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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003-04-17 - 2005-04-15
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
other: ECB/TM/21(97) Sub-chronic inhalation toxicity of synthetic mineral fibers in rats
according to guideline
other: ECB/TM/21(97) Guidance note on counting and sizing of fibers
GLP compliance:
yes (incl. QA statement)
Limit test:

Test material

Constituent 1
Reference substance name:
Acicular Mullite DPF Honeycombs
Acicular Mullite DPF Honeycombs
Details on test material:
Test Material Name
Acicular Mullite DPF Honeycombs
Chemical Name
Acicular Mullite
Supplier, City, State (lot, reference number)
The Dow Chemical Company, Midland, Michigan
Samples provided were ten honeycombs from the same extrusion lot but which were
converted to mullite in different runs: Honeycomb ID (Run #) were: 2003-1554
(R4_51), 2003-1546 (R4_43), 2003-1530 (R4_46), 2003-1629 (R4_52), 2003-1518
(R4_47), 2003-1471 (R4_40), 2002-1309 (R4_27), 2003-1419 (R4_34), 2002-1287
(R4_36), and 2002-1290 (R4_38). Acicular mullite exposure atmosphere was generated
from a stock of test material containing approximately equal portions of all honeycomb

Appearance (physical state, color)
Porous honeycomb monolith, white
Molecular Formula
Nominal composition: 2.95 Al2O3•2 SiO2
Formula Weight
418 g/mole
Chemical Structure
Composite of crystalline mullite grains and amorphous complex silicate glass
Specific Gravity
Density of mullite is 3.15 g/cm3. The bulk density of the DPF honeycomb monolith
is ca. 0.5 g/cm3.

Test animals

Fischer 344

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Remarks on MMAD:
MMAD / GSD: The MMAD of acicular Mullite was 4 microns.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The concentration of particulate ACM (acicular Mullite) present in each chamber was determined by taking
gravimetric samples for each exposure chamber, during each six-hour exposure period.
Each sample was taken by drawing chamber atmosphere, at a set rate (1-3 Lpmdepending on the chamber dust concentration) through a modified exposure chamber nose-piece directly from an unused directed-flow exposure horn (In Tox chambers),
collecting the particulate ACM on PTFE Membrane filters (47 mm, 0.45 mm pore size;
Pall Life Sciences, Ann Arbor, Michigan).
A study nominal concentration for the low- and high-exposure chambers was calculated
from the amount of test material used in the generation apparatus and the total exposure
system airflow.
Duration of treatment / exposure:
six hours/day, five days/week for four weeks (20 exposures)
Frequency of treatment:
five days/week
Doses / concentrations
Doses / Concentrations:
0, 10, 60 mg/m3
analytical conc.
No. of animals per sex per dose:
0 mg/m3: 30/30
10 mg/m3: 30/15
60 mg/m3: 30/30
Control animals:
Details on study design:
Groups of male and female Fischer 344 rats were exposed to target chamber
concentrations of 0, 10, or 60 mg/m3 of acicular mullite (six hours/day, five days/week)
for four weeks (20 exposures) to evaluate the potential for respiratory tract and systemic
toxicity. The mass median aerodynamic diameter (MMAD) of ACM delivered to the
exposure chambers was = 4 microns. Two post-exposure recovery periods were
included to evaluate the persistence of any ACM-induced alterations and the
biopersistence of deposited ACM particles and fibers. Exposures occurred under dynamic airflow conditions using directed-flow nose-only
exposure chambers. In- life observations, feed consumption, body weights, ophthalmic
exams, hematology, clinical chemistry, urinalysis, organ weights, and bronchoalveolar
lavages were conducted. In addition, gross necropsies were conducted with extensive
histopathologic examination of nasal and pulmonary tissues. For the 1-day post-exposure
animals, a full histopathologic examination of tissues collected and preserved at necropsy
(Table 1) was conducted on histopathology group animals exposed to 0 or 60 mg/m3
ACM. Tissues listed in Table 1 were collected and preserved from histopathology group
animals exposed to 10 mg/m3 ACM at the 1-day post-exposure sacrifice and from all
histology group animals at the 4- and 10-week post-exposure sacrifices; however, only
epididymides, testes, and nasal and pulmonary tissues received full histopathologic
examination at all concentrations and timepoints. The right lung lobes of all
histopathology group animals were snap frozen and stored at –80°C for analysis of
acicular mullite biopersistence.


Observations and examinations performed and frequency:
Cage-Side Observations
A cage-side examination was conducted at least once a day, preferably at the same time each day (usually in the morning).

Clinical Observations
Clinical observations were conducted pre-exposure, twice during the first week and
weekly thereafter throughout the study. These examinations were performed at
approximately the same time each examination day and included a careful, hand-held
examination of the animal.

The eyes of all animals were examined by a veterinarian pre-exposure using indirect
ophthalmoscopy. The week prior to necrospsy, ophthalmologic examinations were also
conducted on all animals in the 1-day post-exposure necropsy group.

Body Weights/Body Weight Gains
All rats were weighed during the pre-exposure period, twice during the first week and
weekly during the remainder of the study. Body weight gains were calculated.

Feed Consumption
Feed consumption data were collected pre-exposure, twice during the first week and at
least weekly thereafter for all animals.

Clinical Pathology
Blood samples were collected from the orbital sinus of all fasted, CO2-anesthetized
animals in the histopathology group at the 1-day, 4-week, and 10-week post-exposure
scheduled necropsies.

Anatomic Pathology
Histology Group
Fasted rodents submitted alive for necropsy were anesthetized by the inhalation of
CO2, weighed, and blood samples were obtained. Their tracheas were exposed
and clamped, and the animals were euthanized by decapitation.
A complete necropsy was conducted on all animals by a veterinary pathologist
assisted by a team of trained individuals. The necropsy included an examination
of the external tissues and all orifices.

The number of sections from all preserved tissues were
processed by standard histologic procedures from control- and high-dose group
animals from the 4-week exposure phase of the study and any animal that died
prior to their scheduled euthanasia.

Right lung lobes from each experimental animal were weighed and snap frozen in
liquid nitrogen during the necropsy and stored at -80°C until processed to
determine the amount of retained particulate ACM (biopersistence).

Bronochoalveolar Lavage Group
Bronchoalveolar lavage was performed on animals from each exposure group at each
sacrifice time (5 males/5 females exposed to 0 or 60 mg/m3 ACM at each sacrificetime and 5 males/0 females exposed to 10 mg/m3 ACM at each sacrifice time).
Sacrifice and pathology:
Fasted rodents submitted alive for necropsy were anesthetized by the inhalation of
CO2, weighed, and blood samples were obtained. Their tracheas were exposed
and clamped, and the animals were euthanized by decapitation.
Means and standard deviations were calculated for all continuous data. All
parameters examined statistically (feed consumption is addressed belo w) were first
tested for equality of variance using Bartlett's test (Winer, 1971).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean bodyweight values for all ACM-exposed animals were statistically decreased when compared to their respective controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically- identified increases in feed consumption were noted for weeks 2, 3, and 4 for males and females in the 10 mg/m3 and females in the 60 mg/m3 exposure groups, and in week four in males in the 60 mg/m3 group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Examinations performed on all animals prior to the study and at termination revealed no treatment-related findings.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Males and females exposed to 10 or 60 mg/m3 ACM had slightly higher percentages of neutrophils and lower percentages of lymphocytes as determined by the differential WBC count.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no significant differences in any of the urinalysis parameters for any exposure groups when compared to their respective controls.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related gross pathologic observations.
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Effect levels

Dose descriptor:
No ACM-induced mortality or clinical findings were observed in any exposure group at any time in the study.
Basis for effect level:
other: No ACM-induced mortality or clinical findings were observed in any exposure group at any time in the study.
Remarks on result:
not determinable
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Repeated nose-only inhalation of ACM resulted in a dose-dependent irritant response
within the upper respiratory tract characterized by mucous cell hyperplasia and
hypertrophy in the respiratory epithelium lining the anterior nasal airways and the
nasopharynx. These morphologic changes were reversed during the 10-week postexposure
recovery period.
The centriacinar region of the lung was the primary site of ACM-induced pulmonary
inflammation and injury. ACM exposure was characterized by a dose-dependent increase
in particle- laden macrophages and neutrophils and a slight, diffuse, multifocal influx of
mononuclear cells within alveolar ducts. During the 10-week recovery period there was
an apparent decrease in the occurrence of free macrophages within the lung. This
decrease was associated with a slight, diffuse, multifocal accumulation of macrophages,
and mononuclear cells within the alveolar ducts.
Pulmonary clearance was not inhibited by ACM deposited in the lung. At the end of the
4-week exposure, similar amounts of ACM were present in animals exposed to 10 or
60 mg/m3. However, compared to rats exposed to 10 mg/m3, the clearance of ACM from
the lungs was significantly slower in animals exposed to 60 mg/m3. Compared to 0
mg/m3 controls, there was still significant amounts of ACM within the lung after
10 weeks of recovery. The pulmonary response to inhaled ACM is similar to that
observed following exposure to other inert particulates such as amorphous silica or
titanium dioxide.
Executive summary:

The systemic, nasal, and pulmonary responses to inhaled ACM that were observed in this study were similar to, or less than, that observed in rats similarly exposed to other inorganic particulates such as titanium dioxide (10 mg/m3 TiO2) or amorphous silica (50 mg/m3), respectively. It is significant that the ACM- induced pulmonary effects observed in this study were unlike those observed following exposure to a fibrogenic particulate such as crystalline silica (3 mg/m3) which results in significantly greater, chronic, neutrophilic inflammation and progressive pulmonary fibrotic lesions at exposure concentrations 3 to 20-fold lower than those used in this study. These data suggest that ACM has little or no inherent toxicity except that associated with inhalation of high concentrations of nontoxic, but irritating, inorganic particulates.