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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 2019 - January 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
yes Humidity values lower than what is suggested in the test guidelines to prevent disintegration of the reactive diisocyanate moiety. This deviation had no apparent negative impact on the outcome of the study.
GLP compliance:
yes (incl. QA statement)
Test type:
traditional method

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol
EC Number:
701-041-3
Molecular formula:
C8H6NO [C7H5NO [C3H6O]n C8H7NO ]m C7H4NO with 2<=n<20 and 0<=m<=3
IUPAC Name:
1,1'-Methylenebis(4-isocyanatobenzene) and oligomeric reaction products of 1,1'-methylenebis(4-isocyanatobenzene) and oxydipropanol and oligomerization reaction products of oxydipropanol
Test material form:
aerosol dispenser: spray aerosol
Details on test material:
Molecular Formula
4,4’-MDI/DPG: Variable; C14H10NO[C21H24N2O5]nNCO; n = 0, 1, 2, 3
MDI: C15H10N2O2
Molecular Weight
4,4’-MDI/DPG: Variable, relative MW = 400 g/mol
MDI: 250.3 g/mol
Specific details on test material used for the study:
Lot 0020238005 was used to conduct acute inhalation toxicity exposures to 0.78 and 1.11 mg 4,4’-MDI/DPG per liter of air. Subsequently, the laboratory was unable to completely dissolve the solids in some of the remaining test material containers upon warming to any further extent. Therefore, an additional lot of test material, Lot 35428145, was provided to conduct the acute inhalation toxicity exposure to 1.53 mg 4,4’-MDI/DPG per liter of air.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (CRL) (Raleigh, North Carolina)
- Age at study initiation: Animals were seven weeks at arrival and 8-9 weeks at the time of exposure.-
- Housing: Upon arrival animals were housed two-three per cage in stainless steel cages. Cages had solid floors with corncob bedding. Cages contained a hanging feeder and a pressure
activated lixit valve-type watering system.
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis Missouri) provided ad libitum
- Water (e.g. ad libitum): drinking-quality municipality tap-water provided ad libitum via lixit valve-type watering system
- Acclimation period: The animals were acclimatized to the animal room conditions for at least seven days before use

ENVIRONMENTAL CONDITIONS:
Temperature: 22°C with a range of 20°C-26°C
Humidity: 50% with a range of 30-70%
Air Changes: 10-15 times/hour (average)
Photoperiod: 12-hour light/dark (on at 6:00 a.m. and off at 6:00 p.m.)

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: Test article was aerosolized neat as liquid aerosol; no vehicle was thus used
Mass median aerodynamic diameter (MMAD):
>= 2.98 - <= 3.16 µm
Geometric standard deviation (GSD):
>= 1.54 - <= 1.92
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dow-modified ADG nose-only chamber [
- Exposure chamber volume: 42-liter,
- Method of holding animals in test chamber:Tubes accomodating the animals size were used.
- Source and rate of air: Dry, compressed, filtered air supplied to the chamber was preheated with a flameless heat torch (FHT-4, Master Appliance Corporation, Racine, Wisconsin). Airflow through the chamber was determined with a manometer which measured the pressure drop across a calibrated orifice plate and was maintained at approximately 13-16 liters per minute,
which was sufficient to provide the normal concentration of oxygen to the animals and approximately 19-23 air changes per hour.
- System of generating particulates/aerosols: A liquid aerosol of 4,4’-MDI/DPG was generated by metering the test material with a syringe pump (KD Scientific Inc., Holliston, MA) into a stainless steel, 4-jet BLAM (Blaustein Atomizing Module, CH Technologies, Westwood, New Jersey) aerosol
generator. The heated test material was mixed with heated compressed air in the BLAM and aerosol was sprayed into the chamber. Since the formulation contained materials of varying vapor pressures, the BLAM was operated in single pass mode (test material was not recycled).
- Method of particle size determination: The aerodynamic particle size distribution was determined twice during each exposure period by drawing samples from within the animal breathing zone, at a set rate of 3L/minute, using a constant flow air sampling pump through a multi-stage mercer-style cascade impactor
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber: temperature and humidity measured by compurterized system and measured at the exposure locations. Temperature values in the range of what is suggested in the test guidelines. humidity values were lower than what is suggested in the test guidelines to prevent degradation of the reactive diisocyanate moiety. No impact on the outcome of the study.

TEST ATMOSPHERE
- Brief description of analytical method used: The mass concentration of 4,4’-MDI/DPG aerosol present in the chamber was determined gravimetrically six times during each of the exposure periods. Background measurements of particulates in the chamber were taken prior to starting the atmosphere generation of 4,4’-MDI/DPG and showed no measurable particulate in the chamber prior to the start of each exposure. Samples were taken by drawing the chamber atmosphere, at one L/minute, through an animal nose port of the chamber (Figure 1). The aerosol
particles in the atmosphere were collected on preweighed glass fiber 47 mm filters (PALL Corporation, Ann Arbor, Michigan). After each atmosphere sampling, the filter was reweighed and the average background measurement (0 mg/L) was then subtracted to obtain the net weight of the particles collected. The time-weighted average (TWA) exposure concentration was calculated from the gravimetric measurements.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Remarks:
non-GLP filter samples were drawn concurrently with the gravimetric samples to verify that (1) the concentration and that (2) the composition of components is consistent with the bulk. Results are described in Appx B of the report.
Duration of exposure:
ca. 4 h
Concentrations:
0.78, 1.11, & 1.53 mg/L
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: Animals were weighed and examined prior to exposure to the test material and observed at least every 30 minutes during the exposure period. All surviving rats were weighed on test days 2, 4, 8, 11, and 15 during the two-week post-exposure period.
- Necropsy of survivors performed: yes; The necropsy included an examination of the external tissues and all orifices. The head was removed, the cranial cavity opened and the brain, pituitary
and adjacent cervical tissues were examined. The head was split longitudinally to facilitate examination of the nasal passage. The eyes were examined in situ by application of a moistened microscope slide to each cornea. The skin was reflected from the carcass, the thoracic and abdominal cavities were opened and the viscera examined. All visceral tissues were dissected from the carcass, re-examined and selected tissues were incised.
- Other examinations performed: Detailed clinical observations (DCO) were conducted pre-exposure, twice following exposure (test day 1), and daily thereafter. The DCO was conducted on all animals, at approximately the same time each day according to an established format (Table 1). The examination included cage-side, hand-held and open-field observations that were
recorded categorically or using explicitly defined scales (ranked) as outlined in Appendix A. Categorical observations (descriptive) are summarized under the clinical observations table(s).
Statistics:
Means and standard deviations were calculated for descriptive purposes for chamber concentration (mean only), animal body weights, exposure room temperature and chamber temperature, humidity, and airflow. The LC50 for female rats, and for male and female rats combined, was determined using the probit analysis (Finney, 1971 and 1978),and the LC50 for male rats was determined using the using the moving average method (Thompson and Weil, 1952; Bennett, 1952; Harris, 1959). The probit method is the preferred method to calculate an LC50. However, the response for the male rats resulted in a poor fit for the probit method, therefore, the moving average method was used.

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LC50
Effect level:
1.25 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Sex:
male
Dose descriptor:
LC50
Effect level:
1.11 mg/L air
Based on:
test mat.
95% CL:
0.65 - 2.11
Exp. duration:
4 h
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
1.15 mg/L air
Based on:
test mat.
95% CL:
0.88 - 1.61
Exp. duration:
4 h
Mortality:
0.78 mg/L Exposure
All animals survived the four-hour exposure to 0.78 mg 4,4'-MDI/DPG per liter of air.
Two male rats were found dead on test day 2.

1.11 mg/L Exposure
All animals survived the four-hour exposure. One male and two female rats were found
dead on test day 2 and one female rat was found dead on test day 3.

1.53 mg/L Exposure
All animals survived the four-hour exposure. One male rat was found dead at the onehour
post-exposure observation period and four male and three female rats were found
dead on test day 2.
Clinical signs:
other: Clinical effects noted during the four-hour exposure period to 0.78 mg/L 4,4’-MD/DPG exposure included soiling of the haircoat, labored breathing and mouth breathing. Clinical effects noted during the four-hour exposure periods to 1.11 and 1.53 mg/L 4,4’-
Body weight:
0.78 mg/L Exposure
Mean body weight losses of 10.7 and 11.1% were noted for male and female rats,
respectively, on test day 2 (Table 7 and Table 8). Pre-exposure mean body weight values
of surviving rats were exceeded on test day 8 and the animals continued to gain weight
until the test day 15-scheduled necropsy for both male and female rats.

1.11 mg/L Exposure
Mean body weight losses of 14.0 and 11.7% were noted for male and female rats,
respectively, on test day 2 (Table 7 and Table 8). Pre-exposure mean body weight values
of surviving rats were exceeded on test day 8 and the animals continued to gain weight
until the test day 15-scheduled necropsy for both male and female rats.

1.53 mg/L Exposure
Mean body weight losses of 11.4% were noted for female rats on test day 2 (Table 7 and
Table 8). Pre-exposure mean body weight values were exceeded on test day 8 for one of
the surviving female rats and test day 11 for the second surviving female rat.
Subsequently, the surviving female rats continued to gain weight until the test day 15-
scheduled necropsy.
Gross pathology:
0.78 mg/L Exposure
The two male rats that died on test day 2 were noted to have dark, mottled lungs and
slight or moderate mucus in the nasal cavity at necropsy. There were no visible gross
treatment-related lesions noted in any of the rats exposed to 0.78 mg/L 4,4'-MDI/DPG at
the test day 15-scheduled necropsy (Table 9, Appendix Table 5).

1.11 mg/L Exposure
The male rat that died on test day 2 was noted to have dark, mottled lungs and moderate
mucus in the nasal cavity. The two female rats that died on test day 2 were noted to have
dark, mottled lungs, slight or moderate mucus in the nasal cavity and facial or abdominal
soiling at necropsy. There were no visible gross treatment-related lesions noted in the
rats exposed to 1.11 mg/L 4,4'-MDI/DPG at the test day 15-scheduled necropsy (Table 9,
Appendix Table 5). One male rat was noted to have a non-treatment related herniated
liver at the test day 15-scheduled necropsy.

1.53 mg/L Exposure
The one male rat that died at the one-hour post-exposure observation period was noted to
have slight mucus in the nasal cavity, froth in the trachea, and facial soiling. The four
males that died on test day 2 were noted to have dark, mottled lungs, moderate or severe
mucus in the nasal cavity, and facial soiling. Additionally, two of the four male rats that
died on test day 2 were noted to have froth in the trachea. The three female rats that died
on test day 2 were noted to have dark and/or mottled lungs, moderate or severe mucus in
the nasal cavity, and perineal or facial soiling. Additionally, two of the females that died
on test day 2 were noted to have froth in the trachea. No visible gross treatment-related
lesions were noted in one surviving female rat and a slight, mottled lung was noted in the
second surviving female rat exposed to 1.53 mg/L 4,4'-MDI/DPG at the test day 15-
scheduled necropsy (Table 9, Appendix Table 5).

Any other information on results incl. tables

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on these data, the four-hour LC50 of inhaled particulate 4,4'-MDI/DPG is 1.11 mg/L with 95% confidence limits of 0.65 and 2.11 mg/L for male Crl:WI(Han) rats and 1.25 mg/L for female Crl:WI(Han) rats where the 95% confidence limits could not be calculated due to the limited responses of 0% and 60%. The four-hour LC50 of inhaled particulate 4,4'-MDI/DPG is 1.15 mg/L with 95% confidence limits of 0.88 and 1.61 mg/L for male and female Crl:WI(Han) rats combined.
Executive summary:

This study was conducted as per OECD, Guideline 403 (2009) to determine the acute inhalation toxicological properties of 4,4'-MDI-Polypropylene glycol copolymer (4,4'-MDI/DPG). Three groups of five Crl:WI(Han) rats/sex were exposed for four hours, using a nose-only inhalation exposure system, to time-weighted average (TWA) chamber concentrations of 0.78, 1.11 or 1.53 mg 4,4'-MDI/DPG per liter of air. The mass median aerodynamic diameter (MMAD) of aerosolized 4,4'-MDI/DPG present in the exposure chamber averaged 3.16 microns with an average geometric standard deviation (GSD) of 1.54 microns for the 0.78 mg/L exposure, 3.14 microns with a GSD of 1.89 microns for the 1.11 mg/L exposure, and 2.98 microns with a GSD of 1.92 microns for the 1.53 mg/L exposure. Humidity in the exposure chamber averaged 1.3 ± 2.1%, 0.6 ± 1.6%, and 0.0 ± 0.0%, respectively for each exposure.


0.78 mg/L Exposure


All animals survived the four-hour exposure to 0.78 mg 4,4'-MDI/DPG per liter of air. Two male rats were found dead on test day 2. Clinical effects noted during the four-hour exposure period included soiling of the haircoat, labored breathing, and mouth breathing.  In-life observations post-exposure included combinations of noisy and/or labored respiration with or without mouth breathing, hair standing up, pale skin, and periocular and perineal soiling. All surviving rats appeared normal by test day 7. Mean body weight losses of 10.7 and 11.1% were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded on test day 8 for both male and female rats and the animals continued to gain weight until the test day 15-scheduled necropsy. The two male rats that died on test day 2 were noted to have dark, mottled lungs and slight or moderate mucus in the nasal cavity at necropsy. There were no visible gross treatment-related lesions noted in any of the rats exposed to 0.78 mg/L 4,4'-MDI/DPG at the test day 15-scheduled necropsy.


1.11 mg/L Exposure


A second group of five rats/sex were exposed to 1.11 mg 4,4'-MDI/DPG per liter of air.  All animals survived the four-hour exposure. One male and two female rats were found dead on test day 2 and one female rat was found dead on test day 3. Clinical effects noted during the four-hour exposure period were limited to soiling of the haircoat and labored breathing. In-life observations post-exposure included decreased activity, partially closed eye lids, combinations of noisy and/or labored respiration with or without mouth breathing, hair standing up, and perinasal and perineal soiling. All surviving rats appeared normal by test day 13. Mean body weight losses of 14.0% and 11.7% were noted for male and female rats, respectively, on test day 2. Pre-exposure mean body weight values were exceeded on test day 8 for both male and female rats and the animals continued to gain weight until the test day 15-scheduled necropsy. The male rat that died on test day 2 was noted to have dark, mottled lungs and moderate mucus in the nasal cavity. The three female rats that died on test days 2 or 3 were noted to have dark, mottled lungs, slight or moderate mucus in the nasal cavity and facial or abdominal soiling at necropsy. There were no visible gross treatment-related lesions noted in the rats exposed to 1.11 mg/L 4,4'-MDI/DPG. One male rat was noted to have a nontreatment related herniated liver at the test day 15-scheduled necropsy.


 


1.53 mg/L Exposure


A third group of five rats/sex were exposed to 1.53 mg 4,4'-MDI/DPG per liter of air. All animals survived the four-hour exposure. One male rat was found dead at the one-hour post-exposure observation period. Additionally, four male and three female rats were found dead on test day 2. Clinical effects noted during the four-hour exposure period were limited to soiling of the haircoat and labored breathing. In-life observations postexposure included decreased activity, partially closed eye lids, noisy respiration, labored respiration with or without mouth breathing, partially closed eye lids, hair standing up, extensive body, and perineal and periocular soiling. One surviving female rat appeared normal by test day 5 and the second surviving female rat was noted to have noisy respiration until the test day 15-scheduled necropsy. Mean body weight losses of 11.4% were noted for female rats on test day 2. Pre-exposure mean body weight values were exceeded on test day 8 for one of the surviving female rats and test day 11 for the second surviving female rat. Subsequently, the surviving female rats continued to gain weight until the test day 15-scheduled necropsy. The one male rat that died at the one-hour postexposure observation period was noted to have slight mucus in the nasal cavity, froth in the trachea, and facial soiling. The four males that died on test day 2 were noted to have dark, mottled lungs, moderate or severe mucus in the nasal cavity, and facial soiling. Additionally, two of the four male rats that died on test day 2 were noted to have froth in the trachea. The three female rats that died on test day 2 were noted to have dark and/or mottled lungs, moderate or severe mucus in the nasal cavity, and perineal or facial soiling. Additionally, two of the females that died on test day 2 were noted to have froth in the trachea. No visible gross treatment-related lesions were noted in one surviving female rat and a slight, mottled lung was noted in the second surviving female rat exposed to 1.53 mg/L 4,4'-MDI/DPG at the test day 15-scheduled necropsy.


Based on these data, the four-hour LC50 of inhaled particulate 4,4'-MDI/DPG is 1.11 mg/L with 95% confidence limits of 0.65 and 2.11 mg/L for male Crl:WI(Han) rats and 1.25 mg/L for female Crl:WI(Han) rats where the 95% confidence limits could not be calculated due to the limited responses of 0% and 60%. The four-hour LC50 of inhaled particulate 4,4'-MDI/DPG is 1.15 mg/L with 95% confidence limits of 0.88 and1.61 mg/L for male and female Crl:WI(Han) rats combined.