Registration Dossier

Toxicological information

Acute Toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
2009
Deviations:
no
GLP compliance:
yes
Test type:
traditional method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
Name of test material (as cited in study report: MTDID 20422
- Substance type: Pure active substance
- Physical state: Liquid
- Analytical purity: 99.99%
- Purity test date: 02/16/2011
- Expiration date of the lot/batch: 02/16/2013
- Storage condition of test material: At room temperature in the dark.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Lot 1
- Expiration date of the lot/batch: 05 June, 2019
- Purity test date: 05 June, 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Kept in a controlled temperature area set to maintain 18-24 C
- Stability under test conditions: Stable

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Raleigh
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 11-12 weeks
- Weight at study initiation: 372-401 grams
- Fasting period before study: None
- Housing: All animals will be individually housed following receipt in suspended wire-mesh cages in an environmentally controlled room. Animals will be housed in clean cages elevated above cage board or other suitable material that will be changed at least three times each week. The cages will be cleaned and changed routinely at a frequency consistent with maintaining good animal health. All animals will be maintained in accordance with the Guide for the Care and Use of Laboratory Animals. The facilities at Charles River Ashland are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International). Due to the need for cage pan observations (fecal and/or urinary) in an acute study, animals will be single-housed in wire-mesh caging.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet 5002 (block) will be offered ad libitum during the study, except during acclimation to restraint and the exposure period. Each lot utilized will be identified and recorded. SOPs provide specifications for acceptable levels of
heavy metals and pesticides that are reasonably expected to be present in the diet without interfering with the purpose or conduct of the study. No contaminants are reasonably expected to be present that would interfere with the objectives of the study; therefore, no testing will be conducted as part of the study.
- Water (e.g. ad libitum): Reverse osmosis-treated water will be available ad libitum, except during acclimation to restraint and the exposure period. Filters servicing the automatic watering system will be changed regularly according to SOPs. The municipal water supplying the laboratory will be analyzed for contaminants according to SOPs. No contaminants are reasonably expected to be present that would interfere with the objectives of the study, therefore, no testing will be conducted as part of the study.
- Acclimation period: At least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1-23.0
- Humidity (%): 40.3-53.3
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 03 November, 2017 To: 04 December, 2017

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted using a 0.74-L directed-flow (flow-past) nose-only exposure system (CH Technologies; Westwood, NJ). Animals were restrained in nose-only exposure holding tubes during exposure. Airflow rates through the system were set to provide the airflow required for generation and the dilution airflow, and to provide sufficient volumes for the number of animals to be exposed and for exposure atmosphere sampling.
- Exposure chamber volume: 0.74 L
- Method of holding animals in test chamber: Animals were restrained in nose-only exposure holding tubes during exposure.
- Source and rate of air: Airflow rates through the system were set to provide the airflow required for generation and the dilution airflow, and to provide sufficient volumes for the number of animals to be exposed and for exposure atmosphere sampling. Airflow to the exposure system was provided using a dry, breathing quality, in-house, compressed air source.
- Method of conditioning air: Humidified air was delivered to the nose-only exposure system using a Coilhose regulator (Model No. 8802K) and was controlled using a Linde rotameter-type flowmeter (Model No. FM4349, Union Carbide Corp.; Danbury, CT). To produce humidified air, dry compressed air passed through a muffler-type bubbler submerged in a 2-L Erlenmeyer flask filled with deionized water.
- Treatment of exhaust air: The exhaust atmosphere passed through the facility exhaust system,which consists of redundant exhaust blowers preceded by activated-charcoal and HEPA-filtration units.
- Temperature, humidity, pressure in air chamber: 22-23 C, 46-66 % humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: Exposure atmosphere were sampled and analyzed at approximately every 5 to 30 minute using a gas chromatograph (GC). Samples of the exposure atmosphere were collected from the approximate animal-breathing zone of the nose-only exposure system and directed toward an external multi-position valve (Model E16, Valco Instruments Co., Inc.; Houston, TX) and a Hewlett Packard Model 3396 Series II integrator. Gas sampling injection onto the chromatography column occurred via an internal gas-sampling valve with a sample loop.
The chromatograph was displayed and the area under the sample peak was calculated and stored. The concentration in parts per million (ppm) was calculated using a ln-quadratic formula based on the GC calibration curve.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
148 mg/L (13,956 ppm), 213 mg/L (20,086 ppm)
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 for mortality at the approximate midpoint of exposure and twice daily thereafter for 14 days (once in the morning and once in the afternoon, except on the day of scheduled necropsy). All animals in the 13,956 ppm group were observed once during the exposure, where only clinical signs visible in nose-only exposure restraint tubes were recorded. Each animal in the 13,956 and 20,086 ppm groups was observed following exposure upon unload from the nose-only tubes on Study Day 0, once 1-2 hours post-exposure, and once daily thereafter for 14 days for clinical signs of toxicity. Observations were recorded each day and included, but were not limited to: changes in the skin and fur, eyes and mucous membranes and also changes to the respiratory, circulatory, autonomic and central nervous systems, somatomotor activity, and behavior pattern. Body weights were obtained prior to exposure on Study Day 0 and on Post-Exposure Days 1, 3, 7, and 14. A final body weight was collected for all animals that died on study. Animals at the scheduled necropsy were euthanized by isoflurane anesthesia followed by exsanguination and subject to necropsy. 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.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weights, gross necropsy

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 148 - < 213 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
The overall mortality incidence for the 213 mg/L (20,086 ppm) exposure was 8/10, with 3 male and all 5 female rats found dead by/on Study Day 2. All rats exposed to 148 mg/L (13,956 ppm) of the test article survived the 4-hour exposure and the subsequent 14-day observation period.
Clinical signs:
213 mg/L: Rats exposed to 213 mg/L test article demonstrated labored and shallow respiration, decreased respiration rates, dried red material in the facial area, unkempt appearance, red material around the mouth, nose, eye, trunk and forelimb, and yellow material on the trunk, rump, urogenital area, and anogenital area.

148 mg/L: Clinical observations of toxicity following the 148 mg/L (13,956 ppm) exposure included sporadic reports of increased respiration rate and dried red facial area for up to 2 days following the exposure.
Body weight:
213 mg/L: On Study Day 1, surviving males lost 46 to 52 g and surviving females lost 34 to 40 g in body weight. On Study Day 3, one surviving male lost 1 g and the second gained 4 g, with these 2 surviving males demonstrating weight gains over the remainder of the observation period.

148 mg/L: On Study Day 1, male rats lost 4 to 24 g and females lost 1 to 21 g of body weight. All exposed animals demonstrated body weight gains from Study Day 3 and for the remainder of the observation period.
Gross pathology:
213 mg/L: Gross necropsy of the 8 animals found dead revealed red fluid contents in the thoracic cavity (4/8), dark red discoloration of the lungs (4/8), white areas on the lungs (3/8) and/or white areas on the prostate (1/8). The 2 rats that survived the 213 mg/L (20,086 ppm) exposure to the end of the observation period demonstrated no macroscopic findings at the scheduled necropsy.

148 mg/L: No findings were noted upon gross necropsy of the animals exposed to 148 mg/L (13,956 ppm) at the scheduled necropsy.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the 4-hour LC50 for the test article is greater than 148 mg/L (13, 956 ppm) but less than 213 mg/L (20, 086 ppm).
Executive summary:

The acute inhalation lethality potential of the test article was evaluated in male and female Sprague Dawley rats.  The study was conducted according to OECD 403 (2009) in compliance with OECD GLP. Rats (5/sex/dose) received nose-only exposure to 148 mg/L (13,956 ppm) or 213 mg/L (20,086 ppm) test article (vapor) for 4 hours followed by a 14-day observation period. Rats exposed to 213 mg/L (20,086 ppm) test article demonstrated labored and shallow respiration, decreased respiration rates, dried red material in the facial area, unkempt appearance, red material around the mouth, nose, eye, trunk and forelimb, and yellow material on the trunk, rump, urogenital area, and anogenital area. The overall mortality incidence for the 213 mg/L (20,086 ppm) exposure was 8/10, with 3 male and all 5 female rats found dead by/on Study Day 2. Gross necropsy of the 8 animals found dead revealed red fluid contents in the thoracic cavity (4/8), dark red discoloration of the lungs (4/8), white areas on the lungs (3/8) and/or white areas on the prostate (1/8). The 2 rats that survived the 20,086 ppm exposure to the end of the observation period demonstrated no macroscopic findings at the scheduled necropsy. All rats exposed to 148 mg/L (13,956 ppm) test article survived the 4-hour exposure and the subsequent 14-day observation period. Clinical observations of toxicity following the 148 mg/L (13,956 ppm) exposure included sporadic reports of increased respiration rate and dried red facial area for up to 2 days following the exposure. No findings were noted upon gross necropsy of the animals exposed to 148 mg/L (13,956 ppm) at the scheduled necropsy.  Under the conditions of this study, the 4-hour LC50 for the test article is greater than 148 mg/L (13,956 ppm) but less than 213 mg/L (20,086 ppm).