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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 July 2013-6 March 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was not conducted according to guidelines but was conducted according to GLPs and the report contains sufficient data for interpretation of study results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)
Qualifier:
according to
Guideline:
other: EEC, Part B.29
Principles of method if other than guideline:
This study was also designed to evaluate the potential for local (portal-of-entry) and systemic toxicity from inhalation of 1,3- and 1,4-cyclohexanedicarboxaldehyde.
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: vapour
Details on test material:
-Name of test material (as cited in study report): 1,3 and 1,4-Cyclohexanecarboxaldehyde
- Composition of test material, percentage of components: A mixture of 1,3-Cyclohexanedicarboxaldehyde and
1,4-Cyclohexanedicarboxaldehyde
- Lot/batch No.: Lot# 201200123-WFE 2-3Mr
-The purity of the test material was determined to be 98.24 ± 0.44% area by gas chromatography (corrected for water) with identification by
proton and carbon-13 nuclear magnetic resonance and gas chromatography mass spectrometry

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: see "Details on inhalation exposure"
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
six hours/day, five consecutive days/week for 13 weeks.
No. of animals per sex per dose:
Male and female (each): 10 animals at 0 mg/m3
Male and female (each): 10 animals at 0.3 mg/m3
Male and female (each): 10animals at 2.67 mg/m3
Male and female (each): 10animals at 24.0 mg/m3

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
local signs of irritation in the respiratory tract
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
Systemic
Effect level:
> 24 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; food consumption; food efficiency; water consumption and compound intake; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology; other.
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
ca. 2.67 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based upon the localized, point of contact histopathological effects in the anterior nasal passage.
Dose descriptor:
NOEC
Remarks:
Local
Effect level:
ca. 2.67 mg/m³ air
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based upon the localized, point of contact histopathological effects in the anterior nasal passage.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There were no exposure-related effects on body weights/body weight gains, feed consumption, clinical observations, functional tests,hematology, prothrombin time, clinical chemistry, urinalysis, or organ weights. Based on BAL analyses, male and female rats exposed to1,3- and 1,4-cyclohexanedicarboxaldehyde vaporsat concentrations up to and including 24.0 mg/m3showed no evidence of exposure-related cellular injury or inflammation. Compared to control rats, no increase in total BAL cell numbers and no evidence of acute neutrophilic inflammation were detected in any test material-exposed group. No treatment-related alterations were noted in BAL protein or LDH levels.

There were no treatment-related gross pathologic observations.

There was no histopathological evidence of treatment-related systemic toxicity in males or females exposed to the highest exposure concentration of 24.0 mg/m3. Males exposed to 2.67 or 24.0 mg/m3and females exposed to 24.0 mg/m3had treatment-related histopathological changes that were confined to the anterior nasal cavity consistent withlocalized, point of contact irritant effects resulting from repeated inhalation of 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors. The effects observed in the males at the 2.67 mg/m3 were very slight and represented an adaptive change (increase in mucouse secretion) rather than an adverse effect. Nasal airways of males exposed to 0.30 mg/m3and females exposed to 0.30 or 2.67 mg/m3had no treatment-related changes. There were no treatment-related histopathological changes in the posterior nasal airways, larynx, trachea or lungs in males or females in any of the exposure groups.

A limited assessment of the effects of repeated inhalation exposure to 1,3- and 1,4-cyclohexanedicarboxaldehyde on pulmonary function and non-specific airway reactivity (methacholine-challenge) was also conducted on 4 rats/sex from the control and high exposure groups. The rats were monitored for signs of treatment-related alterations in respiratory parameters after exposure during the 9thexposure week and following the last day of exposure (at the end of the 13thweek of exposure). No treatment-related alterations in pulmonary function were observed during post-exposure monitoring. Prior to necropsy, the previously monitored rats were evaluated for exposure-related changes in nonspecific airway responsiveness (measured as a change in Penh) by exposure to increasing concentrations of aerosolized methacholine hydrochloride (MCh) in whole-body barometric plethysmography chambers. Compared to air-exposed control rats of the same sex, malebut not female rats exposed to 24.0 mg/m3had increased airway responsiveness to MCh challenge as evidenced by Penh values that were statistically higher than control rats. The observed increase in airway reactivity in only one sex and the absence of morphologic evidence of pulmonary airway inflammation or remodeling suggests exposure-related irritation, and not allergic sensitization, as the underlying cause of the increased responsiveness to methacholine challenge.

Histopathological lesions were limited to the anterior nasal cavity, consistent with the irritant qualities of 1,3- and 1,4-cyclohexanedicarboxaldehydeBased on the absence of exposure-related systemic effects, the 13-week no-observed-adverse-effect level (NOAEL) for 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors in male and female F344/DuCrl rats was determined to be greater than the highest concentration tested, 24.0 mg/m3. Based upon the localized, point of contact histopathological effects in the anterior nasal passage, the no-observed-effect level (NOAEL) for male and female F344/DuCrl rats repeatedly exposed to 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors for 13 weeks (65 exposures) was and 2.67 mg/m3.

Applicant's summary and conclusion

Conclusions:
The adminsitration of the test material to male and female rats for 90-days (6h/d) resulted in local, site of contact irritation effects to the upper respiratory tract only. There was no indication of systemci toxicity at any dose level. The methacholine-challenge provided further information for the presence of an irritating effect (rather than an allergic reaction). The NOAEL for local effects is therefore the mid dose group - 2.67 mg/m3, and the NOAEL for systemic toxicity is the top dose of 24 mg/m3.
Executive summary:

This study was designed to evaluate the potential for local (portal-of-entry) and systemic toxicity from inhalation of1,3- and 1,4-cyclohexanedicarboxaldehyde. Groups of ten male and ten female F344/DuCrl rats were exposed six hours/day, five consecutive days/week for 13 weeks (a total of 65 exposures) using a flow-past nose-only inhalation exposure system. The rats were exposed to analytically-determined time-weighted average (TWA) concentrations of0,0.30 ± 0.20, 0, or 24.0 ± 5.2(study TWA±standard deviation)mg 1,3- and 1,4-cyclohexanedicarboxaldehyde vapor/m3air (0, 0.05, 0.47, or 4.2 ppm, respectively). In-life observations (including ophthalmology), functional tests, feed consumption, body weights/body weight gains, urinalysis, coagulation, hematology, clinical chemistry and organ weights were evaluated. Bronchoalveolar lavage (BAL) was performed on all exposure groups to assess exposure-related pulmonary inflammation and injury by measuring the types and numbers of inflammatory cells, the total protein concentration and lactate dehydrogenase (LDH) activity in the recovered lavage fluid. At the end of 13 weeks of exposure necropsy was conducted on all animals and a detailed histopathologic examination of the entire respiratory tract was performed by light microscopy to assess treatment-related portal of entry effects. In addition, a detailed histopathologic examination of all other tissues/organs was performed on the control- and high-exposure group rats to identify treatment-related systemic toxicity.

There were no exposure-related effects on body weights/body weight gains, feed consumption, clinical observations, functional tests,hematology, prothrombin time, clinical chemistry, urinalysis, or organ weights. Based on BAL analyses, male and female rats exposed to1,3- and 1,4-cyclohexanedicarboxaldehyde vaporsat concentrations up to and including 24.0 mg/m3showed no evidence of exposure-related cellular injury or inflammation. Compared to control rats, no increase in total BAL cell numbers and no evidence of acute neutrophilic inflammation were detected in any test material-exposed group. No treatment-related alterations were noted in BAL protein or LDH levels.

There were no treatment-related gross pathologic observations.

There was no histopathological evidence of treatment-related systemic toxicity in males or females exposed to the highest exposure concentration of 24.0 mg/m3. Males exposed to 2.67 or 24.0 mg/m3and females exposed to 24.0 mg/m3had treatment-related histopathological changes that were confined to the anterior nasal cavity consistent withlocalized, point of contact irritant effects resulting from repeated inhalation of 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors. The effects observed in the males at the 2.67 mg/m3 were very slight and represented an adaptive change (increase in mucouse secretion) rather than an adverse effect. Nasal airways of males exposed to 0.30 mg/m3and females exposed to 0.30 or 2.67 mg/m3had no treatment-related changes. There were no treatment-related histopathological changes in the posterior nasal airways, larynx, trachea or lungs in males or females in any of the exposure groups.

A limited assessment of the effects of repeated inhalation exposure to 1,3- and 1,4-cyclohexanedicarboxaldehyde on pulmonary function and non-specific airway reactivity (methacholine-challenge) was also conducted on 4 rats/sex from the control and high exposure groups. The rats were monitored for signs of treatment-related alterations in respiratory parameters after exposure during the 9thexposure week and following the last day of exposure (at the end of the 13thweek of exposure). No treatment-related alterations in pulmonary function were observed during post-exposure monitoring. Prior to necropsy, the previously monitored rats were evaluated for exposure-related changes in nonspecific airway responsiveness (measured as a change in Penh) by exposure to increasing concentrations of aerosolized methacholine hydrochloride (MCh) in whole-body barometric plethysmography chambers. Compared to air-exposed control rats of the same sex, malebut not female rats exposed to 24.0 mg/m3had increased airway responsiveness to MCh challenge as evidenced by Penh values that were statistically higher than control rats. The observed increase in airway reactivity in only one sex and the absence of morphologic evidence of pulmonary airway inflammation or remodeling suggests exposure-related irritation, and not allergic sensitization, as the underlying cause of the increased responsiveness to methacholine challenge.

Histopathological lesions were limited to the anterior nasal cavity, consistent with the irritant qualities of 1,3- and 1,4-cyclohexanedicarboxaldehydeBased on the absence of exposure-related systemic effects, the 13-week no-observed-adverse-effect level (NOAEL) for 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors in male and female F344/DuCrl rats was determined to be greater than the highest concentration tested, 24.0 mg/m3. Based upon the localized, point of contact histopathological effects in the anterior nasal passage, the no-observed-effect level (NOAEL) for male and female F344/DuCrl rats repeatedly exposed to 1,3- and 1,4-cyclohexanedicarboxaldehyde vapors for 13 weeks (65 exposures) was and 2.67 mg/m3.