Ferrate(1-), [[N,N'-1,2-ethanediylbis[N-[[2-(hydroxy-.kappa.O)phenyl]methyl]glycinato-.kappa.N,.kappa.O]](4-)]-, sodium (1:1), (OC-6-13)-

Endpoint summary

Description of key information

The LD50 of greater than 2000 mg/kg bw were established in the acute oral and in the acute dermal toxicity studies. No treatment related effects were observed in the animals during the course of these studies. The substance Fe (Na)HBED is considered to be not acutely toxic by all routes of exposure and does not need to be classified and labelled according to CLP.

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:

2008-07-15 to 2008-10-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

changes in air humidity

Qualifier:

according to guideline

Guideline:

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

Deviations:

yes

Remarks:

changes in air humidity

Principles of method if other than guideline:

Few times during experiment the relative air humidity was above 70%. It did not influence study course and results. No other deviations from guideline / method were stated during the entire experiment.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute of Occupational Medicine, Łódź.
- Age at study initiation: 11 week
- Weight at study initiation: first rat: 203 g; four rats females with the average body weight of 195 g
- Fasting period before study: The day before the start of experiment, about 18 hours before administration of test item, the food was withheld but water was still available. The food was restored 3 hours after administration of test item.
- Housing: individually (the sighting study) or four rats per cage (the main study) in cages with plastic bottom and wired lid, with dimensions: (length x width x height) 58 x 37 x 21 cm. UV-sterilised wooden shavings were used as a bedding.
- Diet (e.g. ad libitum): ad libitum; standard granulated “Murigran” fodder produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz.
- Water (e.g. ad libitum): ad libitum; tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): 44-90
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2008-08-20 To: 2008-09-03 (one animal);
From: 2008-08-22 To: 2008-09-05 (four animals)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the dose level of 2000 mg/kg bw was chosen based on the information available for structurally related chemical Fe NaEDDHA (CAS No. 84539-55-9). No acute toxicity was observed. LD50 > 2000 mg/kg bw.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Evaluation of general condition of animals, i.e. observation of all animals forcmorbidity and mortality during 14-day observation period was conducted twice a day or once a day (on days off). Detailed clinical observations were performed on day of administration (day 0), after 10, 30 and 60 minutes since administration and then in hour intervals – till the 5th hour since administration. From 1st to 14th day of observation period detailed clinical observations were performed once a day.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Body weight of animals was individually determined for each animal directly before administration of test item (day 0) and then on 7th and 14th day – before termination of experiment.

Statistics:

Not reported

Preliminary study:

Following administration of test item in dose 2000 mg/kg b.w. to one female rat in the sighting study, no clinical changes were stated. The female survived 14-day period of experiment.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

One female rat (No. 4) died on the day 11.
Remaining animals survived all until day 14 of post-treatment period.

Clinical signs:

other: The following changes were stated in the female No 4: rounded back from 8th to 11th day of experiment, dejection on 8th and 9th day of experiment, bristled coat on 10th day of experiment. No clinical changes were observed in the remaining animals. The re

Gross pathology:

At necropsy slight congestion of lungs was stated in female No 2; slight congestion of lungs and abscess in left lung in female No 3; uneven congestion of lungs in female No 5. Pleural adhesions, marble-like and enlarged lungs as well as empty alimentary tract were stated in female which died spontaneously (No 4). These changes were caused by microbial infection. The gross changes stated in females were independent on test item. Diseases of respiratory system occur quite often in laboratory rats.
The results of gross examination are presented in Individual Data Sheets attached to this file (pages 20 - 29).

Other findings:

No other findings were reported

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

On the ground of the study one may state that the median oral lethal dose (LD50) for Fe (III) HBED is greater than 2000 mg/kg b.w.

Executive summary:

The acute oral toxicity of the test substance Fe(III) HBED (CAS 1061328 -86 -6) was evaluated in Wistar rats according to the Fixed Dose Procedure (Gruszka, 2008). The study was conducted in compliance with the OECD TG 420. The test substance was prepared in purified water and was administered by oral route (gavage), under a volume of 1 mL/100g, to one fasted female rat. As the test substance was anticipated to be non-toxic at 2000 mg/kg, a limit test was performed by administering 2000 mg/kg to the first animal (sighting study). No clinical changes were observed in the treated animal. The animal survived the 14 -day post-treatment period. As no death occurred, the study was completed by the administration of the dose-level of 2000 mg/kg to four female animals (main study). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test substance. All animals were subjected to necropsy.

Following the administration of the test item, rounded back, dejection and bristled coat were observed in one animal from day 8 of post-treatment period. The female died on 11th day of experiment. No clinical signs were stated in the remaining females. The other females survived 14-day period of experiment. At necropsy, slight congestion of lungs was stated in the female No 2; slight congestion of lungs and abscess in left lung in female No 3; uneven congestion of lungs in female No 5. Pleural adhesions, marble-like and enlarged lungs as well as empty alimentary tract were stated in the female No 4 which died spontaneously. These changes were caused by microbial infection. The clinical signs and the gross changes stated in the treated animals were considered to be unrelated to the test item. Excluding these effects and the death of one animal (as the consequence of the effects), the oral LD50 of the test substance is considered to be higher than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

good quality

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From: 2008-07-15 To: 2008-10-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute of Occupational Medicine in Łódź
- Age at study initiation: 10 weeks
- Weight at study initiation: males with the average body weight of 341 g and females with the average body weight of 210 g
- Fasting period before study: no
- Housing: The animals were kept in cages with dimensions (length x width x height): 58 x 37 x 21 cm; with plastic bottom and wired lid. After application of the test item each animal was kept individually in cage. After removal of test item from animals’ skin during the following days of experiment, the rats were kept five per cage, each sex separately. UV-sterilized wooden shavings were used as a bedding
- Diet (e.g. ad libitum): ad libitum. Standard granulated "Murigran" fodder produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz.
- Water (e.g. ad libitum): ad libitum; tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-65
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2008-09-17 To: 2008-10-01

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Remarks:

the test item was moistened with water and then laid on prepared skin

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10% (42 cm² (males) and 36 cm² (females))
- Type of wrap if used: not reported. The test item was applied to gauze patches, moistened with water and then laid on prepared skin. The gauze
patches were covered with PCV foil and elastic bandage was used to make circular protecting band.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes.The band and gauze patches were taken off and the residual test item was removed using water
- Time after start of exposure: 24 hours

TEST MATERIAL

- For solids, paste formed: yes. The test material was moistened with water

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Evaluation of general condition of animals, i.e. observation of all animals for mortality and morbidity was conducted twice a day or once a day (on days off) during 14-day observation period. After administration of the test item, detailed clinical observations were performed at hour intervals on the day of administration (day 0). Since the first till the 14th day of observation period detailed clinical observations were performed once a day.
Body weight of animals was individually determined for each animal directly before administration of test item (day 0) and then on seventh and fourteenth day - before the finishing of the experiment
- Necropsy of survivors performed: yes. Detailed gross examination of external body surfaces, all apertures, cranial, thoracic and abdominal cavity with content was performed at necropsy
- Other examinations performed: clinical signs, body weight

Statistics:

Not reported

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities were observed during the course of the study

Clinical signs:

other: Clinical signs No clinical changes were observed in the animals. The results of detailed clinical observations are presented in the Table 1 (page 41) as well as in Individual Data Sheets attached to this file (pages 43-62).

Gross pathology:

At necropsy enlargement of left lung and congestion of lungs with inflammatory changes were stated in the female No 5. These changes were not connected with test item. Respiratory system diseases occur quite often in laboratory rats [3]. No pathological changes were stated at necropsy of the remaining animals.
Results of gross examination of animals are presented in Individual Data Sheets attached to this file (pages 43-62).

Other findings:

Following application of test item no pathological changes were stated on the skin of treated animals on the site of application.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

On the ground of the study, one may state that the median dermal lethal dose (LD50) for Fe (III) HBED is greater than 2000 mg/kg b.w.

Executive summary:

Acute dermal toxicity study with Fe (III) HBED (CAS No. 1061328 -86 -6) was performed in Wistar rats according to the OECD TG 402 (Gruszka, 2008). The test item at dose level of 2000 mg/kg bw was applied to the shaved dorsal skin of 10 rats (5 males and 5 females) once and left for a period of 24 hours under semi-occlusive dressing. Purified water was used in order to moisten the test substance and ensure good contact with the skin as well as to remove residual test substance after removal of the dressing. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test substance. All animals were sacrificed after 14 -day observation period and subjected to gross necropsy. Following administration of test item, no changes were stated on skin of animals in the site of test item application. No other clinical changes were stated in animals. All animals survived 14-day period of experiment. At necropsy, enlargement of left lung and congestion of lungs with inflammatory changes (changes independent on test item) were stated in the female No 5. No pathological changes were stated in the remaining animals. On the ground of the study, one may state that the median dermal lethal dose (LD50) for Fe (III) HBED is greater than 2000 mg/kg b.w.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute toxicity - oral:

The acute oral toxicity of the test substance Fe(Na)HBED (CAS 1061328 -86 -6) was evaluated in Wistar rats according to the Fixed Dose Procedure (Gruszka, 2008).The study was conducted in compliance with the OECD TG 420. The test substance was prepared in purified water and was administered by oral route (gavage), under a volume of 1 mL/100g, to one fasted female rat. As the test substance was anticipated to be non-toxic at 2000 mg/kg, a limit test was performed by administering 2000 mg/kg to the first animal (sighting study). No clinical changes were observed in the treated animal. The animal survived the 14 -day post-treatment period. As no death occurred, the study was completed by the administration of the dose-level of 2000 mg/kg to four female animals (main study). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test substance. All animals were subjected to necropsy.

Following the administration of the test item, rounded back, dejection and bristled coat were observed in one animal from day 8 of post-treatment period. The female died on 11th day of experiment. No clinical signs were stated in the remaining females. The other females survived 14-day period of experiment. At necropsy, slight congestion of lungs was stated in the female No 2; slight congestion of lungs and abscess in left lung in female No 3; uneven congestion of lungs in female No 5. Pleural adhesions, marble-like and enlarged lungs as well as empty alimentary tract were stated in the female No 4 which died spontaneously. These changes were caused by microbial infection. The clinical signs and the gross changes stated in the treated animals were considered to be unrelated to the test item. Excluding these effects and the death of one animal (as the consequence of the effects), the oral LD50 of the test substance is considered to be higher than 2000 mg/kg bw.

Acute toxicity - dermal:

Acute dermal toxicity study with Fe(Na)HBED (CAS No. 1061328 -86 -6) was performed in Wistar rats according to the OECD TG 402 (Gruszka, 2008). The test item at dose level of 2000 mg/kg bw was applied to the shaved dorsal skin of 10 rats (5 males and 5 females) once and left for a period of 24 hours under semi-occlusive dressing.Purified water was used in order to moisten the test substance and ensure good contact with the skin as well as to remove residual test substance after removal of the dressing.Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test substance. All animals were sacrificed after 14 -day observation period and subjected to gross necropsy.Following administration of test item, no changes were stated on skin of animals in the site of test item application. No other clinical changes were stated in animals. All animals survived 14-day period of experiment. At necropsy, enlargement of left lung and congestion of lungs with inflammatory changes (changes independent on test item) were stated in the female No 5. No pathological changes were stated in the remaining animals. On the ground of the study, one may state that the median dermal lethal dose (LD50) for Fe(Na)HBED is greater than 2000 mg/kg b.w.

Justification for selection of acute toxicity – oral endpoint
Guideline and GLP key study

Justification for selection of acute toxicity – dermal endpoint
Guideline and GLP key study

Justification for classification or non-classification

Based on the results of the acute oral and dermal key toxicity studies, Fe(Na)HBED is not subject to classification and labelling for acute toxic effects according to Directive 67/548/EEC and Regulation 1272/2008/EC.