Potassium; 2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate; iron(3+)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

October 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well performed and reported GLP study

Justification for type of information:

The underlying hypothesis for the read-across is that chelates have the same mode of action based on their ability to chelate, remove or add metal cations to body causing perturbation of body’s micronutrients balance.
The source substance is a chelating agent in a target substance. The only difference between the target and the main source substance is presence of iron (Fe) and potassium (K) cations instead H+ cations. As iron and potassium are an essential macro- and microelements required by all forms of life, is considered not to influence the toxicological activity.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Sodium hydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl]glycinato(5-)]ferrate(2-)

EC Number:

235-627-0

EC Name:

Sodium hydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl]glycinato(5-)]ferrate(2-)

Cas Number:

12389-75-2

Molecular formula:

C14-H18-Fe-N3-O10.H.Na

IUPAC Name:

Iron(3+) ion sodium 5-[bis(carboxylatomethyl)amino]-3-{[bis(carboxylatomethyl)amino]methoxy}pentanoate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Description: yellow-green powder
Batch: CFC-10333 (429H0352)
Purity/Composition: ~97%
Test substance storage: at room temperature protected from light
Stability under storage conditions: stable
Expiry date: 1 December 2013
Test substance handling: use amber-coloured glassware or wrap container in tin-foil.
pH: 2.7 in water (1% solution)
Stability in vehicle: Water 1 year
Solubility in vehicle: Water 110 g/L

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Source: Charles River Deutschland, Sulzfeld, Germany.
Number of animals: 6 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age and body weight: young adult animals (approx. 8 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification: ear- and tailmark

Conditions: Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were recorded in the raw data and were considered to have had no effect on the outcome of the study.

Accommodation: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).

Water: Free access to tap water.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Rationale: the vehicle was selected based on trial formulations performed at WIL Research Europe and on test substance data supplied by the sponsor.
Preparation: the formulations (w/w) were prepared within 4 hours prior to dosing. The (test substance) formulations were protected from light using amber coloured glassware. Homogeneity was accomplished to a visually acceptable level. No correction was made for purity of the test substance.
Method: oral gavage, using plastic feeding tubes.
Fasting: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
Frequency: single dosage on Day 1.
Dose level (volume): 2000 mg/kg (20 mL/kg) body weight.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

Mortality/Viability: twice daily.
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: at periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
Necropsy: at the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

Not needed, limit test

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Piloerection and/or hunched posture was noted among most animals on Day 1. In addition, brown staining was observed on the back of three animals on Days 2-4.

Gross pathology:

Macroscopic examination did not reveal any toxicologically relevant abnormalities.
Pelvic dilation found in three animals at macroscopic post mortem examination is commonly seen among rats of this age and strain and was therefore considered not toxicologically significant.

Other findings:

None

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 was in excess of 2000 mg/kg bw.

Executive summary:

The study was carried out based on the guidelines described in: OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method"; Commission Regulation (EC) No 440/2008, B1 tris: "Acute Oral Toxicity, Acute Toxic Class Method"; EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity"

JMAFF guidelines (2011) including the most recent partial revisions.

DTPA-FeHNa was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Piloerection and/or hunched posture was noted among most animals on Day 1. In addition, brown staining was observed on the back of three animals on Days 2-4. The body weight gain shown by the animals over the study period was considered to be normal. Macroscopic examination did not reveal any toxicologically relevant abnormalities.

The oral LD50value of DTPA-FeHNa in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, DTPA-FeHNa does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) andRegulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.