Reaction mass of ethoxylated N-oleyl-1,3-propanediamine, hydrofluorides of and ethoxylated N-palmityl-1,3-propanediamine, hydrofluorides of and ethoxylated N-stearyl-1,3-propanediamine, hydrofluorides of and olaflur

Carcinogenicity

Description of key information

Oleaflur, a structure analogue of Olaflur, possessed no carcinogenic potential both in the rat and in the mouse when tested in carcinogenicity studies up to high dose-levels that caused a minimum toxic effects. Consequently, no carcinogenic effects are expected for Olaflur, also taken into account the lack of any mutagen or genotoxic potential in vivo and in vitro.

Justification for classification or non-classification

The test item did not induce any carcinogenic effects when tested in carcinogenicity studies in the mouse and rat, respectively.

Therefore, it is not subject to classification and labelling for carcinogenicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No. 1272/2008 (CLP). This is in line with results obtained when tested for genetic toxicity in vivo and in vitro.

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on toxicity to reproduction, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighth time in Regulation (EU) No 2016/918.

Additional information

Mouse:

In a carcinogenicity study (LTP, 2003), Oleaflur was administered to NMRI CD/Crl:NMRI BR mice (50 animals/sex/dose) by oral gavage at dose levels of 0, 6, 18 or 54 mg/kg bw/day (males) and 0, 6 (12), 18 (36) or 54 (108/72) mg/kg bw/day (females) for 78 weeks. From test week 14 onwards, the dose levels of the female animals were increased, because the body weight reduction of the high-dosed animals was not within the expected range in comparison to the control group. From test week 66 onwards the high dose level of the females was decreased, because of the slightly higher than the expected mortality rate and body weight reduction in this group compared to the control group (Due to the variable dose concentrations given over the test period the mean value of ca. 90 mg/kg bw/d as high-dose level was calculated). The high dose resulted in an average body weight reduction of 8.7 % in the males and 8.6 % in the females compared to the control group. Further, pilo-erection was noted in the high dose. Mortality rates of all dose groups were within the range of the control group. In conclusion, Oleaflur possessed no carcinogenic potential in the mouse tested up to a high dose-level that caused a toxic effect in form of an approx. 9 % weight loss compared to the control. Therefore the NOEL for systemic toxicity was established to be 6 mg/kg bw/d for males and ca. 33 mg/kg bw/d for females, respectively.

In conclusion the NOEL for carcinogenicity is considered to be 54 mg/kg bw/d for males and ca. 90 mg/kg bw/day for females, respectively.

 

Rat:

In a carcinogenicity study (LTP, 2003), Oleaflur was administered to Sprague Dawley rats (50 animals/sex/dose) by oral gavage at dose levels of 0, 2.5, 10 or 40 mg/kg bw/day (males) and 0, 15, 45 or 135 (90) mg/kg bw/day (females) for 104 weeks.

The high dose level of the females was decreased from test week 70 onwards for the rest of the study due to a slightly higher than expected body weight reduction in this group compared to the control group. Due to the variable dose concentrations given over the test period the mean value of ca. 120 mg/kg bw/d as high-dose level was calculated).The high dose resulted in an average body weight reduction of 10.9 % in the males and 10.5 % in the females compared to the control group. A slightly higher incidence of ataxia was noted in the high-dosed females (135/90 mg/kg bw) compared to the control. Mortality rates of all dose groups were within the range of the control group.

In conclusion, Oleaflur possessed no carcinogenic potential in the rat tested up to a high dose-level that caused a toxic effect in form of an approx. 10 % weight loss compared to the control.

Therefore the NOEL for systemic toxicity was established to be 10 mg/kg bw/d for males and ca. 45 mg/kg bw/d for females, respectively.

In conclusion the NOEL for carcinogenicity is considered to be 40 mg/kg bw/d for males and ca. 120 mg/kg bw/day for females, respectively.

An additional study confirms the lack of carcinogenic properties of NaF.

To determine the carcinogenic potential of sodium fluoride (NaF), in a two year carcinogenicity study Sprague-Dawley rats (70 per sex per dose) were fed a diet containing NaF for up to 99 weeks. Rats were receiving NaF at a dose of 4,10, or 25 mg/kg per day added to a low-fluoride diet were compared with controls receiving either a low-fluoride diet or laboratory chow.

A 30 % decrease in weight gain occurred at an NaF dose of 25 mg/kg per day. Evidence of fluoride toxicity was seen in the teeth, bones, and stomach, and the incidence and severity of these changes were related to the dose of NaF and the duration of exposure. Despite clear evidence of toxicity (LOEL Systemic toxicity 4 mg/kg bw/d), NaF did not alter the incidence of preneoplastic and neoplastic lesions at any site in rats of either sex. Results from this study indicate that NaF is not carcinogenic in Sprague-Dawley rats. Hence, the NOEL for carcinogenicity is considered to be 25 mg/kg bw/day.