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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Version / remarks:
June, 2018
Deviations:
no
Remarks:
No deviations occurred that negatively impacted the results of the study.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reactionmass of dodecan-2-yl prop-2-enoate and dodecan-3-yl prop-2-enoate and dodecan-4-yl prop-2-enoate
EC Number:
947-818-2
Cas Number:
1612783-92-2
Molecular formula:
C15H28O2
IUPAC Name:
Reactionmass of dodecan-2-yl prop-2-enoate and dodecan-3-yl prop-2-enoate and dodecan-4-yl prop-2-enoate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Lot 6
- Expiration date of the lot/batch: 04 October, 2019
- Purity test date: 04 October, 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Kept in a room with controls set to maintain 18°C to 24°C
- Stability under test conditions: Stable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None

FORM AS APPLIED IN THE TEST: Aeorosol

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
ca. 1.8 - ca. 2.4 µm
Geometric standard deviation (GSD):
1.7
Remarks on MMAD:
The MMAD (Mean MMAD ranged from 1.8-2.4 microsn) was often between 2.0 and 2.4 microns across all groups (range 1.2 to 2.7 microns). In addition, the GSD for all three exposure levels ranged from 1.40 – 2.09, thus providing a size distribution that exposed the entire respiratory tract.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: A liquid droplet aerosol exposure of the test substance was generated using a single-jet Collison nebulizer. One nebulizer was used for each test substance exposure system. Dry compressed air from the facility compressed air source was supplied to each nebulizer to effect aerolization of the test substance. Aerosol from the outlet of each nebulizer was directed to a settling box, where larger particles within the exposure atmosphere were removed prior to entering the CNOS. Aerosol was then directed from the settling box to a “T” fitting, where a portion of the concentration aerosol was directed towards facility exhaust (siphon). The remainder was directed towards the inlet of the exposure system, where it mixed with humidified supply air prior to entering the venturi tube at the top of the exposure system.
- Method of holding animals in test chamber: Restraining tubes
- Source and rate of air: All nose-only systems were operated under dynamic conditions with airflow rates through the system based on air requirements for aerosol generation and dilution and provided a sufficient volume of air for the number of animals exposed. Air supplied to the nose-only systems was provided from the Inhalation Department breathing quality, in-house compressed air source and a HEPA- and charcoal-filtered, temperature- and humidity-controlled supply air source.
- Method of conditioning air: The in-house compressed air source is HEPA and charcoal filtered as well as humidity-controlled.
- System of generating particulates/aerosols: A liquid droplet aerosol exposure of the test substance was generated using a single-jet Collison nebulizer. One nebulizer was used for each test substance exposure system. Dry compressed air from the facility compressed air source was supplied to each nebulizer to effect aerolization of the test substance. Aerosol from the outlet of each nebulizer was directed to a settling box, where larger particles within the exposure atmosphere were removed prior to entering the CNOS.
- Temperature, humidity, pressure in air chamber: Exposure system temperature and relative humidity were continually monitored and the average temperature and relative humidity of the exposure atmosphere was 22 ± 3°C and 50 ± 20%.
- Air flow rate: All nose-only systems were operated under dynamic conditions with airflow rates through the system based on air requirements for aerosol generation and dilution and provided a sufficient volume of air for the number of animals exposed.
- Air change rate: Each exposure system temperature, relative humidity, and ventilation rate was continually monitored and recorded at approximately 60-minute intervals during each exposure. Oxygen content of the exposure atmospheres was measured during the method development
phase of the study and was 20.9% for all groups.
- Method of particle size determination: Aerosol particle size measurements were conducted using a 7-stage stainless steel cascade impactor.
- Treatment of exhaust air: All nose-only system exhaust was passed through a Solberg canister filter prior to entering the facility exhaust system, which consists of redundant exhaust blowers preceded by activated charcoal and HEPA-filtration units.

TEST ATMOSPHERE
- Brief description of analytical method used: Exposure concentrations were measured using standard gravimetric methods. Samples were collected on pre-weighed 25-mm glass-fiber filters held in a filter holder positioned in the approximate animal breathing zone of the exposure system. Following each sample collection, the filters were re-weighed and the mass concentration (mg/m3) of test substance aerosol was calculated from the filter weight difference divided by the sample volume. The sample volume was calculated by multiplying the sample flow rate by the duration of the sampling period. One sample was collected weekly from the control exposure system and daily from the test substance exposure systems during each animal exposure period.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure concentrations were measured using standard gravimetric methods. Samples were collected on pre-weighed 25-mm glass-fiber filters held in a filter holder positioned in the approximate animal breathing zone of the exposure system. Following each sample collection, the filters were re-weighed and the mass concentration (mg/m3) of test substance aerosol was calculated from the filter weight difference divided by the sample volume. The sample volume was calculated by multiplying the sample flow rate by the duration of the sampling period. One sample was collected weekly from the control exposure system and daily from the test substance exposure systems during each animal exposure period.
Duration of treatment / exposure:
The objective of this study was to evaluate the potential toxicity of MTDID 44430 when administered daily by nose-only inhalation to Sprague Dawley rats on a 5-day per week basis for 13 weeks (minimum of 65 exposures).
Frequency of treatment:
5-days per week.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/m³ air (analytical)
Remarks:
Control
Dose / conc.:
16.1 mg/m³ air (analytical)
Dose / conc.:
65 mg/m³ air (analytical)
Dose / conc.:
201 mg/m³ air (analytical)
No. of animals per sex per dose:
15 (0, 201 mg/m^3), 10 (16.1, 65 mg/m^3)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Rang-finding study.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: Control and High-dose.
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Cage side observations were performed daily, beginning on Day 1 and lasting throughout the exposure and recovery periods. During the exposure period, these observations were performed pre-exposure and 0 to 1 hour (+ 0.25 hour) postexposure. On nonexposure days, observations were performed once daily. Animals were not removed from the cage during observation, unless necessary for identification or confirmation of possible findings.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were removed from the cage, and a detailed clinical observation was performed within 4 days of receipt, 1 week (± 2 days) prior to randomization, on the day of randomization, on Day 1 (prior to exposure), weekly (± 2 days) during the study period, and on the day of the scheduled necropsies.

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually within 4 days of receipt, 1 week (± 2 days) prior to randomization, on the day of randomization, on Day 1 (prior to exposure), weekly (± 2 days) during the study period, on the day prior to the first day of scheduled necropsies, and on the day of the scheduled necropsies. A fasted weight was recorded on the day of the scheduled necropsies.

FOOD CONSUMPTION
- Food consumption was quantitatively measured weekly (± 2 days) starting on Day 1 and continued throughout the dosing and recovery periods

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ocular examinations were conducted by a board certified veterinary ophthalmologist during the pretreatment period (Day -11) and near the end of the dosing period (Day 82). An indirect ophthalmoscope and slit lamp biomicroscope were used to examine the ocular structures. Prior to examination an appropriate mydriatic agent was used for pupillary dilation.
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All
- Parameters checked:
differential leukocyte count
erythrocyte count
total hemoglobin
hematocrit
mean corpuscular volume
mean hemoglobin
mean corpuscular hemoglobin concentration
platelet count
red cell distribution width
reticulocyte count
total leukocyte count

CLINICAL CHEMISTRY: Yes / No / Not specified
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All
- Parameters checked:
Alanine aminotransferase
Albumin
A/G ratio (calculated)
Alkaline phosphatase
Aspartate aminotransferase
Calcium
Chloride
Creatinine
Gamma glutamyltransferase
Globulin (calculated)
Glucose
Phosphorus
Potassium
Sodium
Sorbitol dehydrogenase
Total bilirubin
Total cholesterol
Total protein
Triglycerides
Urea nitrogen
Appearance

URINALYSIS: Yes
- Time schedule for collection of urine: At necropsy (Days 92/93 for main study, Days 120/121 for recovery groups)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked:
Bilirubin
Color and clarity
Glucose
Ketones
Occult blood
pH
Protein
Specific gravity
Volume

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: FOB assessments were recorded for all animals near the end of the exposure period (Week 13).
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / body weight and temperature /

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Adrenal glands (2)
Aorta
Bone with marrow
Femur (with joint)
Sternum
Bone marrow smear (from femur)
Brain
Cervix
Epididymides (2)
Eyes with optic nerves (2)
Gastrointestinal tract
Esophagus
Stomach
Duodenum
Jejunum
Ileum
Cecum
Colon
Rectum
Harderian glands (2)
Heart
Kidneys (2)
Larynx
Liver (sections of 2 lobes)
Lungs (including bronchi, fixed by constant pressure inflation with fixative)
Lymph nodes
Axillary (2)
Mandibular (2)
Mesenteric
Nasal cavity with turbinates
Ovaries (2) with oviducts
Pancreas
Peripheral nerve (sciatic)
Peyer’s patches
Pharynx
Pituitary
Prostate
Salivary glands (mandibular [2])
Seminal vesicles (2)
Skeletal muscle (quadriceps)
Skin with mammary glandg
Spinal cord (cervical, thoracic, lumbar)
Spleen
Testes (2)
Thymus
Thyroid (with parathyroids [2])
Tongue
Trachea
Urinary bladder
Uterus
Vagina
Gross lesions (when possible)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Mortality:
no mortality observed
Description (incidence):
No mortality was observed during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Haematological findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Neuropathological findings:
no effects observed
Description (incidence and severity):
There were no test article-related changes.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related microscopic changes were limited to the nasal level III females exposed to 65 and 201 mg/m3 at the terminal and recovery time points which was characterized by sporadic, minimal to mild focal olfactory epithelial degeneration. Since the lesions were sporadic in nature and only minimal to mild in severity, these changes were considered non-adverse.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no test article-related changes.

Effect levels

Key result
Dose descriptor:
NOAEC
Effect level:
201 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
neuropathology
ophthalmological examination
organ weights and organ / body weight ratios
urinalysis

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, a NOAEC of 201mg/m3 was established.
Executive summary:

The subchronic repeated dose toxicity potential of MTDID 44430 was evaluated in a 90 -day inhalation study. The study was conducted according to OECD 413 in compliance with OECD GLP. Rats were exposed nose-only to MTDID 44430 6-hours/day, 5-days/week for 13 weeks at target concentrations of 0 (control; n=15/sex), 15 (n=10/sex), 65 (n=10/sex), and 200 mg/m3 aerosol (n=15/sex). Achieved mean actual exposure concentrations in the 15, 65, and 200 mg/m3 groups were 16.1, 65, and 201 mg/m3, respectively. The MMAD (GSD) for the exposure atmospheres were 1.8 µm (1.77), 2.0 µm (1.62), and 2.4 µm (1.80), respectively. Ten animals/sex/group were assigned to the terminal necropsy; the remaining 5 animals/sex in the control and 200mg/m3 dose groups were assigned to a minimum of 4 weeks of recovery. The following parameters and endpoints were evaluated in this study: clinical signs, body weights, body weight gains, food consumption, functional observational battery, motor activity, ophthalmology, clinical pathology parameters (hematology, coagulation, serum chemistry, and urinalysis), bronchoalveolar lavage fluid (BALF) evaluation (chemistry and cytology), gross necropsy findings, organ weights, and histopathologic examinations. The following organ tissues were collected and evaluated for histology and histopathology at the control and 200 mg/m3 test group animals (* denotes that the organs were weighed): adrenal glands*, aorta, bone with marrow, femur (with joint), sternum, bone marrow smear (from femur), brain*, cervix, epididymides*, eyes with optic nerves, gastrointestinal tract, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, harderian glands, heart*, kidneys*, larynx, liver* (sections of 2 lobes), lungs* (including bronchi), lymph nodes, axillary, mandibular, mesenteric, nasal cavity with turbinates, ovaries with oviducts*, pancreas, peripheral nerve, peyer’s patches, pharynx, pituitary gland*, prostate*, salivary glands, seminal vesicles, skeletal muscles, skin with mammary gland (female only; males had skin sections taken from the same anatomic area), spinal cord (cervical, thoracic, lumbar), spleen*, testes*, thymus*, thyroid (with parathyroids)*, tongue, trachea, bladder, uterus*, vagina, and gross lesions (when possible). Additionally, selected tissues (kidney, liver, thyroid, and respiratory tract [lungs, larynx, pharynx, trachea, and nasal cavity with turbinates]) were prepared from all animals in the 15 and 65 mg/m3 test groups for histology. All animals survived to the scheduled necropsies. There were no test substance-related clinical observations of toxicity, nor were there any adverse effects in the FOB or motor activity parameters. No effects on BALF parameters (chemistry and cytology), hematology, coagulation, serum chemistry, urinalysis, or organ weights were noted. There were no test substance-related ophthalmic or macroscopic findings. Test substance-related microscopic changes were limited to the nasal level III females exposed to 65 and 201 mg/m3 at the terminal and recovery time points which was characterized by sporadic, minimal to mild focal olfactory epithelial degeneration. Since the lesions were sporadic in nature and only minimal to mild in severity, these changes were considered non-adverse. Based on the results of this study, a NOAEC of 201mg/m3 (aerosol) was established.