 216 232	52 35 42 33 41

* females from the initial experiment

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category V

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the mortality, clinical signs and findings at necropsy in five animal dosed by 2000 mg/kg bw, LD50 is considered to be over 2000 mg/kg bw that corresponds to Cat. 5 (not clasified) in accordance with the ECHA guidance on the Application of the CLP Criteria (2013).

Executive summary:

A study was conducted to test oral toxicity potential of Fe(III)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.