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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

The carcinogenicity of Hexachlorocyclopentadiene was evaluated using a method similar to the OECD Test Guideline 453 (GLP). Rats were exposed at concentrations of 0, 0.01, 0.05 or 0.2 ppm of Hexachlorocyclopentadiene in air (equivalent to 0, 0.11, 0.56 and 2.28 mg/m3) for 6 hours per day, 5 days per week, for 103 to 104 weeks. No animals died as a result of the exposure to Hexachlorocyclopentadiene. Observation were made of granular pigment in a few cells in bronchi and branchioles of the lung of exposed rats as well as in a small number of control animals. In female rats exposed at 0.01 and 0.2 ppm of test substance, significant incidences of squamous metaplasia of the larynx were observed.

Specific gravity measurements of urine from males exposed to 0.01, 0.05, and 0.2 ppm and from females exposed to 0.05 and 0.2 ppm of test substance were significantly greater than those from the controls. Urine volume of females in the 0.2 ppm group was significantly lower than that of the controls. These differences suggest a treatment-related renal disorder, but the lack of chemical-related kidney lesions does not support such as conclusion.

This carcinogenicity study by inhalation allowed to determine a NOAEC above 0.2 ppm (equivalent to 2.28 mg/m3) for both the systemic effects and a LOAEC of 0.01 ppm (equivalent to 0.11 mg/m3) for the local effects based on findings in the respiratory tract. No neoplastic effects were observed that could be attributed to the exposure to Hexachlorocyclopentadiene. It was concluded that the substance was not a carcinogen under the conditions of the study.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2 December 1985 to 4 December 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Ophthalmological examination, haematology, urinalysis, and biochemistry were not included. Temperature and humidity were outside the ranges.
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6-7 weeks
- Weight at study initiation: Females: 110 to 112g / Males: 139 to 143g
- Housing: individually in stainless steel cages (Hazleton Systems)
- Diet (e.g. ad libitum): NIH-07 pelleted rodent diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 19 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C-29°C
- Humidity (%): 21%-88%
- Air changes (per hr): 9-20 changes/h
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel whole-body inhalation chamber (Hazleton Systems)
- Source and rate of air: fresh air
- System of generating particulates/aerosols: Vaporizer. Gardner Type CN condensation nuclei detector
used to ensure the generation of vapour and not of aerosol.

TEST ATMOSPHERE
- Brief description of analytical method used: On-line gas chromatograph with electron capture detector.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A gas chromatograph with an electron capture detector was used. The system was a 3% OV-225 coating on a 100/120 mesh Gas Chrom Q column and an argon/methane (9O:lO) carrier gas at a flow rate of 30 mL/minute. Column was maintained isothermally at 125°C.
Duration of treatment / exposure:
103 to 104 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Dose / conc.:
0 ppm (nominal)
Remarks:
Equivalent to 0 mg/m3.
Dose / conc.:
0.01 ppm (nominal)
Remarks:
Equivalent to 0.11 mg/m3.
Dose / conc.:
0.05 ppm (nominal)
Remarks:
Equivalent to 0.56 mg/m3.
Dose / conc.:
0.2 ppm (nominal)
Remarks:
Equivalent to 2.28 mg/m3.
No. of animals per sex per dose:
60 animals/sex/dose.
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on results of a 13-week repeated dose toxicity study by inhalation performed beforehand
- Rationale for animal assignment (if not random): XYBION PATH/TOX System
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: Initially, weekly for the first 13 weeks, then monthly.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: 15 months
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends.
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Body weight and weight changes:
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Only urinalysis was performed at 15 months. Specific gravity measurements of urine from males exposed to 0.01, 0.05, and 0.2 ppm and from females exposed to 0.05 and 0.2 ppm of test substance were significantly greater than those from the controls. Urine volume of females in the 0.2 ppm group was significantly lower than that of the controls.
These differences suggest a treatment-related renal disorder, but the lack of chemical-related kidney lesions does not support such as conclusion.
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):
In male rats exposed to 0.05 and 0.2 ppm of test substance, absolute lung weight was significantly lower than those of the controls but not the relative lung weight, therefore it was concluded that it was related to the lower body weights rather than to the treatment.
Description (incidence and severity):
Accumulation of granular pigment in nose, trachea, and bronchi and branchioles of the lung.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Observation of granular pigment in a few cells in bronchi and branchioles of the lung of exposed rats as well as in a small number of control animals.
In female rats exposed at 0.01 and 0.2 ppm of test substance, significant incidences of squamous metaplasia of the larynx was observed. This effect was not investigated in male rats.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Significant increased incidence of pars distalis adenoma in pituitary gland was observed in male rats exposed at 0.2 ppm of test substance but was similar to the historical control and not considered to be treatment related.
Relevance of carcinogenic effects / potential:
No neoplastic effects were observed that could be attributed to the exposure to Hexachlorocyclopentadiene. It was concluded that the substance was not a carcinogen under the conditions of the study.
Key result
Dose descriptor:
NOAEC
Remarks:
systemic effects
Effect level:
> 2.28 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Key result
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
0.11 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Critical effects observed:
no
Lowest effective dose / conc.:
0.01 ppm
System:
respiratory system: upper respiratory tract
Organ:
larynx
nasal cavity
trachea
Critical effects observed:
no
Lowest effective dose / conc.:
0.01 ppm
System:
respiratory system: lower respiratory tract
Organ:
bronchi
bronchioles
Conclusions:
A carcinogenicity/chronic study by inhalation was performed on rats using Hexachlorocyclopentadiene that allowed to determine a NOAEC above 0.2 ppm (equivalent to 2.28 mg/m3) for the systemic effects and a LOAEC of 0.01 ppm (equivalent to 0.11 mg/m3) for the local effects based on findings in the respiratory tract. No neoplastic effects were observed that could be attributed to the exposure to Hexachlorocyclopentadiene. It was concluded that the substance was not a carcinogen under the conditions of the study.
Executive summary:

The carcinogenicity of Hexachlorocyclopentadiene was evaluated using a method similar to the OECD Test Guideline 453 (GLP) with deviations.

Rats were exposed at concentrations of 0, 0.01, 0.05 and 0.2 ppm of Hexachlorocyclopentadiene in air (equivalent to 0, 0.11, 0.56 and 2.28 mg/m3) for 6 hours per day, 5 days per week, for 103 to 104 weeks. Mortality, clinical signs and body weight were recorded. Urinalysis was investigated once at 15 months. At the end of the study, surviving animals were subjected to gross necropsy and histopathology.

No animals died as a result of the exposure to Hexachlorocyclopentadiene. Observation were made of granular pigment in a few cells in bronchi and branchioles of the lung of exposed rats as well as in a small number of control animals. In female rats exposed at 0.01 and 0.2 ppm of test substance, significant incidences of squamous metaplasia of the larynx were observed. This effect was not investigated in male rats.

Significant increased incidence of pars distalis adenoma in pituitary gland was observed in male rats exposed at 0.2 ppm of test substance but was similar to the historical control and not considered to be treatment related.

In male rats exposed to 0.05 and 0.2 ppm of test substance, absolute lung weight was significantly lower than those of the controls but not the relative lung weight, therefore it was concluded that it was related to the lower body weights rather than to the treatment.

Specific gravity measurements of urine from males exposed to 0.01, 0.05, and 0.2 ppm and from females exposed to 0.05 and 0.2 ppm of test substance were significantly greater than those from the controls. Urine volume of females in the 0.2 ppm group was significantly lower than that of the controls. These differences suggest a treatment-related renal disorder, but the lack of chemical-related kidney lesions does not support such as conclusion.

This carcinogenicity study by inhalation allowed to determine a NOAEC above 0.2 ppm (equivalent to 2.28 mg/m3) for both the systemic effects and a LOAEC of 0.01 ppm (equivalent to 0.11 mg/m3) for the local effects based on findings in the respiratory tract. No neoplastic effects were observed that could be attributed to the exposure to Hexachlorocyclopentadiene. It was concluded that the substance was not a carcinogen under the conditions of the study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2.28 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The carcinogenicity of Hexachlorocyclopentadiene was evaluated using a method similar to the OECD Test Guideline 453 (GLP) with non-significant deviations.

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

A carcinogenicity/chronic study by inhalation was performed on rats using Hexachlorocyclopentadiene that allowed to determine a NOAEC above 0.2 ppm (equivalent to 2.28 mg/m3) for the systemic effects and a LOAEC of 0.01 ppm (equivalent to 0.11 mg/m3) for the local effects based on findings in the respiratory tract. No neoplastic effects were observed that could be attributed to the exposure of Hexachlorocyclopentadiene. It was concluded that the substance was not a carcinogen under the conditions of the study. It did not meet the criteria for classification according to Regulation (EC) N° 1272/2008.

Additional information