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Description of key information

In a chronic toxicity inhalation study, rats were exposed 6 h/d, 5d/week for 24 months at concentrations up to 10000 ppm (26000 mg/m3). This highest concentration tested was considered a NOAEC.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
26 000 mg/m³

Additional information

In a sub-chronic inhalation study, rats were exposed to 500, 1500, 5000, 15,000 and 50,000 ppm vinylidene fluoride. Transient body weight changes were observed which had subsided at the end of the study. Unexplained body weight changes were also seen in the controls. RBC counts, Hb levels and hematocrit decreased in males of the 1500 and 50,000 ppm group. No such changes were observed in the females. In this study, some changes in clinical chemistry (SGPT, SGOT, SDH, creatinine, BUN) and organ weights (relative and/or absolute: liver, kidney, thymus, brain, heart, testis) were observed. However, there was no dose relationship or clear relation to gender. Histopathological examination revealed one high-dose animal with serious rhinitis and erosion of the epithelium of the nasal cavity. Though observable effects were noted at all exposure levels, dose related effects were only apparent at the highest concentration. The NOEC in this study was < 500 ppm. (Litton Bionetics Inc., 1984)

 

In a sub-chronic inhalation study, mice were exposed to 500, 1500, 5000, 15,000 and 50,000 ppm vinylidene fluoride. Some mortality and transient body weight loss during the study in mice was observed which was suspected to be related to a failing watering system. In this study body weight changes were seen in females. Liver weight changes occurred (1,500 ppm males and 15,000 ppm females) but were not dose related. On histopathology, only mild renal changes indicative of regeneration was observed in very low incidence in all dosed males and high dose females and was not evidently related to dose. The NOEC in this study was < 500 ppm. (Litton Bionetics Inc., 1984)

 

A sub-chronic inhalation toxicity study with vinylidene fluoride was performed by exposing rats to concentrations of 1000, 7000 and 40,000 ppm. In this study changes in body weight (transient in males and females), hematological parameters (from 7000 ppm in males and in 40,000 ppm in females), clinical chemistry (in mid and high dose males and high dose females), urinalysis (in high dose males and transient in mid and high dose females) and organ weight changes (heart, lungs, spleen) were observed. These occurred at different concentrations, were not evidently concentration related and were sometimes transient. Microscopic examination of testis and epididymis showed treatment related changes in mid and high dose groups throughout the study; these were characteristic of impaired spermatogenesis. The spleen showed treatment related changes characterized by lymphocytic depletion of the marginal zone, in males and females of the mid and high dose groups and in females of the low dose group at week 2. Vacuolar degeneration of the vomeronasal organ in the nose was observed in all treatment groups. Mineralization of the kidneys was increased in males of the high dose group after week 4. The NOEC in this study was considered to be < 1000 ppm. (Civo, 1986)

 

As effects observed in the study by Litton Bionetics (1984) were not observed in the study by Civo (1986), and vice versa, the data of both studies has been reviewed (Civo, 1987). The review of the data indicated several potential confounding variables between the study by Litton Bionetics (1984) and the study performed by Civo (1986). These variables were stress due to trans-Atlantic shipment, change from Charles River pellet diet to the Institute's meal stock diet, and possible incompatibility of the immunological profile ofrats and that of the in-house Wistar colony. In order to permit a more relevant risk assessment for employees exposed to vinylidene fluoride on the work place it was deemed necessary to perform an additional study in weanling and young adult rats to verify the effects seen in the previous 13-week inhalation studies.

In the sub-chronic inhalation study in weanling and young adult rats, the exposure to vinylidene fluoride at levels of 250, 1000 or 7000 ppm accounted for only very slight changes in animals exposed to 7000 ppm. No treatment related changes were observed regarding body weight, hematology, urinalysis, mortality, estrus cycle, and organ weights. Gross pathology revealed no changes; on histopathology, no treatment-related effects were noted on sperm concentration, number of sperm cells with deformed heads/tails or on numbers of isolated heads/tails in weanlings or young adults. A slight degeneration of the vomeronasal organ in animals exposed to 7000 ppm was observed. At four weeks, the change was noticed both in weanlings and in young adults. At 13 weeks, it occurred only in weanlings. After 10 weeks recovery, it was not observed in any animal. From these results it was concluded that the NOEC was 1000 ppm. The NOAEC is concluded to be higher than 7000 ppm. (Civo, 1987)

 

In a sub-chronic inhalation study in mice, exposure to vinylidene fluoride at levels of 1000, 7000 and 40,000 ppm resulted in increased locomotor activity in both sexes. Increased sensitivity to touch was seen in high-dose males during the last week of exposure and in mid- and high-dose females during the last two weeks of exposure. Dose related rough haircoat was observed in males after eight weeks of exposure. An increase in mean corpuscular haemoglobin was seen in the high-dose males. There were no treatment-related effects on body weight, food consumption or on organ weights. No treatment related macroscopic or microscopic pathological changes were observed. Since the (subjective) clinical symptoms are not related to pathological changes, the NOAEC is considered to be 7000 ppm. (Bio/dynamics Inc., 1989)

 

In a chronic inhalation study, exposure of rats to vinylidene fluoride at levels of 150, 600, 2500 and 10,000 ppm did not result in clear adverse effects. A decrease in body weight gain in rats exposed to 10,000 ppm was transient and might be related to the slightly lower food intake observed in rats of this group. However, also the other test groups tended to eat slightly less than the controls, without showing a clear concentration-response relationship. The scantiness of the differences in haematological changes observed, their transient character, the lack of a clear concentration-response relationship, and particularly the nature of the effects indicate that the differences observed are toxicologically irrelevant, although a relationship with treatment cannot be completely excluded. Increases in total protein values in females exposed to 2500 or 10,000 ppm and in albumin in females exposed to 10,000 ppm were only observed at day 106. Since the effect on total protein was not concentration-relatedand no other changes were found which could support the toxicologicalsignificance they were considered casual findings unrelated to the exposure.

The minor nasal changes observed in (many) animals of both the satellite and the main groups, controls included are rather peculiar for rats indicating the changes not being primarily related to vinylidene fluoride. The higher or lower incidence of some of these changes in animals of the600, 2500 and/or 10,000 ppm groups as compared to controls might beascribed to an enhancing or inhibiting effect of vinylidene fluoride on the development of these minor changes induced by an agent or condition towhich all animals have been subjected.

Under the (special nasal) conditions of the present study the "no-observed-adverse-effect-concentration" of vinylidene fluoride was found to be 150 ppm for males and 600 ppm for females. In view of:

a) the nature and scantiness of the nasal changes observed, and

b) the fact that the adverse effects concerned higher incidences of changes also occurring in considerable (and unusual) numbers of controls,

the toxicological relevance of the nasal changes is considered negligibly small. Therefore, it is concluded that in the present study vinylidene fluoride did not produce effects of toxicological concern at exposure concentrations of up to and including 10,000 ppm. The NOAEC is 10,000 ppm. (TNO, 1991)

Justification for classification or non-classification

Based on the NOAEC of 10,000 ppm (26000 mg/m3) in a chronic toxicity inhalation studies with rats, classification of vinylidene fluoride for repeated dose toxicity is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.