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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981
Reference Type:
publication
Title:
Toxicity of hexachlorocyclopentadiene: subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice.
Author:
Abdo KM, Montgomery CA, Kluwe WM, Farnell DR, Prejean JD.
Year:
1984
Bibliographic source:
J Appl Toxicol. 1984 Apr;4(2):75-81.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Exposure 5 days per week. FOB and ophthalmological examination were not performed. Urinalysis, haematology, or clinical biochemistry were not examined
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Hexachlorocyclopentadiene
EC Number:
201-029-3
EC Name:
Hexachlorocyclopentadiene
Cas Number:
77-47-4
Molecular formula:
C5Cl6
IUPAC Name:
hexachlorocyclopentadiene
Test material form:
liquid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 52 days
- Weight at study initiation: Females: 99 - 135 g. Males: 130 - 170 g.
- Housing: Five animals per cage in polycarbonate cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72°F to 78°F (22°C to 25°C)
- Humidity (%): 23% to 58%
- Air changes (per hr): 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Lot/batch no.: 1-13-82A
- Amount of vehicle (if gavage): 0.5ml/100g
- Purity: 100%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosage analysis for concentration verification was performed in duplicate on each dose level for the first set of mixings and a set approximately midway through the study.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Once a day, 5 days per week. The frequency was selected to mimic the exposure of workers.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
19 mg/kg bw/day (nominal)
Dose / conc.:
38 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Initially, weekly, and at termination

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: Not specified

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
Not specified

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals treated at 150 mg/kg bw/day displayed a ruffled fur and a slight inactivity that were considered treatment-related. Other clinical observations were attributed to the housing of animals collectively or were not considered as significant due to their low incidence.
Mortality:
mortality observed, treatment-related
Description (incidence):
6/10 male rats receiving 150 mg/kg bw/day died as a result of the treatment. 1/10 female rats receiving 75 mg/kg bw/day died as a result of the treatment. Other deaths occurred in male and female rats at different doses that were attributed to improper gavage technique.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A significant reduction of the bodyweight was observed in male rats receiving 38 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10 and 19 mg/kg bw/day.
A significant reduction of the bodyweight was observed in female rats receiving 75 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10, 19 and 75 mg/kg bw/day.
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, treatment-related
Description (incidence and severity):
In male rats, the increase in relative liver weight at the dose levels of 10, 19, 38, and 75 mg/kg bw was -23% (decrease), 5%, 18%, and 31% respectively. The increase in relative kidney weight was -5% (decrease), 13%, 23% and 39% respectively.
In female rats, the increase in relative liver weight at the dose levels of 10, 19, 38, and 75 mg/kg bw was 17%, 4%, 19%, and 33% respectively. The increase in relative kidney weight was 10%, 12%, 30% and 62% respectively.
Relative organ weights could not be calculated at 150 mg/kg bw/day due to the deaths occurring at this dose level.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In male rats receiving 75 mg/kg bw/day and above and female rats receiving 38 mg/kg bw/day and above, effects in stomach including mass and black areas were observed and considered treatment-related.
Other gross pathological findings were not considered significant or treatment-related.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Animals exposed to 38 mg/kg bw/day and above exhibited acute kidney tubular necrosis characterised by vacuolisation, cytomegaly, karyomegaly, anisokaryosis, and tubular dilation.
In male rats receiving 38 mg/kg bw/day or above and female rats receiving 19 mg/kg bw/day, significant proliferation and inflammatory changes of the epithelia in the stomach were observed.
Histopathological findings: neoplastic:
no effects observed
Details on results:
A NOAEL(systemic) of 10 mg/kg bw/day can be derived for both male and female rats.
A NOAEL(local) of 10 mg/kg bw/day can be derived for female rats.
A NOAEL(local) of 19 mg/kg bw/day can be derived for male rats.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
19 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

open allclose all
Critical effects observed:
yes
Lowest effective dose / conc.:
19 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Critical effects observed:
yes
Lowest effective dose / conc.:
19 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
A subchronic toxicity study by the oral route was performed on rats using Hexachlorocyclopentadiene that allowed to determine a NOAEL(systemic) of 10 mg/kg bw/day for both male and female rats, a NOAEL(local) of 10 mg/kg bw/day for female rats, and a NOAEL(local) of 19 mg/kg bw/day for male rats.
Executive summary:

The repeated dose toxicity of Hexachlorocyclopentadiene by the oral route was evaluated using a method similar to the OECD Test Guideline 408 (non-GLP) with deviations.

Rats received doses of 0, 10, 19, 38, 75 and 150 of Hexachlorocyclopentadiene by gavage once a day, 5 days per week, for 13 weeks. The protocol was determined to mimic the exposure of workers. Mortality, clinical signs and body weight were recorded. At the end of the study, surviving animals were subjected to gross necropsy and histopathology.

Six male rats receiving 150 mg/kg bw/day and one female rats receiving 75 mg/kg bw/day died as a result of the treatment. Other deaths occurred that were attributed to improper gavage technique. Animals treated at 150 mg/kg bw/day displayed a ruffled fur and a slight inactivity that were considered treatment-related. Other clinical observations were attributed to the housing of animals collectively or were not considered as significant due to their low incidence.

A significant reduction of the bodyweight was observed in male rats receiving 38 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10 and 19 mg/kg bw/day. A significant reduction of the bodyweight was observed in female rats receiving 75 mg/kg bw/day or above. A reduction was also observed in male rats receiving 10, 19 and 75 mg/kg bw/day.

In male rats, the increase in relative liver weight at the dose levels of 10, 19, 38, and 75 mg/kg bw was -23% (decrease), 5%, 18%, and 31% respectively. The increase in relative kidney weight was -5% (decrease), 13%, 23% and 39% respectively. In female rats, the increase in relative liver weight at the dose levels of 10, 19, 38 and 75 mg/kg bw was 17%, 4%, 19% and 33% respectively. The increase in relative kidney weight was 10%, 12%, 30% and 62% respectively.

In male rats receiving 75 mg/kg bw/day and above and female rats receiving 38 mg/kg bw/day and above, effects in stomach including mass and black areas were observed and considered treatment-related. Other gross pathological findings were not considered significant or treatment-related.

Animals exposed to 38 mg/kg bw/day and above exhibited acute kidney tubular necrosis characterised by vacuolisation, cytomegaly, karyomegaly, anisokaryosis, and tubular dilation. In male rats receiving 38 mg/kg bw/day or above and female rats receiving 19 mg/kg bw/day, significant proliferation and inflammatory changes of the epithelia in the stomach were observed.

This subchronic toxicity study by the oral route allowed to determine a NOAEL(systemic) of 10 mg/kg bw/day for both male and female rats, a NOAEL(local) of 10 mg/kg bw/day for female rats, and a NOAEL(local) of 19 mg/kg bw/day for male rats.