Bis[2-[2-(1-methylethyl)-3-oxazolidinyl]ethyl] hexan-1,2-diylbiscarbamate

Repeated dose toxicity: inhalation

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

Test material information

Constituent 1

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-isopropyl-1,3-oxazolidin-3-yl)ethyl] hexane-1,6-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 / concentrations

Doses / concentrations 1

Dose / conc.:

500 ppm

Remarks:

approx. 1.5 mg/L air

Doses / concentrations 2

Dose / conc.:

1 000 ppm

Remarks:

approx. 3 mg/L air

Doses / concentrations 3

Dose / conc.:

2 000 ppm

Remarks:

approx. 6 mg/L air

Doses / concentrations 4

Dose / conc.:

4 000 ppm

Remarks:

approx. 12 mg/L air

Doses / concentrations 5

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

1

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

2

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.