Registration Dossier

Administrative data

Description of key information

Acute oral toxicity data arae available for the read-across substance iron sulphate; acute dermal toxicity data are available for the read-across substance iron dichloride.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan Charles River Co. Ltd., Hino Animal Center, Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: males: 99 - 113 g and females: 90 - 101 g
- Fasting period before study: 18 hours
- Housing: stainless steel cages, 755x210x170 mm
- Diet (ad libitum): pellets, CRF-1 (Oriental Yeast Co., Ltd.)
- Water (ad libitum): tap water
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 40-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2001-05-16 To: 2001-06-07
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0, 25, 50, 100, 200 mg/mL. The concentrations of test item in the vehicle were verified using a titration method. The measured concentrations were 96.4 - 104.2% of the nominal concentrations.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
Doses:
250, 500, 1000 and 2000 mg/kg bw/day
No. of animals per sex per dose:
Five
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: once daily for observations and weighing on days 1, 3, 7, 10 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (general observations), body weight and food consumption
Statistics:
Body weight and food consumption were calculated as Mean ± SD. Bartlett and Dunnett test were conducted.
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
5 males exposed to 2000 mg/kg bw showed salivation and reduced activity 4 and 6 hours after treatment. 4 females showed reduced activity 6 hour after treatment. Effects were reversible after 24 hours.
No abnormalities were observed in groups treated with 250, 500 and 1000 mg/kg bw .
Body weight:
Compared to control, a significantly reduced body weight determined in the female animals exposed to 1000 mg/kg bw at 14 days after treatment.
However, no body weight effects observed at 14 days after the treatment in both sexes exposed to 2000 mg/kg bw. The reduced body weight in these groups was only examined at 1 day after treatment.
Gross pathology:
No toxicologically relevant effects observed.
Other findings:
no information
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 for iron sulphate heptahydrate was greater than 2000 mg/kg bw/d.
Executive summary:

In an acute oral toxicity study, conducted in accordance with the extant OECD 401 guideline , and in accordance with principles of GLP, the LD50 for iron sulphate heptahydrate was greater than 2000 mg/kg bw/d. By read-across, based on similar toxicity profiles for iron salts, the test material iron triitrate is also considered not to be classified for acute oral toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Recent guideline-compliant study for a read-across substance supported by (and consistent with) older literature data

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
26 March 2004 to 04 June 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Remarks:
U.S. EPA Good Laboratory Practice Standards, Toxic Substances Control Act (TSCA), 40 CFR Part 792, OECD Principles of Good Labortaory Practice (as revised 1997), ENV/MC/CHEM (98) 17 and NIER Public notice No. 1998-41, under Toxic Chemicals Control Act.
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Orient co. Ltd., Korea
- Age at study initiation: Approximately 8 weeks of age
- Weight at study initiation: 256.9 - 279.7 for males, 223.8 - 233.5 g for females
- Fasting period before study: not stated in report
- Housing: Individually housed in stainless steel cages with wire mesh floors
- Diet: ad libitum access to a certified rodent diet (2014, Lot 0206043MA, Teklad Global 14% Protein Rodent diet, Harlan Teklad, USA)
- Water: ad lbitum access to filtered/UV-treated tap water
- Acclimation period: seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.4 - 24.5°C during acclimation, 18.6 - 25.3°C during study
- Humidity (%): 35.0 - 69.4% during acclimation, 42.1 - 74.4% during study
- Air changes (per hr): not stated in report
- Photoperiod (hrs dark / hrs light): Lighting controlled automatically to provide 12 hours of artificial light (08:00 - 20:00 hours, 150 - 300 Lux) in each 24 hours period.

IN-LIFE DATES: From: March 9th 2004 To: June 3rd 2004
Type of coverage:
semiocclusive
Vehicle:
corn oil
Details on dermal exposure:
TEST SITE
- Area of exposure: Dorsal flank
- % coverage: 10% of total body surface
- Type of wrap if used: Porous gauze dressing secured with a non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test article removed using distilled water at end of the exposure period
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): not applicable
- Constant volume or concentration used: yes
- For solids, paste formed: no

VEHICLE
- Amount(s) applied (volume or weight with unit): Test article moistened with corn oil
- Concentration (if solution): not stated in report
- Lot/batch no. (if required): 122K0131
- Purity: not stated in report
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Checked at least once daily for mortality. Individually observed during first 4 hours after dosing and then daily for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs - changes in skin and fur, eyes and mucous membrane and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behaviour pattern recorded at each observation.
Body weight - recorded on Day 1 (prior to dosing), day 8 and Day 15 (prior to necropsy).
Statistics:
No statistical analysis was performed because of the small sample size and absence of controls.
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths occurred at the limit dose level
Mortality:
There were no unscheduled deaths during the study.
Clinical signs:
Yellowish-brown change on the skin at application site observed in all treated animals from Day 2, but fully reversed by Day 15 except for 3 females. Two males and 4 females had reddish nasal discharge on Day 2.
Body weight:
Normal bodyweight gain was exhibited by all rats throughout the study.
Gross pathology:
No abnormalities observed during macroscopic examination. At the site of application, scarring was observed in one male and one female.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of the test article to rats by a single dermal administration was considered to be greater than 2000 mg/kg bw under the conditions of this study. Therefore the substance (iron dichloride) is not classified for acute dermal toxicity. By read-across the similar iron salt, iron trinitrate, is also not classified for acute dermal toxicity.
Executive summary:

This study was performed (using OECD Guideline No. 402) to assess the acute toxicity of the test article, iron dichloride (CAS No.: 7758 -94 -3) by single dermal administration to Sprague-Dawley rats. Mortality, clinical signs and bodyweight changes were monitored throughout the study. All animals were humanely killed as scheduled and examined macroscopically on Day 15, the end of the observation period.

Five female and five male rats each received 2000 mg/kg bw as a limit test. Because there was no mortality observed, the study was completed.

There were no unscheduled deaths and bodyweight gains were normal during the study.

A yellowish-brown change was observed at the application site in all test animals, and was considered to relate to the colour of the test article. Two males and 4 females had a reddish nasal discharge on Day 2, which was considered a distress symptom caused by pressure of taping on the thorax area.

During macroscopic examination, scarring was observed at the application site on one male and one female. This was considered to relate to application of the test article. internally, no abnormalities were observed.

In conclusion, the LD50 to rats of the test article, iron dichloride (CAS no.: 7758 -94 -3) by a single dermal administration is considered to be greater than 2000 mg/kg bw under the conditions of this study. Therefore the substance (iron dichloride) is not classified for acute dermal toxicity and by read-across, the similar salt, iron trinitrate, is also not classified for dermal toxicity

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Recent guideline-compliant study for a read-across substance

Additional information

The acute oral toxicity of the read-across substance ferrous suphate heptahydrate was found to be >2000 mg/kg bw in a modern, guideline-compliant rat study (MHLW, 2003). Weaver et al (1961) report acute oral LD50 values for ferrous sulphate of 2625 mg/kg bw in the rat and 1025 mg/kg bw in the mouse.

No acute inhalation toxicity data are available.

The acute dermal toxicity of the read-across substance iron dichloride was found to be >2000 mg/kg bw in a modern, guideline-compliant rat study (Choi, 2004).

The results of studies performed with the read-across substances therefore show low acute oral and dermal toxicity and indicate comparably low acute oral and dermal toxicity for iron trinitrate.


Justification for selection of acute toxicity – oral endpoint
Most recent, guidelline-compliant study in the preferred species

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

Based on the results of modern, guideline-compliant acute oral and dermal toxicity studies performed with read-across substances in the rat, no classification is proposed for iron trinitrate.