Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Fielding Douglas, et al. (1982) was selected as the key study for this endpoint based upon the reliability of the study according to its Klimisch score and depth of results. The key study reported a LOAEL value of 10ppm which is equal to 76.83mg/m3 based upon a molecular weight of 187.8612.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
T25
3.2

Carcinogenicity: via dermal route

Endpoint conclusion
Dose descriptor:
T25
75 mg/kg bw/day

Additional information

Fielding Douglas, et al, 1982, was selected as the key study for this endpoint. The study was conducted in a similar manner to the OECD 451 guideline (carinogenicity studies) on rats and mice (male and females in both species). Both species were exposed to 10 and 40 ppm.

In rats only 5/50 of the high concentration group survived until the end of the study. The high mortality rate in this group may have acted as a masking effect to the formation of tumors over the course of the exposure period.

A statistically significant incidence of tumors was seen in both rats and mice at both test concentrations. The LOAEC was therefore set at 10ppm based upon these results.

The following studies are presented as supporting information only as they are considered to be less reliable.

Ghanayem et al, 1986, was conducted via the oral route. The registered substance suspended in corn oil was administered by gavage for 2 weeks into the forestomach, the site of examination. 24 hours after the final administration the test animals were sacrified and the forestomach subject to gross and histopathological examination. Based upon the incidence of tumors the LOAEC value was set at 40ppm.

NCI (1978) conducted a study by the oral route in rats and mice. In rats, increased tumour incidences of stomach and spleen tumours were concluded in males; females showed increased incidences of tumours in stomach and liver. Among male and female mice, inceased incidences of stomach and lung tumours were concluded.

Huff, 1983, is a representation of the key study (Fielding-Douglas et al, 1982), with a more consise write up and results presentation. As this is only secondary literature and no additional conclusions have been drawn from it this source has been considered secondary information and is therefore awarded a reliability score of 4 according to the criteria of Klimisch et al, 1997.

Van Duuren et al (1979) used a skin painting protocol in female mice only, in a study predating guidelines and GLP. However, identity of the test material was confirmed analytically; duration and groups sizes were sufficient to detect a carcinogenic effect. The study concluded increased tumour incidences of skin and lungs. Since the study predates GLP, individual animal data is not available, and it would appear only a limited tissue list was evaluated histologically (although all tumours visible at necropsy were addressed) then the quality of data in this study requires an additional assessment factor of 5.

Following Chapter R8 guidance (R.8.5.2), data is not adequate to derive the preferred BMD endpoints (inadequate number of dose groups in each study). T25s for the relevant tumour type in each study are therefore derived. There is insufficient information to support use of a non-linear response, therefore simple linearity (tumour incidence proportional to dose) is assumed. In the following table, T25s are derived. It should be noted that in studies of short duration but with high induced tumour incidences, the correction for “observation period” is limited to an incidence of 100% tumour-bearing animals (the maximum level achievable in the study), instead of the guidance (number of weeks of observation/ guideline duration of study).

Justification for classification or non-classification

The registered substance is currently classified as R45: May cause cancer according to Annex I of 67/548/EEC and Carc. 1B according to EC Regulation 1272/2008.

The above available information supports these classifications and therefore no changes to the classifications are proposed at this time.