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Administrative data

Description of key information

In a short-term repeated dose inhalation study, (3E)-3 -decen-2 -one was given by inhalation administration to CRL:CD(SD) rats, six hours daily, for variable durations. Administration for 5 consecutive days was performed at achieved exposure levels of 139, 278 and 531 μg/L. Based on the findings, the NOAEC is considered to be 139 μg/L.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2014-01-29 to 2014-06-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: The purpose of this study was to investigate the toxicity of the test item in rats after daily inhalation for five consecutive days. The data generated will allow the selection of dose levels for subsequent toxicological studies.
- Short description of test conditions: In this study three groups were to receive AMV-1018 at target exposure levels of 125, 250 or 750 μg/L and a similarly constituted control group was to receive air only, at the same operating conditions as the highest exposure group. Following an adverse response in the highest exposure group, attributed to a much higher than intended chamber concentration, the high exposure animals were killed on Day 2. Exposure of control animals ceased after 3 days, with one male and one female being transferred to a pilot phase added to assess tolerability at 750 μg/L; the low and intermediate exposure level groups completed the scheduled exposure period. Two further groups received either a target concentration of 500 μg/L or air at the same operating conditions as the 500 μg/L group.
- Parameters analysed/observed: During the study, clinical condition, body weight, food consumption, organ weight, macropathology and histopathology investigations were undertaken.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Purity: 99.4%
- Batch No: HA-2013/02
- Physical state: clear colourless liquid
- Storage conditions: under nitrogen, room temperature
- Expiry date: January 2015
Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
The rat was chosen as the test species because it is accepted as a predictor of toxic change in man and the requirement for a rodent species by regulatory agencies. The Crl:CD(SD) strain was used because of the historical control data available at this laboratory.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: from 59 to 87 days
- Weight at study initiation: males: from 341 to 424 g; females: 232 to 288 g
- Housing: One, two or three of the same sex in cages with a polycarbonate body with a stainless steel mesh lid
- Diet (e.g. ad libitum): ad libitum, rat and mouse No. 1 Maintenance Diet.
- Water (e.g. ad libitum): ad libitum, potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals
- Acclimation period: at least 10 days

DETAILS OF FOOD AND WATER QUALITY: Certificates of analysis for the diet were scrutinised and approved before any batch of diet was released for use. Certificates of analysis are routinely provided by the water supplier. Certificates of analysis were also received from the suppliers of the wood based bedding, and Aspen chew blocks. No specific contaminants were known that may have interfered with or prejudiced the outcome
of the study and therefore no special assays were performed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks on MMAD:
No MMAD was determined
Details on inhalation exposure:
Components of the exposure system:
Exposure system:
- Flow through snout only chamber
- Aluminum alloy construction comprising a base unit, three animal exposure sections, a top section and a pre chamber
Animal Restraint:
- Restraint tube
Aerosol Generation:
- A stainless steel concentric jet atomiser (manufactured in-house by Inhalation Engineering Services), designed to produce and maintain an atmosphere containing a high proportion of respirable droplets. The test substance was supplied to the generator, via a Polyethylene feed line, from a syringe (All Plastic) driven at a constant rate by a syringe pump (Harvard)
Inlet Airflow:
- From in-house compressed air system – breathing quality
- Generator flow: 13 L/minute per system
- Supplementary air: 6 L/minute per system (Groups 1 to 4 and 6)
16 L/minute per system for Groups 7 and 8 (Exp 1)
19 L/minute per system for Groups 7 and 8 (Exp 2)
22 L/minute per system for Groups 7 and 8 (Exp 3 onwards)
Extract Airflow:
- Drawn by in-house vacuum system
- Filtered locally
- Flow: 20 L/minute per system (Groups 1 to 4 and 6)
30 L/minute per system for Groups 7 and 8 (Exp 1)
33 L/minute per system for Groups 7 and 8 (Exp 2)
36 L/minute per system for Groups 7 and 8 (Exp 3 onwards)
Airflow Monitoring:
- High quality tapered tube flowmeters - calibrated daily
- In-line flowmeters monitored continuously
System Containment:
- Systems housed in separate ventilated cabinets
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Aerosol samples collected as follows:
- Trapping solvent: ACN/H2O/Antifoam, in bubbler
- Sample flow: 2.0 L/minute
- Sample volume: Measured by wet-type gas meter
- Sample frequency: Minimum of 3 samples/ exposure system/day
- Sample location: Spare animal port
- Sample analysis: Chemical – analysis via UPLC
Duration of treatment / exposure:
- Group 1: 6 hours for 3 consecutive days
- Groups 2 and 3: 1 week (6 hours, 5 days a week)
- Group 4: single 6 hour exposure
- Group 6: 6 hours for 2 consecutive days
- Groups 7 and 8: 1 week (6 hours, 5 days a week)
Frequency of treatment:
- Group 1: 6 hours for 3 consecutive days
- Groups 2 and 3: 1 week (6 hours, 5 days a week)
- Group 4: single 6 hour exposure
- Group 6: 6 hours for 2 consecutive days
- Groups 7 and 8: 1 week (6 hours, 5 days a week)
Dose / conc.:
0 mg/L air (nominal)
Remarks:
Control (Group 1: 6 h for 3 consecutive days; Group 7: 6 hours, 5 days a week)
Dose / conc.:
125 mg/m³ air (nominal)
Remarks:
Low conc. (Group 2: 6 hours, 5 days a week)
Dose / conc.:
250 mg/m³ air (nominal)
Remarks:
Mid conc. (Group 3: 6 hours, 5 days a week)
Dose / conc.:
750 mg/m³ air (nominal)
Remarks:
High conc. (Group 4, single 6-hour exposure)
Dose / conc.:
750 mg/m³ air (nominal)
Remarks:
Pilot phase (Group 6, 6 hours for 2 consecutive days)
Dose / conc.:
500 mg/m³ air (nominal)
Remarks:
Group 8, 6 hours, 5 days a week
No. of animals per sex per dose:
3 animals per group, except for group 6 (pilot phase): 1
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Based on the results from a previous 4-hour acute inhalation study an exposure level of 750 µg/L was selected. The control and high dose animals (Groups 1 and 4) commenced treatment one week after Groups 2 and 3 so that any potential treatment related effects could be assessed prior to exposure at a target of 750 μg/L. The Group 4 animals were exposed higher than target exposure level on Day 1 (approximately 1100 μg/L) and were terminated on Day 2 as a result of treatment related clinical signs. In order to assess tolerability, a pilot phase comprising of 1 male and 1 female were exposed at a level targeted at 750 μg/L for 2 days, but as the achieved exposure level of 816 μg/L was not tolerated in the pilot phase, a lower exposure level, targeted at 500 µg/L was selected for a new high dose group (Group 8) which was exposed concurrently with an additional control group (Group 7).
Observations and examinations performed and frequency:
Mortality:
A viability check was performed near the start and end of each working day. Animals were isolated or killed for reasons of animal welfare where necessary. A complete necropsy was performed in all cases.

Clinical Observations:
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupants. Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate. During the acclimatisation period, observations of the animals and their cages were recorded at least once per day.
Detailed observations were recorded daily at the following times in relation to exposure:
- Pre-exposure observation
- As each animal was returned to its home cage
- As late as possible in the working day
In addition observations were made in the treatment period, on days without exposures, at the following times during the day:
- Early in the working day (equivalent to pre-exposure observation)
- As late as possible in the working day
In addition: A detailed weekly physical examination was performed on each animal to monitor general health.

Body Weight:
The weight of each animal was recorded daily from Day -5 (Day P3) throughout the study and before necropsy.

Food Consumption:
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded daily from Day -5 (Day P3) throughout the study.
Sacrifice and pathology:
Sacrifice:
All study animals were subject to a detailed necropsy (except the control (Group 1) animals that were not selected for transfer to the pilot phase (Group 6)). After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
The retained tissues were checked before disposal of the carcass.
Schedule:
- Animals of Groups 2 and 3 were killed on Day 8.
- Animals of Group 4 were killed on Day 2, following a single exposure.
- Animals of Group 6 were killed on Day 3, following 2 days of exposures.
- Animals of Groups 7 and 8 were killed on Day 8.

Organ weights:
For bilateral organs, left and right organs were weighed together, unless specified above. Requisite organs were weighed for study animals killed at scheduled intervals. The following organs were weighed: brain, heart, kidneys, liver, lungs and spleen

Fixation:
Tissues were routinely preserved in 10% Neutral Buffered Formalin with exception of the yes (Davidson´s fluid)

Histology:
Tissue samples were dehydrated, embedded in paraffin wax and sectioned at a nominal four to five micron thickness. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required.

Tissues preserved for examination were examined as follows (after staining with haematoxylin and eosin):
- Premature deaths: all animals from all groups
- Scheduled kill: all animals of group 2, 3, 7 and 8

See also Table 1 in box "Any other information on materials & methods incl. tables".
Statistics:
All statistical analyses were carried out separately for males and females using the individual animal as the basic experimental unit. The following data types were analysed at each timepoint separately:
- Body weight, using gains over appropriate study periods
- Organ weights, absolute or relative to terminal body weight
The following comparisons were performed:
- Group 1 vs 2, 3 and 4 and Group 7 vs. 2, 3 and 8
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Mortality:
no mortality observed
Description (incidence):
Please refer to box " Details on results".
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Please refer to box " Details on results".
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
Clinical Signs and Mortality:
There were no clinical signs or dosing observations considered to be related to exposures with AMV-1018 in the groups which received 139 or 278 µg/L (Group 2 and 3). The clinical signs of wet fur and red staining to the head in these groups were attributed to the method of restraint. Following a single exposure at a target concentration of 750 µg/L (Group 4) post exposure clinical signs of elevated/unsteady gait and slow breathing were evident at the time that the animals were returned to the home cage. At the Day 2 pre-exposure observation one male and one female were also observed to have wet râles. At a detailed clinical signs-check these animals were noted to have wet râles, irregular breathing, and, in some animals, gasping. Decreased activity, hunched posture and elevated gait were also reported. Body weight losses of between 9 and 26 g in males and between 9 and 27 g in females were recorded, alongside marked
reductions in food intake.
In view of the range of signs that occurred and the loss of body weight, this excessive response precluded further exposures at 750 µg/L. The chemical analysis of the test atmosphere indicated that the animals had been exposed to a chamber concentration of 1103 µg/L, which was approximately 147% of target, and therefore to a test atmosphere significantly higher than target. Because of the progressive nature of the signs it was concluded that the recovery required to enable continuation of treatment on this repeat dose study would take several days and the effects of being exposed to AMV-1018 at a concentration significantly higher than expected may have compromised these animals. Consequently the Group 4 animals were killed on Day 2. In order to make an assessment of the potential effects at an atmosphere concentration closer to 750 µg/L, an additional pilot phase (Group 6) comprising one male and one female was added using animals previously assigned as controls. Following a single exposure at an achieved concentration of 816 µg/L (i.e. 109% of target) the signs observed on return to the home cage consisted of dry râles, irregular breathing, decreased activity, hunched posture, elevated/unsteady gait, reduced body temperature and salivation. Following a second day of exposures additional signs of shallow breathing, partially closed eyes and piloerection were observed. Similar signs were reported during the detailed physical examination. Body weight losses of 54 g and 20 g occurred for the male and female, respectively, alongside marked reductions in food intake. Based on the extent of the signs, which persisted until the end of the working day, it was considered that this level was not tolerated and these two animals were sacrificed for welfare reasons on Day 3 of the phase. A revised target high exposure level of 500 µg/L was selected (Group 8). Signs that were observed on return to the home cage consisted of elevated/unsteady gait, chin rubbing and reduced body temperature. The onset of breathing signs (wet râles, irregular breathing) occurred later in this group, generally from Day 3, and persisting until the end of day observations and
remaining evident the following morning prior to the next exposure. During the detailed weekly clinical signs check, all animals were reported as having irregular breathing with wet râles.

Body Weight:
Reduced gains, compared with the concurrent control on days of exposure, were observed in animals receiving 139 µg/L (Group 2) whilst for animals which received 278 µg/L (Group 3), group mean body weight losses of 10 and 5 g were observed over the five-day exposure period for males and females, respectively. During the two-day off-dose period there was significant recovery at both exposure levels, with the greatest gains occurring in the animals given
278 µg/L. The effect of treatment in the animals that received a single exposure of 1103 µg/L (Group 4) is discussed in Section 3.2. Body weight losses also occurred in the pilot phase (Group 6) following two exposures at a mean aerosol concentration of 816 µg/L. A body weight loss of 54 g occurred in the male and 20 g in the female. Body weight losses were observed in animals which received 531 µg/L over five days of exposures (Group 8), with group mean losses of 55 g and 21 g occurring, in males and females, respectively. Significant recovery was evident during the two-day off dose period in females, with an increase of 24 g occurring during the off-dose period. In males a 14 g weight gain was observed during this period but this was only slightly higher than the concurrent controls over the same period.

Food Consumption:
Slightly reduced food consumption was evident for animals exposed to 139 µg/L (Group 2) for the first 3 days of treatment when compared to pre-treatment values. Food consumption values for this group were generally comparable to pre-treatment thereafter. A reduction in food consumption was observed at 278 µg/L and above, the magnitude of which was dose-related. Food consumption for pilot phase animals (Group 6) following two exposures at a mean aerosol concentration of 816 µg/L was greatly reduced following the first exposure, being approximately 50% of the pre-treatment consumption. In males a greater reduction in food consumed was observed on the second day but, in contrast, the females consumed a similar amount to that reported before treatment commenced. A marked reduction of food consumption was also observed in animals receiving 531 µg/L (Group 8), when compared with that of the concurrent control group and the pre-treatment values. There was only slight recovery during the two-day off-dose period.

Organ weights:
For the assessment of organ weight data Groups 2, 3 and 8 (139, 278 and 531 µg/L) were compared with Group 7 (control). Group mean lung weights for animals exposed to 531 µg/L, relative to terminal body weight, were higher when compared to control, with the increase being approximately 42% in males and
13% in females. There were some other differences from controls but these generally lacked a relationship to exposure level, or were confined to one sex. Such differences included the variability in absolute and relative spleen weights for females and relative liver weights for males. In the absence of any histopathological correlate, these findings were considered not treatment related.

Gross pathology:
Animals killed during the treatment period:
The macroscopic examination performed for animals killed or dying during the treatment period revealed changes in the lungs, tracheobronchial lymph nodes and the gastro-intestinal tract.
Lungs:
Incomplete deflation was seen in one male animal exposed to 1103 µg/L. Abnormal colour (dark/patchy) was noted in one male and one female animal exposed to 1103 µg/L.
Tracheobronchial lymph nodes:
Enlargement of the tracheobronchial lymph nodes was observed in one male animal exposed to 1103 µg/L.
Gastro-intestinal tract:
Distension (gaseous) of the gastro-intestinal tract was seen in one male and one female animal exposed to 1103 µg/L.
Animals killed after one week of treatment:
The macroscopic examination performed after 1 week of treatment revealed the following changes in tracheobronchial lymph nodes and lungs.
Lymph node, tracheobronchial:
Enlargement of the tracheobronchial lymph nodes was seen in two male animals and one female exposed to 531 µg/L.
Lungs:
Incomplete deflation was seen in all animals exposed to 531 µg/L, abnormal coloration was observed in all males and one female animal exposed to 531 µg/L and the lungs were considered firm in two males exposed to 531 µg/L.

Histopathology:
Animals killed prematurely during the treatment period:
Treatment related findings:
Changes related to treatment with AMV-1018 at 1103 μg/L were seen in the nasal turbinates, larynx, trachea, tracheal bifurcation, lung and tracheobronchial lymph nodes.
Nose/ turbinates:
In the olfactory, respiratory and transitional epithelium, degeneration, inflammation and ulceration were seen in all animals. In the squamous epithelium, inflammation and ulceration were seen. Inflammatory cell exudate in the airways was seen in all animals. In the nasopharynx, ulceration was seen in two females.
Trachea:
Luminal inflammatory cell exudate, serosal inflammatory cell infiltration and ulceration of the respiratory epithelium were seen in one male. Inflammation and ulceration of the respiratory epithelium were seen in one female.
Tracheal bifurcation:
Inflammation and ulceration of the respiratory epithelium and loss of cilia at the point of bifurcation were seen in one male.
Larynx:
In the respiratory and squamous epithelium, inflammation, ulceration and luminal inflammatory cell exudate were seen.
Lungs and bronchi:
Increased cellularity of the BALT, hemorrhage, interstitial pneumonitis, inflammation of the terminal bronchioles and ulceration of the bronchiolar epithelium were seen in some of the males.
Lymph node, tracheobronchial:
Generalised increased cellularity was seen in one male.

Animals killed after one week of treatment:
Treatment related findings:
Changes related to treatment with AMV-1018 were seen in the nasal turbinates, larynx, trachea, tracheal bifurcation, lung and tracheobronchial lymph nodes.
Nose/ turbinates:
In the nasal turbinates, in those animals most affected, the lesion got progressively greater the further back in the nose the section was taken, the front regions of the nose were less affected than those further back, and the olfactory mucosa, particularly in the region of the dorsal meatus, showed the most severe effects. In the olfactory epithelium, degeneration was seen in one male and in all of the females exposed to 531 μg/L and in a single female exposed to 278 μg/L. Inflammation was seen in animals exposed to 531 μg/L and was also evident in one male exposed to 278 μg/L. Erosion was seen in two females exposed to 531 μg/L and ulceration was seen in a male exposed to 278 μg/L. In the respiratory epithelium, degeneration was seen in all animals exposed to 531 μg/L and in all males, but not in females exposed to 278 μg/L. Inflammation at slight level and above was seen in males and females exposed to 531 μg/L and in males exposed to 278 μg/L. Erosion was seen in all males and one female exposed to 531 μg/L. In the transitional epithelium, degeneration was seen in two males exposed to 531 μg/L. Inflammation, graded at slight was seen in a male exposed to 531 μg/L and in two males and two females exposed to 278 μg/L. Erosion of the mucosa was seen in animals exposed to 278 μg/L but was not evident at 531 μg/L. Squamous metaplasia was seen in all males and in one female
exposed to 278 μg/L and in a single male, at a slight grade, at 139 μg/L, but the change was not seen in females at the other exposure levels, or in the males at 531 μg/L. Mucosal ulceration of the transitional epithelium was seen in a single male exposed to 278 μg/L. Degeneration of the respiratory epithelium of the nasopharynx was seen in a male exposed to 531 μg/L and inflammatory cell exudate in the airway was seen in all animals exposed to 531 μg/L and two males exposed to 278 μg/L.
Trachea:
Inflammation and ulceration of the respiratory epithelium were seen in two males exposed to 278 μg/L but were not evident at 531 μg/L.
Tracheal bifurcation:
Erosion of the respiratory epithelium was seen in a male exposed to 531 μg/L. Inflammation of the respiratory epithelium was seen in a male exposed to 278 μg/L. Hyperplasia of the respiratory epithelium was seen in a male exposed to 531 μg/L. Loss of cilia at the point of bifurcation was seen in in one male and one female exposed to 531 μg/L and also in males exposed to 278 μg/L.
Larynx:
In the respiratory epithelium, inflammation was seen at one male exposed to 531 μg/L and all males exposed to 278 μg/L. Squamous metaplasia was seen in animals exposed to 531 μg/L.
Lungs and bronchi:
Increased cellularity of the BALT was seen in males and females exposed to 278 μg/L. Submucosal/luminal fibrosis and respiratory epithelial hyperplasia were seen in all males exposed to 531 μg/L. Terminal bronchiolar inflammation was seen in males exposed to 278 or 531 μg/L. Bronchiolar epithelial ulceration was seen in males exposed to 278 or 531 μg/L. In addition, submucosal/luminal fibrosis, respiratory epithelial hyperplasia and bronchiolar epithelial ulceration were seen in one female exposed to 531 μg/L.
Lymph node, tracheobronchial:
Generalised increased cellularity was seen in one male and one female exposed to 531 μg/L.
Key result
Dose descriptor:
NOAEC
Effect level:
139 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
278 mg/m³ air (analytical)
System:
respiratory system: upper respiratory tract
Organ:
lungs
nasal cavity
trachea
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Table 2: Atmosphere analysis

Group Nominal (µg/L) Actual (µg/L)
1 0 0
2 125 139
3 250 278
4 750 1103
6 750 816
7 0 0
8 500 531
Conclusions:
In a short-term repeated dose inhalation study, AMV-1018 was given by inhalation administration to CRL:CD(SD) rats, six hours daily, for variable durations. Administration for 5 consecutive days was performed at achieved exposure levels of 139, 278 and 531 µg/L. Based on the findings, the NOAEC is considered to be 139 µg/L.
Executive summary:

In a short-term repeated dose inhalation study, AMV-1018 was given by inhalation administration to CRL:CD(SD) rats (3/sex/group), six hours daily, for variable durations. Administration for 5 consecutive days was performed at achieved exposure levels of 139, 278 and 531 µg/L. Five days of exposure for six hours each day at 278 or 531 μg/L, followed by two day off dose period, produced a range of histopathological findings in the nasal turbinates, larynx, trachea (including the bifurcation) and lungs that were attributed to a response to an irritant test material, with secondary findings to the changes in the lungs being evident in the tracheobronchial lymph nodes. The findings reported at 278 μg/L or above, which also included reductions of body weight and food consumption, were adverse changes. Test article-related histopathological findings at 139 μg/L were confined to a single incidence of a localised, low grade, squamous metaplasia in the transitional epithelium of the frontal section of the nose, and therefore in a region that was dissimilar to that at higher exposure levels, and this was considered not adverse Based on the findings, the NOAEC is considered to be 139 µg/L.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
139 mg/m³
Study duration:
subacute
Species:
rat
System:
respiratory system: upper respiratory tract

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
139 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

In a short-term repeated dose inhalation study, (3E)-3 -decen-2 -one was given by inhalation administration to CRL:CD(SD) rats (3/sex/group), six hours daily, for variable durations. Administration for 5 consecutive days was performed at achieved exposure levels of 139, 278 and 531 μg/L. Five days of exposure for six hours each day at 278 or 531 μg/L, followed by two day off dose period, produced a range of histopathological findings in the nasal turbinates, larynx, trachea (including the bifurcation) and lungs that were attributed to a response to an irritant test material, with secondary findings to the changes in the lungs being evident in the tracheobronchial lymph nodes. The findings reported at 278 μg/L or above, which also included reductions of body weight and food consumption, were adverse changes. Test article-related histopathological findings at 139 μg/L were confined to a single incidence of a localised, low grade, squamous metaplasia in the transitional epithelium of the frontal section of the nose, and therefore in a region that was dissimilar to that at higher exposure levels, and this was considered not adverse. Based on the findings, the NOAEC is considered to be 139 μg/L.

Justification for classification or non-classification

Based on the results of available data, no classification for specific target organ toxicity for (3E)-3 -decen-2 -one is warranted.