Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Isobutyraldehyde administered by inhalation (whole body exposure) for up to 13 weeks or two years was a respiratory tract toxicant but was not carcinogenic in F344/N rats and B6C3FI mice.
Author:
Abdo, KM, Haseman, JK., Nyska, A.
Year:
1998
Bibliographic source:
Toxicol. Science 42: 136-151

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate
EC Number:
261-879-6
EC Name:
Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate
Cas Number:
59719-67-4
Molecular formula:
C24H46N4O6
IUPAC Name:
bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate
Test material form:
liquid

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: not specified
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 6 weeks
- Weight at study initiation: approx. equal weight
- Fasting period before study: not specified
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: not specified

DETAILS OF FOOD AND WATER QUALITY: not specified

ENVIRONMENTAL CONDITIONS: not specified

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Vapor was dynamically generated by bubbling nitrogen gas through a column of liquid maintained at a constant temperature in a water bath. Diluting air was added to the nitrogen-isobutyraldehyde vapor immediately above the bubbler to prevent condensation of isobutyraldehyde in the manifold or deliver lines when cooled to room temperature. Inhalation chambers (1.15 cubic meters) of the Rochester design were used. Chamber ventilation provided 12 to 15 clean-air (charcoal and HEPA filtered) changes per hour. A small particle detector was used to ensure that aldehyde vapor and not aerosol was produced. Chamber concentrations were monitored 6 to 14 times per exposure interval with an infrared spectrophotometer, which measured total aldehydes present.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
500 ppm
Remarks:
approx. 1.5 mg/L air
Dose / conc.:
1 000 ppm
Remarks:
approx. 3 mg/L air
Dose / conc.:
2 000 ppm
Remarks:
approx. 6 mg/L air
Dose / conc.:
4 000 ppm
Remarks:
approx. 12 mg/L air
Dose / conc.:
8 000 ppm
Remarks:
approx. 24 mg/L air
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
In the 13 weeks repeated dose study, B6C3F1 mice were randomized into 5 dose groups (500; 1000; 2000, 4000, 8000 ppm of Isobutyraldehyde) and one control group (air only). The animals were exposed for 6 hours in inhalation chambers for a total of 10 times.
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
Clinical observations were recorded once per week. Animals were weighed prior to initiation, and then weekly and at the end of the study. Necropsy was performed on all animals. The brain, heart, right kidney, liver, lungs, right testis, and thymus were weighed. Visible lesions and tissues masses were subject to microscopic examination.
Sacrifice and pathology:
Complete histopathologic examination was performed on control and 2000 ppm mice.
The following tissues were examined during the gross necropsy. A complete gross necropsy is defined as external examination including body orifices and examination and fixation of these tissues: gross lesions, skin, mandibular lymph node, mammary glands, thigh muscle, sciatic nerve, sternum (including marrow), pancreas, spleen kidneys adrenals, urinary bladder, seminal vesicles, prostate, testes/epididymides/vaginal tunics of the testes and scrotal sac, esophagus, stomach, duodenum, tissue masses or suspect tumors and regional lymph nodes, ileum, colon, cecum, rectum, mesenteric lymph node, liver, costochondral junction (rib), thymus, oral cavity, larynx and pharynx, trachea, lungs and bronchi, heart and aorta, thyroid, parathyroids, ovaries, uterus, nasal cavity and nasal turbinates, jejunum, tongue, brain, pituitary, spinal cord, preputial or clitoral glands, eyes, Zymbal's glands (auditory sebaceous glands), vagina.
Other examinations:
Hematology, clinical chemistry, sperm morphology and vaginal cytology evaluation

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Description (incidence):
One male in the control group, one male in the 1000 ppm group, nine males in the 4000 ppm group, and all males in the 8000 ppm group died before the end of the study as well as all females of the 4000 and 8000 ppm groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Final mean body weights and mean body weight gains of male mice were similar to those of the controls. The final mean body weight and mean body weight gain of female mice in the 1000 ppm group were significantly lower than those of the controls.
Food consumption and compound intake (if feeding study):
not examined
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, non-treatment-related
Description (incidence and severity):
Kidney weights of males in the 1000 and 2000 ppm groups were increased, liver weights in females in the 1000 ppm and 500 ppm groups were decreased. Thymus weights in females were decreaed in the 2000 and 1000 ppm groups. Because of lack of dose response and the absence of lesions related to exposure to isobutyraldehyde in these organs, these variations in organ weights are not considered to be chemically related.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions observed at necropsy that could by associated with isobutyraldehyde exposure.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Increased incidences of non-neoplastic lesions of the nasal cavity were observed in male and female mice exposed to 1000 ppm or greater. These lesions included necrosis, inflammation, hyperplasia, and squamous metaplasia of the epithelium; serous and suppurative exudate within the nasal passages; olfactory epithelial degeneration; and osteodystrophy of the turbinate bone.
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
1 500 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
6 000 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
3 000 mg/m³ air
System:
respiratory system: upper respiratory tract
Organ:
larynx
nasal cavity
Treatment related:
yes
Dose response relationship:
yes

Applicant's summary and conclusion

Conclusions:
The NOAEC (inhalation) for the read-across substance after repeated exposure to vapour for a period of 13 weeks was determined to be 1500 mg/m3 for local effects and 6000 mg/m3 for systemic effects.
Executive summary:

The read-across substance was studied for toxicity by exposing male and female B6C3F1 mice. Animals were exposed to vapours 6 h per day, 5 days per week for up to 13 weeks at concentrations of 0, 500, 1000, 2000, 4000, or 8000 ppm corresponding to approx. 1.5, 3, 6, 12, 24 mg/L. One male in the control group, one male in the 1000 ppm group, nine males in the 4000 ppm group, and all males in the 8000 ppm group died before the end of the study as well as all females of the 4000 and 8000 ppm groups. Chemical-related body weight depression and deaths occurred in mice exposed to 4000 and 8000 ppm. Exposure to 8000 ppm or 4000 ppm resulted in necrosis of the epithelium lining of the nasal turbinates. Osteodystrophy of the nasal turbinate bone and squamous metaplasia of the nasal respiratory epithelium were noted in mice exposed 4000 ppm. Degeneration of the olfactory epithelium was noted in males exposed to 2000 ppm and in females exposed to 4000 ppm. The NOAEC was determined to be 1500 mg/m3 (500 ppm) for local effects and 6000 mg/m3 (2000 ppm) for systemic effects.

Categories Display