Prop-2-yn-1-ol

Carcinogenicity

Description of key information

Considering the incidences and distribution of the few benign neoplasms observed in rats and/or mice following 2-year inhalation exposure to Propargyl alcohol vapour, and with special regard to the evidence of carcinogenic activity when referring to respiratory epithelial adenomas, it is concluded that Propargyl alcohol has no carcinogenic potential overall.

Justification for classification or non-classification

Considering the incidences and distribution of the few benign neoplasms observed in rats and/or mice following 2-year inhalation exposure to Propargyl alcohol vapour, and with special regard to the very weak but still equivocal evidence of carcinogenic activity when referring to respiratory epithelial adenoma, adenomas are supposed to form solely as a reaction to the described sustained damage and inflammation of the respiratory epithelium. It is concluded that Propargyl alcohol has no carcinogenic potential and is not subject to classification for carcinogenicity according to Regulation 1272/2008/EC. This conclusion is supported by the lack of mutagenic activity of Propargyl alcohol.

Additional information

Findings in rat

In a 2-year carcinogenicity whole body inhalation study groups of 50 male and 50 female rats were exposed to propargyl alcohol vapor at concentrations of 0, 16, 32, or 64 ppm (corresponding to 0, 37.5, 75 or 150 mg/m³ ), 6 hours plus T90 (14 minutes) per day, 5 days per week for 105 weeks. Propargyl alcohol (>99% a.i.) was used. Survival of 32 and 64 ppm males was significantly less than that of the chamber control group. The decreased survival was mostly a result of moribund sacrifice of animals with a total of 26 and 30 in the 32 and 64 ppm groups, respectively. Almost all of the moribund sacrifices were attributed to excessive lethargy. Mean body weights of males exposed to 64 ppm were less than those of the chamber controls after week 24 of the study. The nose was the primary target organ. Nasal respiratory epithelial adenomas were present in three 64 ppm males and one 32 ppm female; the incidence in 64 ppm males exceeded the historical control ranges. A spectrum of non-neoplastic nasal lesions was observed in the respiratory and olfactory epithelium at all exposure concentrations (16 ppm or greater). A NOAEL was not identified. The incidences of respiratory epithelial hyperplasia, respiratory glandular hyperplasia, and olfactory basal cell hyperplasia were significantly increased in all exposed groups of rats. The incidences of lesions of the olfactory epithelium including hyperplasia, glandular hyperplasia, atrophy, respiratory metaplasia, degeneration, necrosis, hyaline droplet accumulation, and chronic active inflammation were significantly increased in one or more exposed groups of males and/or females. The presence and distribution of non-neoplastic lesions including hyperplasia and chronic inflammation which was correlated with adenoma incidences in male rats provided a strong indication that adenoma formation in the nasal epithelium was secondary to dose‑dependent cytotoxic effects of Propargyl alcohol and its metabolites, thus representing an adaptive response to sustained chemical-induced tissue damage and not being associated with potential genotoxic and/or tumour promoting activity of Propargyl alcohol. The incidence of mononuclear cell leukemia was significantly increased in males exposed to 64 ppm, and the incidence exceeded the historical control ranges. The finding of slightly increased leukaemia incidence in only one sex and only one rodent species is clearly without relevance for human health risk assessment. The fact that the limits of historical controls were slightly exceeded is not considered relevant since mononuclear cell leukaemia represents a common tumour in F344/N rats. Therefore, the slight increase in leukaemia incidence noted only in high-dose male F344/N rats, which most probably represents an incidental finding without relation to dose reflecting just a variation in spontaneous incidence, should be categorized as no evidence of carcinogenic activity.

To sum up, under the conditions of the 2-year inhalation study, there was if at all equivocal evidence of carcinogenic activity of Propargyl alcohol in male F344/N rats based on increased incidences of nasal respiratory epithelial adenoma and no evidence of carcinogenic activity in mononuclear cell leukemia. Nasal epithelial adenomas are supposed to form solely as a reaction to the described sustained damage and inflammation of the respiratory epithelium. There was no evidence of carcinogenic activity of Propargyl alcohol in female F344/N rats exposed to 16, 32, or 64 ppm. Under the conditions of the 2-year inhalation study, with regard to the evidence of carcinogenic activity, it is concluded that Propargyl alcohol has no carcinogenic potential in rats and is not subject to classification for carcinogenicity.

 

Findings in mice

In a 2 -year whole body exposure carcinogenicity study groups of 50 male and 50 female mice were exposed to Propargyl alcohol vapor at concentrations of 0, 8, 16, or 32 ppm (corresponding to 0, 18.5, 37.5 or 75 mg/m³ ), 6 hours plus T90 (14 minutes) per day, 5 days per week for 105 weeks. Propargyl alcohol >99% a.i. was used. Survival of exposed groups was similar to that of the chamber control groups. Mean body weights of 16 and 32 ppm females were less than those of the chamber control group after weeks 73 and 21, respectively. Eye abnormality (unspecified) was observed after one full year of exposure with the incidence increasing in an exposure concentration-related manner; most likely due to the irritant properties of Propargyl alcohol.

The incidences of nasal respiratory epithelial adenoma increased with a positive trend and were significantly increased in groups exposed to 32 ppm. A spectrum of non-neoplastic lesions occurred in the nasal respiratory and olfactory epithelium of mice at all exposure concentrations (8 ppm or greater). A NOAEC was not identified in the 2-year study. The incidences of respiratory epithelial hyperplasia, respiratory glandular hyperplasia, and squamous metaplasia were significantly increased in most exposed groups of mice. Suppurative inflammation was often associated with the squamous metaplasia, and turbinate atrophy was present in all exposed mice (except one 16 ppm male). The incidences of olfactory epithelial atrophy and respiratory metaplasia were increased in the 16 and 32 ppm groups. The presence and distribution of non-neoplastic lesions including hyperplasia and chronic inflammation which was correlated with adenoma incidences in male and female mice provided a strong indication that adenoma formation in the nasal epithelium was secondary to dose‑dependent cytotoxic effects of Propargyl alcohol and its metabolites, thus representing an adaptive response to sustained chemical-induced tissue damage and not being associated with potential genotoxic and/or tumour promoting activity of Propargyl alcohol. Significantly increased incidences of Harderian gland adenoma occurred in 8 and 32 ppm male mice. The adenoma incidence in the 32 ppm males slightly exceeded the historical control range for inhalation studies (range: 6‑20 %) and was at the upper bound of the range for all routes of administration (range: 4‑22 %). While the rate of Harderian gland carcinoma in the control group of the NTP study corresponded to historical control data with a relative incidence of 5.7 %, the rate of adenoma was clearly lower as would have been expected from historical control data with 11 % (NTP, 2009). This low adenoma incidence of 6 % in concurrent controls contributed substantially to the statistically significant increases noted at 8 and 32 ppm. In view of the highest incidence of Harderian gland adenoma reported for NTP historical controls of 20 %, the observed incidences of 21 and 23 % at 8 and 32 ppm, respectively, were within the range of biological variation that can reasonably be expected for male mice of this strain and age. In conclusion, there was no test substance‑related increase of Harderian gland adenoma of toxicological relevance noted in male mice following long-term exposure to Propargyl alcohol.

To sum up, under the conditions of the 2-year inhalation study, there was if at all equivocal evidence of carcinogenic activity of Propargyl alcohol in B6C3F1 mice based on increased incidences of nasal respiratory epithelial adenoma and no evidence of carcinogenic activity in Harderian gland adenoma in male B6C3F1 mice. Nasal epithelial adenomas are supposed to form solely as a reaction to the described sustained damage and inflammation of the respiratory epithelium. Under the conditions of the 2-year inhalation study, with regard to the evidence of carcinogenic activity, it is concluded that Propargyl alcohol has no carcinogenic potential in mice and is not subject to classification for carcinogenicity.

General statement on rodents

Under the conditions of the 2-year inhalation study, a further evaluation (Harder et al., 2010) showed that there was if at all equivocal evidence of carcinogenic activity of Propargyl alcohol in male F344/N rats and in B6C3F1 mice based on increased incidences of nasal respiratory epithelial adenoma. Adenomas are supposed to form solely as a reaction to the described sustained damage and inflammation of the respiratory epithelium. Neither a crystal clear evidence of carcinogenic activity in mononuclear cell leukemia in male F344/N rats nor a crystal clear evidence of carcinogenic activity in Harderian gland adenoma in male B6C3F1 mice was found in the long-term inhalation study. Furthermore, no evidence of carcinogenic activity of Propargyl alcohol was found in female F344/N rats exposed to 16, 32, or 64 ppm. Considering these information, it is concluded that Propargyl alcohol has no carcinogenic potential in rodents.

Reference

Harder V, Roth T, Hofer M (2010). Review of Mutagenicity and Carcinogenicity Studies with Propargyl Alcohol. Unpublished expert evaluation prepared by SCC Germany. Data owner: BASF AG, Ludwigshafen, Germany