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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 412, dose range finding study
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium dihydrogen ethylenediaminetetraacetate
EC Number:
205-358-3
EC Name:
Disodium dihydrogen ethylenediaminetetraacetate
Cas Number:
139-33-3
Molecular formula:
C10H14N2Na2O8
IUPAC Name:
disodium dihydrogen 2,2',2'',2'''-(ethane-1,2-diyldinitrilo)tetraacetate
Test material form:
solid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.: of test material: 06088797V0

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
Age: 7 weeks (approx)
Identification: Tattooing of ears
All animals free of disease and clinical signs
Rats housed together (5 animals per cage) in Polysulfon cages
Bedding: Type Lignocel fibres, dust free bedding
Woodne gnawing blocks for enrichment
Rooms: Fully ariconditioned, temperature range 20 to 24 degrees celcius, 30 to 70% humidity
Light/dark cycle of 12 hours (6 am to 6pm light, 6pm to 6 am dark)
Food, drinking water and bedding/enrichment materials were analysed for chemical and microbiological contaminants.

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Remark on MMAD/GSD:
MMAD / GSD: MMAD : 2.0 - 2.7 µm
GSD: 2.0 - 2.22
Details on inhalation exposure:
A dust aerosol was generated using a dust generator and compressed air inside a mixing stage mixed with conditioned dilution air and passed into the inhalation system. The test substance was mixed with Aerosil R972 prior to facilitate aerosol generation.

The inhalation atmosphere was maintained inside aerodynamic exposure systems consisting of cylindrical inhalation chamber made of stainless steel sheeting and cone shaped outlets and inlets. The rats were restrained in glass exposure tubes with their snouts projecting into the inhalation chamber.
The animals did not ave access to feed or water during the exposure period.
Analytical verification of test atmosphere concentrations:
yes
Remarks on duration:
Exposures: 6 hours per day High dose group (1000 mg/m³) was exposued for 1 day only All other groups were exposed for 5 consecutive days
Concentrations:
Concentrations of the inhalation atmospheres were analyzed using gravimetry. Daily means were calculated based on 2 measured samples per concentration and exposure. From the Daily mean values of each concentration, mean concentrations and standard deviations were derived.
Consistency of concentrations in each inhalation system was continuously monitored using scattered light photometry.
Particle size analysis was conducted using a cascade impactor.
The concentrations were [mg/m³]:
- dose group one: 30 (nominal), 33.3 +- 2.3 (actual)
- dose group one: 300 (nominal), 320 +- 27 (actual)
- dose group one: 1000 (nominal), 1103 +- 52 (actual)
No. of animals per sex per dose:
10 animals per dose group
An additional 10 animals for the high dose group and control
Control animals:
yes
Details on study design:
The animals were exposed to a respirable dust aerosol for 6 hours per day for 5 consecutive days. The exception was the high dose group (1000mg/m³) where exposure was for one day only due to mortality observed.
In the control, low and mid dose groups, 5 animals were sacrificed on the day after the last exposure period and 5 were sacrificed 17 days after the last exposure.
10 additional control animals and the 14 surviving high dose group animals were sacrificed on day 14 of the study (14 days after first exposure).

Results and discussion

Effect levels
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
>= 1 103 mg/m³ air (analytical)
95% CL:
>= 1 051 - <= 1 155
Exp. duration:
6 h
Mortality:
6 deaths in the high dose group on days 0 and 1. Accelerated respiration, respiration sounds, piloer
ection, red encrusted nose, hunched position; Mid dose group - accelerated respiration, respiration
sounds, piloerection, reduced fur care

Any other information on results incl. tables

Detials on Results

Histopathology results:

High dose: Multifocal hemorraghes in the lungs; Inflammatory cell infiltrates

Mid dose:

Larynx: laryngeal, epithelial necrosis, multifocal, in various levels of the larynx

Inflammatory cell infiltrates in various levels of the larynx

laryngeal squamous metaplasia, multifocal, in various levels of the larynx

Regenerative hyperplasia of the laryngeal epithelium, multifocal, in various levels of the larynx

Lungs: Regenerative hyperplasia of bronchiolar epithelium (predominantly: medium bronchi, terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells

Low dose:

Larynx: Laryngeal, epithelial necrosis, multifocal, at the base of the epiglittis (level 1)

Inflammatory cell infiltrates at the base of the epiglottis (level 1)

Lungs: Regenerative hyperplasia of the bronchiolar epithelium (predominantly medium bronchi and terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells.

There were no histopathological findings in any of the recovery group animals. Thus all pathology was reversible within the recovery period.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In a repeated dose range finding study rats were exposed to aerosol of the test substance.
6 death occured in the high dose group. No deaths occured in the middle dose group (300 mg/m³).
Taking into account that the exposure duration was significantly extended compared to an acute toxicity study it is reasonable that less than 50% of the animals of the highest dose group would die when exposed to the substance once for 4 hours.
Thus the LC50 can be stated as:
LC50 > 1000 mg/m³ (nominal)
LC50 > 1103 mg/m³ (actual)
Executive summary:

Inhalation exposure to 1000 mg/m3 disodium EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant lesions inthe larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dosegroup a no observed effect level could not be determined.


In a subacute repeated dose toxicity study (BASF, 2009) 10 male Wistar rats per dose were exposed to a respirable dust aerosol of Na2H2EDTA for 6 hours per day for 5 consecutive days at concentrations of 0, 30, 300, 1000 mg/m³ air (also see capter 7.5).

Exposure in the high dose group (1000 mg/m3) was for one day only due to mortality observed. Inhalation exposure to 1000 mg/m³ disodium EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates.

Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dose group a no observed effect level could not be determined.

The LOAEC was considered to be 30 mg/m³ air.