Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Key value for chemical safety assessment

Additional information

BASF (1992) reported a two-year inhalation study (whole-body exposure). Male and female Sprague-Dawley rats were offered vapour concentrations of 5, 10 or 20 ppm for 6 hours per working day. The following results were obtained:

No treatment-related mortality occurred.

Neoplastic changes first became evident after 12 months. No animals in this group died prematurely. Although no macroscopic changes could be detected at this time, microscopic examinations revealed the presence of a hepatocellular adenoma in one top dose male and adenomas of the nasal cavity in one low dose male and one male and female from the top dose group. These adenomas arose from the respiratory epithelium or from the submucosal glands in the anterior part of the nasal cavity. Metaplasia of respiratory epithelium into squamous epithelium was also seen at this time in rats from the top dose group.

In rats exposed for 18 months and allowed a 6 month recovery period, macroscopical masses in the liver of 2 low dose males and one male and two females from the high dose group. Microscopically, hepatocellular carcinomas were found in 3 male and 2 females and in the nasal cavity, adenomas were seen in one mid dose group male and 2 males and 2 females from the high dose group. Findings occurred both in animals surviving until study termination and in those dying prematurely. A total of 141 males and 106 females survived until the end of the study (24 months). The incidence of macroscopically detectable masses in the liver was clearly dose-related. In males, masses could be seen in 23 animals and in females, masses were visible in 36 animals. Masses were also evident in the nasal cavities of 1 male in the 10 ppm group and 2 males and 2 females in the 20 ppm group. Most macroscopically visible masses in the liver were identified microscopically as hepatocellular carcinomas. In males the incidence of microscopically detectable hepatocellular carcinoma was 29 and in females 36. The following table shows the tumor incidences:

 NVP concentration (ppm)  Sex  0  5  10  20
 No. of animals/group    70  60  60  60
 Liver: liver cell carcinoma  male  1  6  5  17
   female  1  3  6  26
 Nasal cavity: adenoma  male    8  9  10
   female    2  8  12
 Nasal cavity: adenocarcinoma  male      4  6
   female        4
 Larynx: squamous cell carcinoma  male        4
   female      4

This study clearly shows that NVP (with 3 ppm Kerobit as stabilizer) is carcinogenic in rats, causing hepatocellular carcinomas, nasal adenomas and adenocarcinomas and squamous cell carcinomas in the larynx. Furthermore, 3 haemangiosarcomas in liver were noted in 3 animals of the top dose. It was not possible to identify a NOAEL from this study, increased tumour incidences being produced at 5 ppm, the lowest dose used.

Klimisch et al. (Food and Chemical Toxicology 35, 1997) reported about the long-term inhalation toxicity of N-Vinylpyrrolidone-2 vapours. Female Sprague-Dawley rats were offered a vapour concentration of 45 ppm for 6 hours per day and 5 days per week over a study period of 3 months. The animals were killed at 3 or 12 and 24 months post-exposure. The effect of NVP on body weight evident at 3 months disappeared before 1 year, but effects on liver pathology persisted throughout the subsequent 21-month exposure-free period, and a few liver tumours were seen at 2 years.

Justification for classification or non-classification

N-vinylpyrrolidone (NVP) is currently classified according to EU DSD criteria (EU Directive 67/548/EEC) as R40: Limited evidence of a carcinogenic effect, Carc. Cat. 3 and under the EU CLP criteria (Regulation (EC) 1272/2008) as Carc. 2. These classifications are supported by the key study (BASF, 1992) which clearly shows that NVP (with 3 ppm Kerobit as stabilizer) is carcinogenic in rats, causing hepatocellular carcinomas, nasal adenomas and adenocarcinomas and squamous cell carcinomas in the larynx. Furthermore, 3 haemangiosarcomas in liver were noted in 3 animals of the top dose.