Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
25.04.1990 - 26.02.1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline Study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
expanded by ophthalmologic examinations, neurofunctional observational battery and perfusion fixation
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Piperidine
- Test Substance No.: 89/523
- Physical state: Iiquid / colourless
- Analytical purity: 99.4 %
- Impurities (identity and concentrations): 0.06 % unknown, 0.12 % N-Methylpiperidine, 0.20 % 2-Methylpiperidine
- Lot/batch No.: 05-0475
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Wistar-rats/Chbb:TH0M
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: about 7 weeks
- Mean weight at study initiation: males: 239.9 g; females: 170.6 g
- Fasting period before study: During exposure food and water were withdrawn
- Housing: singly, in wire cages (type DK III of Becker, Castrop-Rauxel, Germany)
- Diet: KLIBA rat/mouse laboratory diet 24-343-4, 10 mm pellets, Klingentalmühle AG, Kaiseraugst, Switzerland, ad libitum.
- Water: and tap water, ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- System of generating an inhalation atmosphere:
One part of the air of the total conditioned supply air stream was branched off and directed via a generator system.
Test groups 2 (20 ppm) and 3 (100 ppm) were supplied an additional compressed air stream. In detail, the following systems were used:
Test group 1 (5 ppm): The generation was carried out in a heatable glass evaporator with a mixer stage.
Test groups 2 and 3: The generator was carried out in a heatable glass evaporator with a mixer stage by means of a two-component atomizer with compressed air and counter-streamwise to supply air 2.
The vapor/air mixture in test groups 1 to 3 were then mixed again with conditioned air and introduced to a whole body exposure system (gIass-steel inhalation chamber). In addition, the exposure system was connected to an exhaust air system.
- Exposure apparatus: Glass-steel inhalation chamber with a volume of about 1.4 m³,
- Method of holding animals in test chamber: Animals were kept singly in wire cages in the glass-steel inhalation chamber.
- Measurement of the operation conditions (air flows, relative humidity, temperature and pressure conditions) of the exposure system:
In addition to the partial stream of the total supply air via the generator systems, the air volumes, pressure conditions in the chamber, relative humidity, and chamber temperatures were measured continuously with a measuring system. They were partially regulated and checked against the defined limit values. This system was also used to record the generator parameters (temperature and compressed air).
- Temperature, humidity, pressure in air chamber:
Control: chamber temperature ± SD [°C]: 22.4 ± 0.2; rel. humidity in the chamber ± SD [%]: 56.2 ± 3.6; chamber pressure ± SD [Pa]: 10.7 ± 0.6
Test group 1 (5 ppm): chamber temperature ± SD [°C]: 21.9 ± 0.5; rel. humidity in the chamber ± SD [%]: 56.9 ± 5.1; chamber pressure ± SD [Pa]: -9.8 ± 0.4.
Test group 2 (20 ppm): chamber temperature ± SD [°C]: 22.3 ± 0.6; rel. humidity in the chamber ± SD [%]: 56.4 ± 5.0; chamber pressure ± SD [Pa]: -9.8 ± 0.2.
Test group 3 (100 ppm): chamber temperature ± SD [°C]: 21.8 ± 0.5; rel. humidity in the chamber ± SD [%]: 55.4 ± 5.2; chamber pressure ± SD [Pa]: -9.5 ± 0.3.
Thus, the mean temperature in the exposure systems was about 21.8 to 22.4 °C and the mean relative humidity was from 55.4 to 56.9%. The mean chamber pressure was from -9.8 to 10.7 Pascal.

- Measurement of the partial stream via the generator system was done continuously with a rotameter and recorded once daily. The volume streams of the dosed test substance was recorded once daily.
- Amounts of test substance, air and evaporation temperatures:
Control: Fresh air, Conditioned air: 28.1 - 28.2 m³/h, compressed air: -, exhaust air: 27.6 - 27.8 m³/h
Test group 1 (5 ppm): 0.7 - 1.0 mL/h amount of test substance, Evaporation temperature: 25.4 - 27.7 °C; Conditioned air: 27.6 - 28.3 m³/h, compressed air: -, exhaust air: 27.9 - 28.9 m³/h.
Test group 2 (20 ppm): 2.4 - 2.8 mL/h amount of test substance, Evaporation temperature: 23.5 - 26.3 °C; Conditioned air: 27.7 - 27.9 m³/h, compressed air: 0.3 - 0.6 m³/h, exhaust air: 28.6 - 29.1 m³/h.
Test group 3 (100 ppm): 12 - 14 mL/h amount of test substance, Evaporation temperature: 25.0 - 26.5 °C; Conditioned air: 27.8 - 28.0 m³/h, compressed air: 0.3 - 0.5 m³/h, exhaust air: 28.2 - 28.8 m³/h.
- Method of conditioning air:
Control: The exhaust air system was set lower than the supply air system (positive pressure). This ensured that no laboratory air reached the control animals.
Test groups: The exhaust air system was set higher than the supply air system (negative pressure). This ensured that the laboratory was not contaminated as the result of any leakages from the inhalation chambers.
A positive pressure was chosen for all test groups during the preflow period.
Animals of the same concentration were exposed in the same chambers.
- Other: In order to accustom the animals to the exposure conditions they were exposed to supply air in whole-body exposure systems on 4 days before the exposure period. Then all test groups were exposed for 6 hours on workdays over a time period of 29 days (28 days test). The number of exposure days was 20.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration in the inhalation chambers was monitored by means of a total hydrocarbon analyzer.
Samples were taken from the animals' breathing zones in the inhalation chambers on the days of exposure.
Sampling was carried out intermittently at intervals of 19 minutes in the main test groups (5, 20, 100 ppm). There was a sweeping period of 20 minutes between the sampling cycles (1 sampling cycle = 3 sampling intervals).
The total hydrocarbon analyzer was calibrated with mixtures of the test substance and air that were generated in the inhalation chambers not containing animals according to the test group concentrations. Thereby, a gas chromatography method was used for calibrating the total hydrocarbon analyzer and for the quantitative determination of the vapor concentrations in the exposure chambers. Various concentrations were generated in the inhalation chambers for the test groups. The total hydrocarbon analyzer was connected to an exposure chamber for the calibration and the measured signal was recorded. Absorption samples were taken simultaneously. The vapor samples were taken up in about 40 ml of dimethylformamide and analyzed after the addition of an internal standard (C8 paraffin).
Mass values of the test substance were obtained from the area integrals. The concentrations of the test substance concerning the test groups were calculated from these mass values obtained by gas chromatographic determination in relation to the injected volume and the sample volume of the inhalation atmosphere.

The result of the gas chromatography was correlated with the signal measured by the total hydrocarbon analyzer.

The gas chromatograph was calibrated with weighed amounts of the test substance and internal standard.

- Samples taken from breathing zone: yes, samples were taken from the animals' breathing zones in the inhalation chambers on the days of exposure.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration monitoring with the total hydrocarbon analyzer:
A study mean with standard deviation was calculated from the daily means of the individual concentrations of the tretament groups obtained with the total hydrocarbon analyzer. The following study means were obtained:
Treatment group 5 ppm: analytical concentration ± standard deviation: 5.0 ± 0.45 ppm; nominal concentration: 7.0 ppm
Treatment group 20 ppm: analytical concentration ± standard deviation: 20.0 ± 1.5 ppm; nominal concentration: 22 ppm
Treatment group 100 ppm: analytical concentration ± standard deviation: 100.0 ± 9.1 ppm; nominal concentration: 114 ppm
Duration of treatment / exposure:
28 days
Frequency of treatment:
6 hours per day, 5 days per week (20 exposures in total).
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5 ± 0.45, 20 ± 1.5, 100 ± 9.1 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0.02, 0.07, 0.35 mg/L (5, 20, 100 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
10 (all dose groups);
5 (recovery groups; control and 100 ppm)
Control animals:
other: A control group of 15 male and 15 female rats inhaled clean air under similar exposure conditions.
Details on study design:
- Dose selection rationale: A range-finding study (5 exposures on rats) was performed.
According to the results of this pretest the following concentrations were selected for this study:
100 ppm was selected as highest concentration. At this concentration toxic effects should occur.
20 ppm was selected as intermediate concentration in order to characterize a concentratio-response-relationship
5 ppm was selected as lowest concentration. This concentration was expected to reperasent a NOEL.
- Post-exposure recovery period in satellite groups: 2 weeks (only highest dose-group [100 ppm] and control group, 5 males and 5 females, respectively)

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: on workdays at least 3 times on exposure days and, as a rule, once during the preflow period and the post-exposure observation period. A check for dead animals was made daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The behavior and state of health of the test animals were checked on workdays at least 3 times on exposure days and, as a rule, once during the preflow period and the post-exposure observation period.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of the animals was checked at the beginning of the preflow, one day before beginning of the exposure period and then, as a rule, once a week. As a rule, the animals were weighed at the same time of the day.
Body weight change: The difference between the body weight on the day of weighing and the body weight on the day before the first
exposure was calculated as a group mean. This value was defined as body weight change.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At the beginning of the preflow period (day -8), respectively one day before beginning of the exposure period (day -1), the eyes of all animals and at the end of the study (day 30), the eyes of the animals of the control groups and of the highest concentration. At the end of the post-exposure observation period (day 44) the eyes of the animals of the control group and of the highest concentration were examined with a focusable hand slit lamp for any changes to the refracting media.
- Dose groups that were examined: Main groups and post-exposure observation groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning of the nominal day 30, blood was taken from the retroorbital venous plexus
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 5 animals per test group and sex

Clotting analyses: The clotting analyses were carried out using a ball coagulometer (KC 10 model, by Amelung, Lemgo, Germany).
The following parameter was determined:
- thromboplastin time (Hepato Quick's test)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning of the nominal day 30, blood was taken from not anesthetized animals from the retro orbital venous plexus
- Animals fasted: No
- How many animals: 5 animals per test group and sex

URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected overnight on the nominal day 26 and in the recovery period on the nominal day 44.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- How many animals: 5 animals per test group and sex. At the end of the recovery period only the urine sample of the 5 remaining male rsp. female animals of the control group and the highest dose group were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once before the beginning of the 1. exposure (day 0), and on the days 2, 8, 14 and the last exposure day (day 29) of the study just before the exposure started.
- Dose groups that were examined: all animals of the main test groups (control, 5, 20, 100 ppm) and the satellite groups (control, 5, 20, 100 ppm)
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
The examination of the neural functions were performed using a "functional observational battery" which includes
various parameters of sensoric and motoric functions as follows:
Procedure:
Each animal was evaluated according to the following descriptions:
Tremors: Periods of continued fine movements. Normal case is to have none.
Convulsions: Periods of involuntary muscle contractions. Normal case is to have none.
Piloerection: Elevation of the fur on the animals' back. Normal state is to have a smooth fur.
Lacrimation/secretion of pigmented tears: Secretion and discharge of tears. In rats the tears contain a reddish pigment. Not having any discharge 1s normal.
Salivation: Discharge of clear fluid from mouth, most frequently seen as beads of moisture on lips. Normal state is to see none.
Pupil size: Determination of the pupils; pupils are contracted or dilated in the dark.
Diarrhea: Examination of the waste trays beneath the animals cages if there are any signs of loose or liquid feces.
Vocalization: While handling, note if animals make any noises. Except while testing the pain reflex (toe and tail pinch), the animal should not be vocalizing if normal.
Paresis: Restricted movement of one or more than one muscle. Normal case is no restriction of movements.
Paralysis: Complete lass of ability to move one or more than one muscle. Normal ease is no restriction of movements.
Ataxia (inability of all the muscles to act in unison): Impairment of normal gait.
General appearance: Note if the animals' general state of health is affected.
Body tone: The tone of the muscles of the animals' back and of the animals' stomach region are evaluated while handling the animal.
Posture: The body position of the animals during the test is evaluated for abnormalities, such as hunched back, gathering up in a ball, etc.
Animal body (appearance): Note if there is anything abnormal on the animal body.
Locomotor activity: Quantitative evaluation if the animals' movements on the standard arena is hypo- or hyperactive.
Respiration: Observation of the animals' respiration cycle while the animal is at rest in the standard arena.
Urination: Examination of the waste trays beneath the animals' cages if there are any abnormalities concerning volume, odor and color of urine.
Skin color: Determination if the skin color of the animals is changed, e.g. red, blueish, pale etc.
Righting reflex: The animal is placed on its back on the standard arena and the normal animal should turn onto its feet. If it turns sideways or stays on its back, this will be documented.
Behavior: Observation if the animals show any impairment of behavior other then normal such as aggressiveness, passivity etc.
Grip strength: Instrumental measurements of the grip strength of the fore- and hindlimbs are performed according to MEYER et al., 1979 (Neurobehavioral Tox. 1, 233 - 236). Measurements are repeated 3 times.
Pupillary reflex: The animals are kept in the dark for several seconds, thereafter the beam of light from a light pen (Varta 645) is played across the eyes of the animals, and the changes in pupil size are noted. Normally, the pupil should contract when the beam is on it.
Winking reflex: The eye lids are slightly touched with a glass stick and the animal should blink.
Vision: Vision check by approaching the animal with a piece of paper from the side. If normal, the animal should turn towards paper.
Audition: Audition check in a closed chamber at 5000 Hz and a volume of 90 db. If normal, the animal should have startle reflex.
0lfaction: Check of olfactory organ by bringing up to the nose a stick with cotton impregnated with a strong smelling agent. If normal, the animal should bite the cotton or turn its head away.
Sensitivity of the body surface: The back of the animals are slightly touched with a blunt probe. The normal animal should show a reflective moving.
Pain perception (hot plate test): The animal is placed on a hot plate (55°C). The reaction time until paws are licked or the animal jumps onto the edge of the plate is measured.
Tail pinch: The finger nails are used to bring pressure to the tail. This should evoke a response from the normal animal. Repeat 3 times.
Toe pinch: A cannula or a forceps is used to bring pressure to one of the digits. This should evoke a response from the normal animal. Repeat 3 times.
Visual placing response: The animal is taken by the tail and lowered towards a grill. Normal reaction is for the animal to stretch its forelimbs toward the grill before contact. Repeat 3 times.
Miscellaneous: All other visible clinical signs.



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Liver, lungs, kidneys, testes, brain, adrenal glands, forestomach, pancreas, skin

HISTOPATHOLOGY: Yes
all gross lesions, parathyroid glands, heart, spleen, testes, accessory genital organs (prostate, seminal vesicle), skin, jejunum, rectum, lymphnodes (mandibular lymph nodes, mesenteric lymph nodes), sciatic nerve, bone marrow (femur), harderian gland, brain, thymus, aorta, kidneys, epididymides, esophagus, ileum, ureter, female mammary gland, sternum, eyes, spinal cord (cervical, mid thoracic, lumbar cord), pituitary gland, trachea, salivary glands mandibular glands and sublingual glands), adrenal glands, ovaries, stomach, cecum, urethra, femur with articular surface, extraorbital lacrimal glands, head (head with nasal cavities and paranasal sinus), thyroid glands, lungs, liver, pancreas, uterus, duodenum, colon, urinary bladder, skeletal muscle
Statistics:
Clinical examinations
Means and standard deviation were calculated for the variables (bodyweight and body weight change) of the animals of each test group and means and standard deviation were calculated for the variables (grip strength forelimbs, grip strength hind limbs and hot plate test).
Statistical relevance was established using methods of ANOVA, DUNNETT at the main and satellite groups and MANN-WHITNEY U-test at the post-exposure observation groups.
Clinical chemistry and hematology
Mean and standard deviation were calculated for each test group. Except for the differential blood count a statistical one-way analysis of variance is done via the KRUSKALWALLIS-h-test. If the resulting p-value is equal or less than 0.05 a pairwise comparison of each dose group with the control group was carried out using the MANN-WHITNEY-U-test for the hypotheses of equal medians. The results are considered significant for p ≤ 0.05.
Urinalyses
The assessment to whether certain characteristics differed in degree in the control and test groups was carried out using the chi² test in appropriate two-by-two contingency tables. The results are considered significant for S ≥ 95 %.
Pathology
Mean and standard deviation were calculated for the statistical evaluation for the variables of body weight and of absolute and relative organ weights (related to body weight) and of the length and width values of the brain of the animals in each test group.
For the test animals of the main goups (F1) a non-parametric one-way analysis of variance is done via the KRUSKAL-WALLIS-h test. If the resulting p-value is less than 0.05 a pairwise comparisan of each dose group with the control group was carried out using the WILCOXON-U test for the hypotheses of equal means. For the test animals of the recovery group (R1) the statistical analysis was carried out via the WlLCOXON-Test for the hypothesis of equal medians. The results are considered significant for p ≤ 0.05.

Results and discussion

Results of examinations

Details on results:
MORTALITY
No deaths were recorded throughout the study.

CLINICAL SIGNS
During the preflow period, the exposure period and the post-exposure observation period the animals showed no clinical signs and findings different from normal except of animals exposed to 100 ppm:
(1) Main test group:
Exposure period (before and during exposure): Sparse fur in the abdominal region and on the right flank observed in one female animal from day 14 of the study onwards.
Exposure period (after exposure): Reddish crusts on the nasal edges (blood test positive): Males: One animal on day 2 of the study. From day 3 to 29 of the study all animals. Females: From day 21 to 29 of the study all animals.
Sparse fur in the abdominal region and on the right flank: Females: One animal from day 14 of the study onwards.
(2) Satellite group:
Exposure period (after exposure): Reddish crusts on the nasal edges (blood test positive): Males: From day 3 to 29 of the study all animals. Females: On day 4 of the study 3 animals. On day 8 of the study 2 animals. From day 9 to 29 of the study all animals.
(3) Post-exposure observation group: Exposure period (after exposure): Reddish crusts on the nasal edges (blood test positive): Males: On day 2 of the study 2 animals. From day 3 to 29 of the study all animals. Females: On days 3 and 7 of the study 2 animals. From days 8 to 29 of the study all animals.

The reddish crusts around the noses, observed on the rats exposed to 100 ppm are obviously an irritant effect on the nasal mucosa resulting in bloody nasal discharge.

BODY WEIGHT AND WEIGHT GAIN
The body weights of the male and female animals of the main (5, 20, 100 ppm), satellite (5, 20, 100 ppm) and post-exposure (100 ppm) observation groups compared with the control groups was not statistically significantly different.

The body weight change of the male and female animals of the main and satellite groups (20, 100 ppm) as well as of the male and female animals of the post-exposure observation group (100 ppm), compared to the respective control groups, was not statistically significantly different.

The body weight change of the male animals of the main and satellite (5 ppm), compared to the control group were statistically significantly increased (p ≤ 0.05) on days 8 to 22 of the study. This body weight change is regarded as an incidental finding.

Only the male rats of the 100 ppm groups showed a slight trend towards retardation in body weight (main group and satellite group about 3.4% decrease, post-exposure observation group about 5.7% decrease). Because female animals of these groups did not show this trend and because of the lack of a statistical significance if is not clear whether this is an indication of a minimal toxic effect.

FOOD CONSUMPTION
No data.

WATER CONSUMPTION
No data.

OPHTHALMOSCOPIC EXAMINATION
The ophthalmological examinations carried out with a hand slit lamp at the beginning of the preflow period and at the end of the study did not show any impairment of the refracting media.

HAEMATOLOGY
No substance-induced changes.
Clotting analyses
No substance-induced changes.

CLINICAL CHEMISTRY
No substance-induced changes.

URINALYSIS
No substance-induced changes.
The decreased urine volume and the slight increased urinary specific gravity observed in the males of test group 3 (100 ppm) at the end of the exposure period are assessed to be incidental since the differences between the data of the control group and the highest dose group are marginal and were noted in one sex only.

In summary, in the clinicochemical and haematological examinations and in the urinalyses no changes were observed which are due to the inhaled test substance. Alltogether, there are some statistical significant inter-group differences in the results of the hematological and urinalytical data. These deviations are marginal, inconsistent or lacked dosage-relationship. Accordingly, these changes are considered to be of no toxicological significance.

NEUROBEHAVIOUR
On day 8 of the study, the grip strength of the hind limbs of the male animals of the main test group (100 ppm) was statistically significantly increased (p ≤ 0.05). On day 14 of the study, the values of hot plate test was statistically significantly decreased in males of the low dose main test group (p ≤0.05), and of the high dose main test group (p ≤ 0.01).
All other animals of the test groups showed no statistically influenced results of the "functional observational battery".
The statistically significantly increased values of grip strength and decreased values of the hot plate test - both not representing an adverse effect - were assessed as being incidental due to the fact, that they both were observed only on a single day and only in one sex.
Thus, the neurofunctional test did not reveal any substance-related changes.

ORGAN WEIGHTS
There were no statistically significant increase or decrease in absolute organ weights noted.
Only the relative liver weights of the females of concentration group 3 (main group, 100 ppm) were statistically slightly significantly increased, but this is seen to be of incidental character, without any visible histomorphological correlate.

GROSS PATHOLOGY
Macroscopically, there were no substance-induced findings present.

HISTOPATHOLOGY: NON-NEOPLASTIC
Pathohistological findings which were identified as substance-related were not found in the examined organs. Especially there were no signs of neuropathological disorders in the examined spinal cord, brain sections or peripheral nerve using light microscopy. Additionally, the length and width measurements of the brain did not show any statistical significant changes in the test group animals examined when compared with the control animal values.
Alltogether, the inhalation of piperidine in concentrations of 5, 20 and 100 ppm for a period of 28 days did not lead to any substance-related, pathomorphological changes in the male and female test animals.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
>= 350 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related adverse systemic effects were observed in the highest dose tested.
Dose descriptor:
LOAEC
Remarks:
systemic
Effect level:
> 350 mg/m³ air
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOEC
Remarks:
systemic
Effect level:
70 mg/m³ air
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
70 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: bloody nasal discharge

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion