Cyclododeca-1,5,9-triene

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

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 1

Reference Type:

publication

Title:

Inhalation toxicity of cyclododecatriene in rats.

Author:

Bamberger JR, Scott RS, Kelly DP, Kennedy GL jr. and Elliott GS

Year:

1999

Bibliographic source:

Drug Chem. Toxicol. 22, 435-454.

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Principles of method if other than guideline:

Method: as described in the reference (Bamberger et al)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,5,9-Cyclododecatriene

IUPAC Name:

1,5,9-Cyclododecatriene

Details on test material:

1,5,9-cyclododecatriene of DuPont Nylon, Victoria (Texas, USA);
Purity approximately 100%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD(R)(SD)BR

Sex:

male

Details on test animals or test system and environmental conditions:

Strain: Crl:CD(R)(SD)BR
- Source: Charles River Breeding Laboratories, Raleigh (USA)
- Age: ca. 8 weeks
- Weight at study initiation: ca. 245 g (mean)
further information : see reference (Bamberger et al)

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Particle size: vapour at 5 and 50 ppm;
 aerosol at 260 ppm;   particle size: MMAD 3.5 or 3.7 um,    35 or 36% of particles < 3 um;   98 or 99% of particles < 10 um

Details on inhalation exposure:

see reference

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

-analysed by gas chromatography and gravimetric analysis in 60 min intervalls

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

6 hours/day, 5 days/week, total 9 exposures

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 ppm

Remarks:

33.4 mg/m3; 5 +/- 0 ppm (analytical concentration)

Doses / concentrations 2

Dose / conc.:

50 ppm

Remarks:

334 mg/m3; 51 +/- 1.0 ppm (analytical concentration)

Doses / concentrations 3

Dose / conc.:

260 ppm

Remarks:

1740 mg/m3; 260 +/- 5.7 ppm (analytical concentration)

No. of animals per sex per dose:

10 per group

Control animals:

yes, concurrent no treatment

Details on study design:

- Number of animals: 10 animals per group
-  2 groups per concentration:     
1 for standard toxicological evaluations      
1 for neurotoxicity testing
-Post-exposure period: 2 weeks (half of the animals)
- SATELLITE GROUPS AND REASONS THEY WERE ADDED: neurotoxicity

Examinations

Observations and examinations performed and frequency:

- Clinical signs: groupwise during exposure, individually after each  exposure
- Mortality: before / during / after exposure
- Body weight: before each exposure; daily except weekends during  recovery period
- Haematology: end of exposure period
- Biochemistry: end of exposure period
- Urinalysis: end of exposure period

Sacrifice and pathology:

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 

-5 animals per group sacrificed 1 day after last exposure; other animals sacrificed after (additional) 14 days of recovery

- Macroscopic:    weights of liver, kidneys, lungs, testes, brain;   examination of liver, kidneys, lungs, duodenum, heart, spleen, brain  (cerebrum, midbrain, cerebellum, medulla / pons), spinal cord, stomach,  jejunum, ileum, pancreas, cecum, colon, rectum, mesenteric lymph node,  thymus, adrenal glands, sciatic nerve, thyroid gland, parathyroid glands,  trachea, esophagus, pharynx / larynx, eyes, prostate, seminal vesicles,  urinary bladder, testes epididymides, sternum (with bone marrow), nose;  samples of all plus of gross lesions were saved

- Microscopic:    control and high dose animals sacrificed without recovery period: all  organs listed above (macroscopic examination);   animals from other dose groups sacrificed without recovery and control  and high dose animals sacrificed after recovery: nose, pharynx / larynx,  lungs, liver, kidneys

Other examinations:

OTHER EXAMINATIONS: 
Neurotoxicity groups   Functional observational battery (FOB) of tests   + motor activity (MA) evaluations   immediately after 4th and 9th exposures;   Neuropathology evaluation in 6/10 control and high dose animals after  9th exposure

Statistics:

- Mean, standard deviation, standard error;
- Incidences: Cochran-Armitage test for trend;
- Body & organ weights: one-way analysis of variance;
- Pairwise comparison with controls: Dunnett's test
- Homogeneity of variances: Bartlett's test
- Clinical pathology: one-way analysis of variance, Bartlett's test;  Dunnett's test for comparison of means to control; Kruskal-Wallis test  and Mann-Whitney U test when Bartlett's test showed significance  (p<0.005) 
- FOB: Cochran-Armitage test for trend, Fisher's exact test for  significance of deviations from control 
- Other test in neurobehavioral evaluations: Bartlett's test for  homogeneity (p<0.005), univariate analysis of variance, Shapiro-Wilk's  test, Levene's test, Kruskal-Wallis followed by Dunn's test, block (all  p<0.05)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Irregular respiration in the high dose group. Other clinical observations occurred sporadically in all groups including controls and were considered incidental.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

significantly reduced at >= 50 ppm, reversible

Haematological findings:

no effects observed

Description (incidence and severity):

Compound-related or biologically adverse changes did not occur during this study.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Compound-related or biologically adverse changes did not occur during this study.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Statistically significant or biologically adverse changes did not occur during this study.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

A diminished or absent response to an alerting stimulus was observed in the high dose group. Mean foot splay was significantly decreased on days 4 and 9 in the high dose group. The incidence of defecation was decreased in the 50 and 260 ppm groups during the motor activity assessments. Beyond this, there were no statistically significant or toxicologically remarkable neurobehavioral differences between the control and treatment groups.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related changes were observed. (Absolute but not relative lung weights were reduced in the high dose group.)

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related changes were observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Effects only occurred in the nasal tissue of the high dose group. Minimal degeneration / necrosis of olfactory epithelium occurred in the anterior portion of the nose of 4/5 rats exposed to 260 ppm. This lesion was observed neither in the 260 ppm recovery group, which suggests reversibility, nor in the lower dosed groups.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

33.4 mg/m³ air

Sex:

male

Basis for effect level:

other: no adverse effects observed

2

Dose descriptor:

LOAEC

Effect level:

334 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Critical effects observed:

no