Acetic acid, oxo-, sodium salt, reaction products with cresol and ethylenediamine, iron sodium salts

Endpoint summary

Description of key information

The LD50 value derived from the acute oral toxicity study with EDDHMA-Fe is > 5000 mg/kg bw. The dermal LD50 is > 2000 mg/kg bw.  The inhalation (4h) LC50 is > 1.24 mg/L air (maximally attainable concentration).

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:

April 6-21, 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Relatively well reported study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (U.K) Limited, Margate, Kent, England
- Age at study initiation: young adult rats, approximately 5 weeks old
- Weight at study initiation: (pre-fasted) males 110 - 117 g; females 97 - 110 g.
- Fasting period before study: approximately 18 hours before administration of test material
- Housing: 5 animals of the same sex (in type RCI cages with stainless steel grid floors)
- Diet (e.g. ad libitum): fed without restriction (Laboratory animal diet no. 1 from Labsure, Manea, Cambridgeshire, England)
- Water (e.g. ad libitum): free access to tap water
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 (range 18 - 25)
- Humidity (%): 55 (range 40 - 70)
- Air changes (per hr): 15 complete air changes per hour, without re-circulation
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light per day

IN-LIFE DATES: From: April 6, 1987 To: April 21, 1987

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25% w/v formulation in distilled water (250 mg/mL)
- Justification for choice of vehicle: not indicated

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg

Doses:

Dose: 5000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (terminated on Day 15)
- Frequency of observations and weighing: Three separate inspections were made during the first hour after administration and two further inspections during the remainder of Day 1. From Day 2 onwards, the animals were inspected twice daily. The type, time of onset and duration of reactions to treatment were recorded. The bodyweight of each animal was recorded on the day before dosing and on Days 1, 8 and 15. The test was terminated on Day 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology

Statistics:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

One female rat died during the first overnight period. There were no other deaths.

Clinical signs:

other: Decreased motor activity, hunched posture, piloerection and urinogenital staining from purple urine were observed in all rats during the first five hours after dosing. Surviving rats were ungroomed on Day 2, but all had fully recovered by Day 3 and remain

Gross pathology:

Necropsy of the decedent revealed fur staining, abnormal gastro-intestinal contents and extensive cannibalisation. Necropsy of the surviving rats revealed red staining of the perineum or ventral surface of several animals and less frequent observations of altered gastro-intestinal contents or dark lungs.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute oral median lethal dose to rats of Bolikel FE was found to be greater than 5000 mg/kg bodyweight. According to OECD-GHS Bolikel FE is not classified.

Executive summary:

The study was performed according to OECD Guideline 401 (Acute Oral Toxicity) and according to GLP standards.

The test material, Bolikel FE was evaluated in a limit test for its acute oral toxicity potential in rats when administered as a gavage dose at a level of 5000 mg/kg to a group of 5 males and 5 females. One female rat died during the first overnight period. Clinical signs of toxicity included decreased motor activity, hunched posture, pilo-erection and urinogenital staining from purple urine; recovery was complete on Day 3. Gross pathologic examination at termination revealed red staining of the perineum or ventral surface of several animals and less frequent observations of altered gastro-intestinal contents or dark lungs.

The acute oral median lethal dose to rats of Bolikel FE was found to be greater than 5000 mg/kg bodyweight. According to OECD-GHS Bolikel FE is not classified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LD50> 5000 mg/kg bw. All GLP or in-house audited studies.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April-May 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Relatively well reported study with some doubts on the results of the particle szie measurements, which, however, do not invalidate the outcome of the study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Guideline was not mentioned in the report.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CD (remote Sprague Dawley origin)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd.
- Age at study initiation: 6-11 weeks on arrival, 7-12 weeks at start
- Weight at study initiation: 251-273 g (males) and 235-250 g (females)
- Fasting period before study: ca. 17 h
- Housing: in polypropylene cages with stainless steel grid floors and tops; 5 per sex
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: ca. 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): targeted at mean of 22 and range of 19-25
- Humidity (%): targeted at mean of 55 and range of 40-70
- Air changes (per hr): ca. 17
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29 April To: 21 May 1987

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose/head only

Vehicle:

other: air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 30 cm diameter alumnium ally cylinder with a volume of ca. 60 L containing 3 exposure sections with 20
animal ports each. Chamber and dust generator were placed in a large cabinet equipped with an extract fan
- Exposure chamber volume: 60 L
- Method of holding animals in test chamber: in restraining tubes
- Source and rate of air: dry, oil free, compressed air
- Method of conditioning air: no info except that air was dry and free of oil
- System of generating particulates/aerosols: Wright dust feeder, flow rate 25 L/min. Test material was first conditioned by a single pass through the 1 mm screebn of an ultracentrifugal mill
- T90 (theoretical time to reach 90% of the final concentration): 5.5 min; thereafter exposure was timed for 4 h
- Method of particle size determination: 2 times per h; cyclone sampler (at 2 L/min to obtain the fraction of particles that had an
Equivalent Aerodynamic Diameter < 5 micrometer), and a 5-stage cascade impactor (Casella) (at 17.5 L/min)
- Treatment of exhaust air: via absolute filter, also at a rate of 25 L/min
- Temperature, humidity, pressure in air chamber: T = 21.6±0.33 degrees C, RH = 63±2%, zero pressure difference between
chamber and extract cabinet air

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetry, 2 times per h, 2 L/min
- Samples taken from breathing zone: yes (spare animal port)

VEHICLE: air

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The cyclone method showed that on average 80.7±4.3% of the particle mass had an aerodynamic
equivalent diameter< 5.0 microns, indicating that a large fraction of the particles was respirable.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMEAD (Mass Median Equivalent Aerodynamic
Diameter) was reported to be 0.274 microns (GSD not indicated).
The latter value is considered unreliable (also because of lack of data) because:
- if almost 81% of the particles < 5 microns and therefore 19% > 5 microns, it is not likely to obtain an MM(E)AD of 0.274 micron
(indicating that 50% of the particles was smaller than 0.274 microns). This is only possible when particles (or better: agglomerates of particles) break up in the cascade impactor or that the test material is rather fluffy in air.
- no indication was given on the cut-off value for each stage of the cascade impactor (missing info to better judge on the validity of the results of the particle-size measurements)
- on average 62% was found on the last stage (i.e. the back-up filter). This would mean that a substantial fraction of the test
particles had just 'flown' through the cascade impactor, which normally only happens with very fluffy material (such as amorphous silica), or that agglomerates may have been broken up.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Actual concentration 1.24±0.052 mg/L (stated to technically highest attainable concentration)
Nominal concentration: 8.44 mg/L

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: on days 1 (day of exposure), 2, 3, 4, 5, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: absolute and relative weight of liver, kidneys and lungs

Statistics:

Not required

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.24 mg/L air (analytical)

Exp. duration:

4 h

Remarks on result:

other: technically highest attainable concentration

Mortality:

None

Clinical signs:

other: During exposure: progressive contamination of the fur on the head and abdomen was observed for all rats After exposure: reduced motor activity was evident in all rats immediately following exposure. Subsequently the behaviour of all rats was normal throu

Body weight:

Following exposure the rate of bodyweight gain for male rats was reduced for one day. Female rats lost bodyweight or gained
weight at a reduced rate for several days. Subsequently the rate of bodyweight gain was similar to that expected for rats of this
age and strain.

Gross pathology:

The presence of test material on the fur was noted for seven rats at necropsy. Other minor macroscopic changes noted were
considered to be of spontaneous origin and unrelated to exposure to the test compound.

Other findings:

The relative lung, liver and kidney weights of all rats were within normal Iimits.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

There were no deaths and hardly clinical signs following the exposure of five male and five female rats to Bolikel Fe at the maximum level that could be achieved in air using the methods described in this report. The median lethal concentration for four hours of
exposure (LC50 4-h) for Bolikel Fe is therefore in excess of 1.24 mg/l.

Executive summary:

The acute inhalation toxicity of Bolikel Fe was investigated by exposing a group of five male and five female rats to the maximum concentration of the test substance that could be generated. The test group was subjected to a single four-hour, continuous snout-only exposure. Signs of reaction to treatment were recorded during a subsequent 14 -day observation period. The animals were sacrificed at the end of the observation period and subjected to detailed necropsy. The actual concentration of Bollikel Fe was 1.24±0.052 mg/L, the proportion of of particles smaller than 5 micron (Equivalent Aerodynamic Diameter) was 81%. There were no deaths as a result of exposure. During exposure, progressive contamination of the fur with the test material was seen. Clinical signs during the observation period consisted of reduced motor activity in all rats immediately following exposure. Subsequently, behaviour was normal throughout the observation period. Staining of the fur by the test material was also observed following exposure and this sign persisted through the observation period in some rats. Following exposure the rate of bodyweight gain of male rats was reduced for one day. Female rats lost bodyweight or gained weight at a reduced rate for several days. Subsequently, the rate of bodyweight gain was similar to that expected for rats of this age and strain. The relative lung, liver and kidney weights of all exposed rats were within normal limits. There were no significant changes attributable to exposure to Bollikel Fe. Conclusion: The median lethal concentration of Bolikel Fe for four hours of exposure (LC50 4 -hours) is greater than 1.24 mg/L, the maximum concentration that could be achieved using the methods described in this report. Because of this maximally achievable concentration, and the absence of toxicity, the test material does not need classification for acute inhalation toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

4-h LC50 value in excess of 1.24 mg/L (technically highest attainable concentration); GLP study.

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:

September-October 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited reported study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Age at study initiation: not indicated
- Weight at study initiation: 269-281 g (males), 194-225 g (females)
- Fasting period before study: not applicable
- Housing: 5 per sex per cage
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 50-85
- Air changes (per hr): no info
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 September To: 2 October 1990

Type of coverage:

semiocclusive

Vehicle:

physiological saline

Details on dermal exposure:

TEST SITE
- Area of exposure: an area of roughly 5 x 10 cm was clipped
- % coverage: not indicated
- Type of wrap if used: porous gauze dressing and Eloplast

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not indicated
- Time after start of exposure: not indicated

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg was moistened sufficiently with physiological saline taking into account 72% active ingredient
- Concentration (if solution): not applicable
- Constant volume or concentration used: not applicable
- For solids, paste formed: no

VEHICLE: physilogical saline was used for sufficient moisturing

Duration of exposure:

24 h

Doses:

2000 mg/kg bw (taking 72% active ingredient into account) based on a RF study with 2 females

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 after patch removal: 10 min, 1, 2, 6 and 24 h, and once daily thereafter
- Frequency of weighing: weekly
- Necropsy of survivors performed: yes

Statistics:

Not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Mortality:

None

Clinical signs:

other: No signs of erythema and oedema were observed.

Gross pathology:

Gross pathological examinations at 14 days revealed no test article-dependent findings except hair growth reduction on treated skin areas.

Other findings:

None

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute dermal LD50 is > 2000 mg/kg bw.

Executive summary:

The study was performed according to OECD Guideline 402 (Acute Dermal Toxicity) and according to GLP standards.

The test material, EDDHMAFeK was evaluated in a limit test for its acute dermal toxicity potential in rats when administered onto the skin for 24 h at a level of 2000 mg/kg (active ingredient) to a group of 5 males and 5 females. None of the rats died. No clinical signs were observed and body weight gains were as expected. Except for hair grwoth reduction on treated skin areas, no gross abnormalities were observed at necropsy 14 days after dosing.

The acute dermal median lethal dose of EDDHMAFeK to rats was found to be greater than 2000 mg/kg bodyweight (active ingredient) or greater than 2743 mg/kg bw (test article). According to OECD-GHS, EDDHMAFeK is not classified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LD50 in excess of 2000 mg/kg bw

Additional information

Oral route

In three acute oral toxicity studies according to OECD Guideline 401, the LD50 in rats was determined to be greater than 5000 mg/kg bw. Body weight development was not impaired. Only a single death was observed in one of the studies.

Inhalation route

An acute inhalation toxicity study (according to OECD Guideline 403) was performed in albino rats. Upon a 4 -h acute inhalation exposure and a 14 -day post-treatment observation period, no mortalities were elicited by the test item at the technically maximally attainable concentration of 1.24 mg/L. This was supported by a second study at which no mortality occurred in rats exposed to 0.83 mg/L (maximally attainable concentration) for 6 h.

Dermal route

One acute dermal toxicity study (limit test), according to OECD Guideline 402 was performed with the test substance in rats.

All animals survived the 2000 mg/kg bw dermal application. No mortalities occurred and body weight development was not impaired.

The acute dermal LD50 value of EDDHMA-Fe was considered to be greater than 2000 mg/kg bw (active ingredient) or greater than 2743 mg/kg bw (test article).

Justification for selection of acute toxicity – oral endpoint
One key study and two supporting studies availabe

Justification for selection of acute toxicity – inhalation endpoint
One key study (GLP) and one supporting study available

Justification for classification or non-classification

Based on the results of the acute oral, dermal and inhalation toxicity studies, EDDHMA-Fe is not subject to classification and labelling for acute toxic effects according to Regulation 1272/2008/EC.