Registration Dossier

Administrative data

Description of key information

1,5 -Cyclooctadiene is of low to moderate acute toxicity with an oral LD50 (rat) of 1900 mg/kg bw (Hüls AG, 1983), a dermal LD50 (rabbit) of > 10000 mg/kg bw and an approximate lethal concentration (ALC, rat, 4 h, vapour) of 12 -19 mg/L after inhalation exposure. The test item may be fatal if swallowed and enters airways.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-04-18 to 1983-05-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Strain: Bor: WISW (SPF TNO)
- Source: F. Winkelmann, Borchen (Germany)
- Weight at study initiation: males mean 140 g, females mean 119 g
- Controls: no
- Fasting period before study: 16 hours
- Diet: ad libitum, R10 special diet for rats, SSniff R
- Water: ad libitum, tap water
- Acclimation period: 4 - 8 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 +/- 1 °C
- Humidity: 60 +/- 5 %
- Photoperiod: 12 hours artificial light, 12 hours dark
- Air changes: 15 per hour
Route of administration:
oral: gavage
Vehicle:
other: no vehicle
Details on oral exposure:
ADMINISTRATION: 
- Doses per time period: single dose (gavage)
- Volume administered or concentration: < 10 ml/kg bw
- Post dose observation period: 14 days
Doses:
1250; 1580; 1990; 2510 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
EXAMINATIONS:
- Body weights: before, and 1, 7, 14 days post dosing
- Clinical signs and mortality: within 6 hours after dosing, thereafter  daily
- Necropsy: 1-5 per sex and dose group (macroscopic), no further details
Statistics:
LD50 is generally determined according to Litchfield and Wilcoxon, reported with 95 % confidence limits.
Means of body weights were calcultated
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 900 mg/kg bw
Mortality:
- Number of deaths at each dose:    
1250 mg/kg bw: no deaths   
1580 mg/kg bw: 0 males, 2 females dead within 33 hours   
1990 mg/kg bw: 2 males, 4 females dead within 120 hours   
2510 mg/kg bw: 4 males, 5 females dead within 96 hours
Clinical signs:
CLINICAL SIGNS: All dosed animals showed toxic symptoms about 45 minutes  after dosing and mostly fading within 6 days after treatment. (one  surviving animal from the highest dose group had a ruffled fur even after  14 days.) Reported symptoms are piloerection, difficult breathing,  impairment of balance, staggering gait, tremor, diuresis, abdominal  position, squatting position and sedation. 
Body weight:
Body weight gain was not affected.
Gross pathology:
NECROPSY FINDINGS: Post mortem sections showed irritated epithelia of the  gastro-intestinal tract and colored spots in the liver. Surviving animals  did not show pathological changes in any tissue after the end of the 14  days observation period. 
Other findings:
no other findings
Conclusions:
Under the present test conditions, the LD50 value (oral) was determined to be 1900 (1667-2166) mg/kg bw in male and female rats for the test item.
Executive summary:

In a study according to OECD TG 401 (1981) the test item was applied once to 4 dose groups of rats (5 male and 5 female Wistar rats per dose group) in doses of 1250, 1580, 1990, 2510 mg/kg bw undiluted. The observation period was 14 days.

Some mid-dose animals died between 33 and 120 hours, 9 of 10 high dose animals died during 96 hours after oral application of the test item. All dosed animals showed toxic symptoms about 45 minutes after dosing and mostly fading within 6 days  after treatment (one surviving animal from the highest dose group had a ruffled fur even after  14 days). Reported symptoms are piloerection, difficult breathing,  impairment of balance, staggering gait, tremor, diuresis, abdominal  position, squatting position and sedation. Post mortem sections showed irritated epithelia of the gastro-intestinal tract and colored spots in the liver. Surviving animals did not  show pathological changes in any tissue after the end of the 14  days observation period. The LD50 value (oral) was determined to be 1900 (1667-2166) mg/kg bw in rats for the test item.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 900 mg/kg bw
Quality of whole database:
The study is valid without restrictions (Klimisch score 1).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 1
Composition 2
Principles of method if other than guideline:
Method: other: See Test Conditions: standard acute inhalation toxicity study; nose-only
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Crl:CD(R) BR
Sex:
male
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Source: 
- Age: approximately 8 weeks
- Weight at study initiation: 268-292 g
- Number of animals: 6
- Controls: no
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
other: houseline air
Details on inhalation exposure:
ADMINISTRATION: 
- Type of exposure: single nose-only exposure
- Concentrations: measured at approximately 15-minute intervals by GC
- Type or preparation of particles: No particles. Chamber atmospheres  were generated by vaporizing the test substance in a heated nitrogen  stream  and dilution with houseline air.
- Temperature, humidity in chamber: 23 +/- 2 °C, 50 +/- 10 %
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Concentrations was measured at approximately 15-minute intervals by GC
Duration of exposure:
4 h
Concentrations:
1400, 2700, or 4300 ppm = 6.30, 12.1, or 19.3 mg/l
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
EXAMINATIONS:
mortality and response to stimuli during exposure; clinical  signs and mortality immediately following exposure; body weight and  clinical signs daily 
thereafter for 14 days (during weekends only when  warranted by the health status of the rats). 
Statistics:
Evaluation with simple  statistics at p <= 0.05.
Key result
Sex:
male
Dose descriptor:
other: ALC (approximate lethal concentration)
Effect level:
ca. 12 - ca. 19 mg/L air
Exp. duration:
4 h
Mortality:
- 1400 ppm: 0/6
- 2700 ppm: 1/6 night after exposure
- 4300 ppm: 4/6 during exposure 
Clinical signs:
- Response to external sound stimuli: Absent for all animals after 3  hours exposure
- Immobility: 2 surviving rats at 4300 ppm and 4 rats at 2700 ppm
- Ataxia: 3 rats at 1400 ppm
- Ocular discharge, ruffled fur, or stained perineum: Up to 4 days  following exposure
- Lethargy, irregular respiration: Only on day of exposure
- No other clinical signs; all clinical signs reversible within 4 days
Body weight:
Body weights: Losses of 4-14% were recorded the day after exposure,  followed by body weight gains in all animals.
Gross pathology:
no data
Other findings:
no other findings

no further results

Conclusions:
Under the present test conditions, test item is considered slightly toxic in an acute inhalation toxicity study.
Executive summary:

Three groups of 6 male rats each were exposed nose-only for a single, 4 hour period to vapors of the test item in air at chamber vapor concentrations of 1400, 2700 or 4300 ppm. Mortality was 0/6, 1/6 and 4/6 at 1400, 2700 and 4300 ppm respectively. By 3 hours into the exposure all rats failed to respond to external sound stimuli. At the end of exposure, the 2 rats at 4300 ppm and 4 rats at 2700 ppm were immobile. Threee rats at 1400 ppm exhibited ataxia. Other clinical signs of toxicity observed after exposure: ocular discharge,  lethargy, irregular respiration. Ocular discharge, ruffled fur or stained perineum were observed up

to 4 days following exposure.

On an acute inhaltion basis, test item is considered slightly toxic.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The study is valid with restrictions (Klimisch score 2).

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-05-25 to 1983-06-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ORGANISMS: 
- Strain: Bor: WISW (SPF TNO)
- Source: F. Winkelmann, Borchen (Germany)
- Weight at study initiation: males mean 251 g, females mean 191 g
- Controls: no
- Diet: ad libitum, R10 special diet for rats, SSniff R
- Water: ad libitum, tap water
- Acclimation period: 4 - 8 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 +/- 1 °C
- Humidity: 60 +/- 5 %
- Photoperiod: 12 hours artificial light, 12 hours dark
- Air changes: 15 per hour
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
ADMINISTRATION: 
- Doses per time period: three doses within 4 hours
- Post dose observation period: 14 days
Duration of exposure:
not rinsed
Doses:
10000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
EXAMINATIONS:
- Body weights: before, and 1, 7, 14 days post dosing
- Clinical signs and mortality: within 6 hours after dosing, thereafter  daily
- Necropsy: 2 per sex and dose group (macroscopic), no further details
Statistics:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Mortality:
MORTALITY: No deaths
Clinical signs:
CLINICAL SIGNS: Straub reaction immediately after application, sedation  after one hour, and later ataxia and slight erythema of the dorsal skin  
(up to 48 hours after treatment)
Body weight:
No effect on body weight gain
Gross pathology:
NECROPSY FINDINGS: No indications of substance related effects were  observed after the end of the observation period of 14 days.
Other findings:
no other findings

no further remarks

Conclusions:
Under the present test conditions, the dermal LD50 value was determined to be greater then 10000 mg/kg bw in rats for the test item.
Executive summary:

In a determination of the acute dermal toxicity on male and female rats it was found that the LD50 of the test item is greater than 10000 mg/kg. The treated animals showed signs of toxicity for up to 48 hours. There was no influence on the increase in body weight. Dissection at the end of the experiment revealed no evidence of macroscopically detectable organ changes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
10 000 mg/kg bw
Quality of whole database:
The study is valid without restrictions (Klimisch score 1).

Additional information

Justification for classification or non-classification

Based on the results of the acute oral and inhalation studies and according to the criteria of CLP Regulation 1272/2008 1,5 -cyclootadiene has to be classified as harmful if swallowed and harmful if inhaled. Based on the results of the acute dermal study the test item has a very low acute toxicity if it comes in contact with skin. Therefore, 1,5 -cyclooctadiene must not be classified regarding this toxcicological endpoint.