Hexachlorocyclopentadiene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: An assessment was performed based on available results from dedicated toxicokinetic studies performed on the substance, along with data from toxicological studies and physical properties of the substance.

Adequacy of study:

weight of evidence

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An assessment was performed based on available results from dedicated toxicokinetic studies performed on the substance, along with data from toxicological studies and physical properties of the substance.

Data source

Reference

Reference Type:

other: expert assessment

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

An assessment was performed based on available results from dedicated toxicokinetic studies performed on the substance, along with data from toxicological studies and physical properties of the substance.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexachlorocyclopentadiene

EC Number:

201-029-3

EC Name:

Hexachlorocyclopentadiene

Cas Number:

77-47-4

Molecular formula:

C5Cl6

IUPAC Name:

hexachlorocyclopentadiene

Radiolabelling:

yes

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

see 'details on absorption'

Main ADME results 2

Type:

distribution

Results:

see 'details on distribution in tissues'

Main ADME results 3

Type:

metabolism

Results:

see 'details on metabolites'

Main ADME results 4

Type:

excretion

Results:

see 'details on excretion'

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral Exposure:
- Radiolabelled 14C-Hexachlorocyclopentadiene was administrated by the oral route to rats by Yu et al. (1980). This study showed that the substance or its metabolites generated in the gastrointestinal tract were absorbed following an oral exposure. Administration of the same dose of radiolabelled substance by intravenous injection (IV) allowed to compare the body burden and the bioavailability of the substance between the two routes. Body burden following oral exposure represented 1/10 of the IV and the bioavailability 1/70. It can be concluded that only a fraction of Hexachlorocyclopentadiene or its metabolites are absorbed following oral exposure.
- Studies were used for the purpose of this REACH Registration investigating the effects of Hexachlorocyclopentadiene following an acute or repeated oral exposure. Systemic effects were identified – including mortality, piloerection, reduced body and organ weights, effects on kidney – indicating that absorption occurred following oral exposure.
Inhalation Exposure:
- Radiolabelled 14C-Hexachlorocyclopentadiene was administrated by inhalation as vapours to rats by Southern Research Institute (undated). Elimination of the radiolabelled elements through urine and faeces proves that the substance has been absorbed. Radioactivity in tissues was higher than that following oral exposure but lower than the radioactivity measured following an IV; this suggest that the absorption following inhalation is higher than absorption following oral exposure.
- Studies were used for the purpose of this REACH Registration investigating the effects of Hexachlorocyclopentadiene following an acute or repeated exposure by inhalation. Systemic effects were identified – including ataxia, listlessness, reduced body weight, changes in blood and urine parameters, effects on kidney and liver – indicating that absorption occurred following an exposure by inhalation.
Dermal Exposure:
- The dermal absorption was not investigated as part of the available toxicokinetic studies on Hexachlorocyclopentadiene as these studies were focused on the oral and inhalation routes. Therefore the dermal absorption of the substance was assessed based on its physicochemical properties and the available toxicological studies performed via the dermal route.
- Hexachlorocyclopentadiene has a molecular mass of 272.77 below the threshold of 500 Da (Bos et al, 2000) so a dermal absorption is possible.
- Studies were used for the purpose of this REACH Registration investigating the effects of Hexachlorocyclopentadiene following an acute or repeated exposure by the dermal route. Mortality was observed in the acute toxicity studies. This result suggests that dermal absorption occurred.
- In addition IRDC (1972) observed during an in vivo eye irritation study that all animals died before the 9th day following the treatment. It was concluded that the deaths were due to the substance and that an absorption through the eye occurred.

Details on distribution in tissues:

- Following an IV of radiolabelled 14C-Hexachlorocyclopentadiene to rats, Yu et al. (1980) observed that the highest concentrations of radiolabelled elements were found in the kidney, liver, blood, and fat. The biological half-life of the substance and its metabolites was calculated to be 32 hours following the IV, showing that despite the concentrations of radiolabelled elements in the fats the substance does not tend to accumulate in the body.
- Following the inhalation of vapours of 14C-Hexachlorocyclopentadiene (Southern Research Institute, undated), substantial radioactivity was detected in kidney, liver, carcass, and lungs at concentrations higher than following oral exposure but lower than following the IV.
- Southern Research Institute (undated) observed that Hexachlocyclopentadiene can strongly bind with unspecified components of plasma, whole blood, and liver homogeneates.
- Studies were used for the purpose of this REACH Registration investigating the effects of Hexachlorocyclopentadiene. In addition to the local effects to the skin and respiratory tract identified as part of these studies, significant effects on liver and kidney were observed. These results are consistent with the observations made by Yu et al. (1980).

Details on excretion:

o Following an oral administration of radiolabelled Hexachlorocyclopentadiene to rats, Yu et al. (1980) observed that the substance and its metabolites were mainly eliminated in the faeces (70%) and in urine (17%). These results are consistent with the limited oral absorption of the substance. When the substance was administrated by IV, the substance and its metabolites were eliminated equally in faeces (21%) and urine (18%).
o A small fraction of radiolabelled Hexachlorocyclopentadiene administrated by inhalation (1%) or IV (unspecified) was eliminated as CO2 by the respiration (Southern Research Institute, undated).

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

- Yu et al. (1980) observed that Hexachlorocyclopentadiene was rapidly degraded in rats by the liver, but also in the gut and faeces due to microbial action. The metabolites were not identified but were determined to be mostly polar.
- El Dareer et al. (1983) considered that the lower toxicity of Hexachlorocyclopentadiene following oral exposure when compared to the other routes of exposure may be related to the degradation that occurs in the intestinal tract before the unchanged substance is being absorbed.
- Southern Research Institute (undated) observed that a fraction of the radiolabelled carbon administrated by inhalation and IV was found in CO2 as a metabolisation product of Hexachlorocyclopentadiene.

Applicant's summary and conclusion

Conclusions:

Toxicokinetic data were available from dedicated studies investigating the absorption, distribution, and excretion of Hexachlorocyclopentadiene following an oral or inhalation exposure. In addition it was possible to derive information from acute and repeated-dose toxicity studies by the oral, inhalation, and dermal route, and from an eye irritation study. It is not considered appropriate to perform further animal studies on this substance to investigate its toxicokinetic behaviour.

Executive summary:

Hexachlorocyclopentadiene is absorbed following an exposure by inhalation and the oral route. The properties of the substance suggest that absorption could occur by the dermal route which is supported by the available data on the acute dermal toxicity of the substance. In addition it is considered that absorption of the substance can occur following eye contact.

The highest concentration of absorbed Hexachlorocyclopentadiene and its metabolites is found in liver, blood, fat, and carcass. Based on the elimination of the radiolabelled carbon of 14C-Hexachlorocyclopentadiene, the biological half-life of the substance and its metabolites was calculated to be 32 hours following an IV, showing that despite the concentrations of radiolabelled elements in the fats, the substance does not tend to accumulate in the body.

The absorbed substance is rapidly metabolised in the liver. Following oral exposure, metabolisation of Hexachlorocyclopentadiene starts in the gastroinestinal tracts. Degradation products were not identified apart from CO2.

Due to the limited absorption following oral exposure, Hexachlorocyclopentadiene is mainly eliminated through the faeces. Absorbed substance and its metabolites are eliminated equally by the faeces and the urine, while a small fraction is eliminated by the respiration metabolised into CO2.

It is not considered appropriate to perform further animal studies on this substance to investigate its toxicokinetic behaviour.