Registration Dossier

Some information in this page has been claimed confidential.

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 January 2015 - 12 February 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
None
Specific details on test material used for the study:
None

Test animals

Species:
rat
Strain:
other: Crl:CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh
- Age at study initiation: approximately 9 weeks old
- Weight at study initiation: from 300 g to 347 g for males and from 213 g to 221 g for females
- Fasting period: during acclimation to the nose-only restraint and during the exposure period
- Housing: Individually in suspended wire-mesh cages. On the day of exposure, the animals were placed in nose-only exposure holding tubes in the animal room, transported to the exposure room, exposed for the requisite duration then returned to their home cages.
- Diet: PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (block), ad libitum
- Water: reverse osmosis-treated water supplying the facility, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.6 to 21.7
- Humidity (%): 40.2 to 47.9
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29 January 2015 To: 12 February 2015

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel, conventional nose-only exposure system with rubber grommets in exposure ports
- Exposure chamber volume: 7.9 L
- Method of holding animals in test chamber: restrained in nose-only exposure holding tubes
- Source and rate of air: a dry, breathing quality, in-house, compressed air source, with a minimum of 12 air changes per hour through the exposure system
- Method of conditioning air: Dry compressed air was supplied to the micronizing and inlet ports of the jet mill to affect aerosolization of the test substance using 2 regulators (model no. 8802K, Coilhose Pneumatics Inc., East Brunswick, NJ). The resulting aerosol from the jet mill was delivered to a 12”×12”×12” settling box where large particles were removed from the aerosol atmosphere. The test substance atmosphere was delivered from the settling box to the nose-only exposure system through 22-mm corrugated respiratory tubing.
- System of generating particulates/aerosols: The test substance was delivered at a constant rate to a jet mill air micronizer (model 00, Jet-O-Mizer, Fluid Energy Equipment Division, Telford, PA) using an auger-type dry material feeder (Schenck AccuRate, Inc., Whitewater, WI). The Accurate feeder was equipped with a ½-inch solid core auger and 2 Syntron electronic vibrators (FMC Technologies, Houston, TX).
- Method of particle size determination: Three aerosol particle size measurements were conducted during the exposure using a 7-stage stainless-steel cascade impactor (model no. 01-130, In-Tox Products, Moriarty, NM). Pre weighed, 22-mm stainless-steel collection substrates were used as collection substrates for stages 1 through 7 and a 25-mm glass-fiber filter (Type A/E, PALL Corporation) was used as the collection substrate for the final stage. Samples were collected at approximately 1.0 L/minute for 1 minute. The filters were re-weighed and the particle size was calculated based on the impactor stage cut-offs.
- Treatment of exhaust air: Exhaust atmosphere was filtered using a Solberg filter (Solberg Manufacturing, Inc., Itasca, IL) prior to entering the facility exhaust system, which consists of activated-charcoal and HEPA-filtration units.
- Temperature, humidity, pressure in air chamber: temperature 19 °C, relative humidity 17%, airflow rate 68.6 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: A nominal exposure concentration was calculated from the total amount of test substance used during the exposure and the total volume of air that passed through the exposure system. The amount of test substance removed using the settling box was not accounted for in the nominal calculation. Actual exposure concentrations were determined approximately every 27-39 minutes using standard gravimetric methods. Samples were collected on pre-weighed, 25-mm glass-fiber filters held in a closed-face filter holder positioned in the animal exposure port of the nose-only exposure system. A measured volume of the exposure atmosphere was pulled through the filter to quantitatively collect aerosol particles. Following sample collection, the filters were re weighed and the concentration calculated as the filter weight difference divided by the sample flow rate and time. Samples were collected at approximately 292-301 mL/minute for 2 minutes.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): mean particle size of 3.3 ± 2.27 µm (MMAD ± GSD)

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
1.5 mg/L (analytical)
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: Each animal was observed immediately following exposure on study day 0, once approximately 1-2 hours following exposure, and once daily thereafter for 14 days for clinical signs of toxicity. Body weights were obtained prior to exposure on study day 0 and on post-exposure days 1, 3, 7, and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination. The major organ systems of the cranial, thoracic, and abdominal cavities were examined for all animals. No tissue or organs were retained and the carcasses were discarded after necropsy.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.5 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: particle size <4 µm
Mortality:
None of the animals died during the exposure or during the 14-day post-exposure observation period.
Clinical signs:
other: Significant clinical observations immediately following exposure included complete closure of the right eye for 1 female and wet red material around the nose for 1 female. Significant clinical observations at the 1-2 hour post-exposure period included par
Body weight:
From study day 0 to 1, all males lost 8 to 13 grams and 4 females lost 1 to 6 grams. From study day 1 to 3, four females lost 2 to 4 grams. From study day 3 to 7, one female lost 3 grams. All males and females surpassed their initial (study day 0) body weight by study days 3 and 14, respectively.
Gross pathology:
Blue areas/blue discoloration was observed in lungs, ears, skin, tail and traches of males and/or females. Blue contents in the stomach and clear fluid contents in the uterus was observed in one female.

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The 4-hour LC50 of FAT 40868/A TE was greater than 1.5 mg/L, the maximum attainable concentration, with a particle size <4 µm.
Executive summary:

Acute inhalation toxicity of FAT 40868/A TE was studied in rats according to OECD 403 and EPA OPPTS 870.1300 guidelines. Five rats/sex were nose-only exposed for 4 hours to 1.5 mg/L aerosol, the maximum attainable concentration, with a particle size <4 µm. Rats were observed for a 14 days period. The mean particle size of the aerosol (MMAD) was 3.3 ± 2.27 µm. No mortality was observed. Clinical observations included (partial) closure of the eyes and red material around the nose following exposure, and increased respiration and vocalizaton upon handling until study day 11. Body weight loss was observed until day 7, but all animals surpassed their initial body weight by study day 14. Macroscopic findings at necropsy included blue discoloration of the lungs, ears, skin and tail, blue areas on lungs and trachea, blue contents in the stomach and clear fluid contents in the uterus. The 4 -hour LC50 of FAT 40868/A TE in rats is >1.5 mg/L, the maximum attainable aerosol concentration with a particle <4 µm.