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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
September 2009
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Sodium [N-[2-[bis(carboxylatomethyl)amino]ethyl]-N-(2-hydroxyethyl)glycinato(3-)]zincate(1-)
EC Number:
275-554-1
EC Name:
Sodium [N-[2-[bis(carboxylatomethyl)amino]ethyl]-N-(2-hydroxyethyl)glycinato(3-)]zincate(1-)
Cas Number:
71501-24-1
Molecular formula:
C10H15N2O7Zn.Na
IUPAC Name:
Reaction mass of Ammonium;Sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate;zinc and Ammonium;Sodium;2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetate;zinc and Ammonium;Sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetate;zinc

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Han
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals, approximately 11 weeks old
- Weight at study initiation: Males: 308 to 326 / Females: 191 to 225 g
- Fasting period before study: no
- Housing:
On arrival and following assignment to the study, animals were group housed (up to 5 animals of the same sex and same exposure group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles. The room(s) in which the animals were kept were documented in the study records.
Animals were separated during designated procedures/activities. Each cage was clearly labeled.
- Diet (e.g. ad libitum):
Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility.
It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water (e.g. ad libitum):
Municipal tap-water was freely available to each animal via water bottles.
Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
It is considered that there were no known contaminants in the water that would interfere with the objectives of the study.
- Acclimation period:
The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20 to 22°C with an actual daily mean relative humidity of 44 to 53%. A 12 hour light/12 hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.

IN-LIFE DATES: From: 25/01/2018 To: 08/02/2018

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
4 µm
Geometric standard deviation (GSD):
>= 1.9 - <= 2
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The design of the exposure chamber is based on the directed flow nose only inhalation chamber (Am. Ind. Hyg Assoc. J. 44(12): 923-928, 1983).
- Exposure chamber volume: /
- Method of holding animals in test chamber: polycarbonate restraining tubes
- Source and rate of air: The main inlet of the test atmosphere was located at the top section and the main outlet was located at the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal. The number of animal sections and number of open inlets were adapted to the air flow in such a way that at each animal port the theoretical air flow was at least 1 L/min.
- Method of conditioning air: /
- System of generating particulates/aerosols:
Administering the test item to a stream of pressurized air using a combination of a spiral feeder (Randcastle Extrusion Systems, Cedar Grove, NJ, USA) with a vibrator attached and air mover (AIR-VAC, Milford, CT, USA) generated an aerosol. The aerosol was passed through a series of two cyclones, allowing larger particles to settle. The primary aerosol was diluted with pressurized air before it entered the exposure chamber (Figure 1.1). The mean total airflow was 17 L/min.
From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Method of particle size determination:
The particle size distribution was characterized twice during each exposure period. The samples were drawn with a flow of 2 L/min. from the test atmosphere through a tube mounted in one of the free animal ports of the exposure chamber (Figure 1.2). The samples were collected with an 8 stage Marple personal cascade impactor containing fiber glass filters (TE-290-GF. Tisch Environmental, Cleves, Ohio, USA) and a fiber glass back-up filter (SEC-290-F1, Westech, Upper Stondon, Bedfordshire, England). Amounts of test item collected were measured gravimetrically. Subsequently the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) were determined based on OECD guidance document No 39. Graphs of the cumulative mass of test item collected (percentage of total collected) against the cut points of the impactor stages were drawn on log-normal paper. When drawing the graphs more weight was given to the cut points where the cumulative mass sampled was within the range of 5 to 95%. The Mass Median Aerodynamic Diameter (MMAD), i.e. the particle size where 50% of the particle mass was borne by particles smaller than the MMAD and the PS84, (the particle size where 84% of the particle mass was borne by particles smaller than the PS84 was read from the graph. The geometric standard deviation (gsd) was calculated as PS84 / MMAD.

- Temperature, humidity, pressure in air chamber:
The temperature and relative humidity were measured with a humidity and temperature indicator (E+E Elektronik, Engerwitzdorf, Austria) and recorded after the animals were connected to the exposure chamber and at 30 minute intervals after initiation of exposure. The probe was inserted in a tube mounted in one of the free animal ports of the exposure chamber (Figure 1.2). The temperature of the atmosphere during the exposure was between 20.7 and 21.7oC. The relative humidity was between 18 and 21% which was considered appropriate for this relatively short 4 hours exposure duration.

TEST ATMOSPHERE
- Brief description of analytical method used:
A total of 20 representative samples were taken for determination of the actual concentration during exposure at 5 mg/L. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the exposure chamber. Samples were drawn through a glass fiber filter (type APFC04700, Millipore, Billerica, MA, USA). Sample volumes were measured by means of a dry gas meter (type G 1.6, Actaris Meterfabriek B.V., Dordrecht, The Netherlands). The collected amount of test item in the air sample was measured gravimetrically. Subsequently the time-weighted mean concentration with the standard deviation was calculated.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): air
- Concentration of test material in vehicle (if applicable): 5 mg/L
- Justification of choice of vehicle: standard protocol
- Lot/batch no. (if required): /
- Purity: /

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5 mg/L
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.
Animals were checked for mortality, behavioral signs of distress and effects on respiration at least three times during exposure.
Post exposure observations were performed at periodic intervals on the day of exposure (at least two times) and once daily thereafter. The observation period was 14 days.
Animals were weighed individually on Day 1 (pre exposure), 2, 4 and 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (animals were checked for mortality, behavioral signs of distress and effects on respiration), body weight,

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.1 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred
Clinical signs:
other: During exposure, no clinical signs were seen (not presented in the table). After exposure, hunched posture was seen for all animals 1 hour after exposure. The animals had recovered from the clinical signs within 3 hours after exposure.
Body weight:
Overall body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The inhalation LC50, 4h value of Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA in Wistar rats was established to exceed 5 mg/L.
Based on these results Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Executive summary:

The objective of this study was to assess the acute inhalation toxicity of Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA in rats of both sexes in rats following a single 4 hour nose-only exposure to one or more defined concentrations. Animals were retained for a 14 day post exposure observation period.

 

The study was carried out based on the guidelines described in:

·      Acute Inhalation Toxicity- Acute Toxic Class Method, September 2009.

 

Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA was administered as a dust by nose only inhalation for 4 hours to one group of three male and three female Wistar rats at a target concentration of 5 mg/L. Mortality and clinical signs were observed daily during the observation period and body weights were determined on Days 1, 2, 4, 8 and 15. Macroscopic examination was performed after terminal sacrifice (Day 15).

 

The time-weighted mean actual concentration was 5.1 ± 0.13 mg/L. The nominal concentration was 203 mg/L. The generation efficiency was 2.5%.

The mass median aerodynamic diameter (MMAD) was 4.0 µm and 4.0 µm with a geometric standard deviation (gsd) of 1.9 and 2.0, respectively. 

No mortality occurred.

During exposure, no clinical signs were seen. After exposure, hunched posture was seen for all animals 1 hour after exposure. The animals had recovered from the clinical signs within 3 hours after exposure. 

Overall body weight gain in males and females was within the range expected for rats of this strain and age used in this type of study and were therefore considered not indicative of toxicity.

No abnormalities were found at macroscopic post mortem examination of the animals.

 

The inhalation LC50, 4hvalue of Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA in Wistar rats was established to exceed 5 mg/L.

Based on these results Reaction mixture of ZnEDTA, ZnDTPA and ZnHEEDTA does not have to be classified and has no obligatory labelling requirement for acute inhalation toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).