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Description of key information

The oral LD50 value is in excess of 2000 mg/kg bw; the 4-h LC50 value for DTPA-FeHNa is in excess of 5.08 g/m3 and that of EDTA-FeNa in excess of 2.75 mg/L. No acute dermal toxicity studies are available but based on read across (see also section 13), acute dermal toxicity following exposure to HEDTA-FeNa is not expected.

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:
October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well performed and reported GLP study
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
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.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Vehicle: water (Elix, Millipore S.A.S., Molsheim, France).
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 (10 mL/kg) body weight.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females
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
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mL/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.

Clinical signs:
other: Hunched posture and/or piloerection was noted among all animals on Day 1. In addition, diarrhoea was shown by three animals on Day 2.
Gross pathology:
Macroscopic examination did not reveal any toxicologically relevant abnormalities.
Diaphragmatic hernia of the liver noted in one animal was a background finding for rats of this age and strain.
Other findings:
None
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 value 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.

HEDTA-Fe(III)Na 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. Hunched posture and/or piloerection was noted among all animals on Day 1. In addition, diarrhoea was shown by three animals on Day 2. 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 HEDTA-Fe(III)Na 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, HEDTA-Fe(III)Na 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.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
One well performed study; result comparable to other metal chelates.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of acute toxicity – oral endpoint
Well performed and reported GLP study

Justification for classification or non-classification

No classification needed for acute oral and inhalation exposure as the oral LD50 value is in excess of 2000 mg/kg bw, and the 4-h LC50 value is in excess of 5.08 g/m3. Based on the expec ted absence of acute dermal toxicity, no classification needed for acute dermal toxicity.