Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

The lowest NOAEL derived from repeated dose oral toxicity studies in rats (28-d and 90-d) was 5 mg/kg bw/d.  A NOAEL (local and systemic) of 10-20  mg/kg bw/d (highest test dose) was derived from a subchronic dermal toxicity study in rabbits. From the results of repeated dose inhalation toxicity study in rats and mice a systemic NOAEC of 9.4 mg/m³  (4 ppm), a subchronic local NOAEC of 4 ppm and a chronic local LOAEC of 8 ppm was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
9.4 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Additional information

Repeated dose toxicity: oral

 

In a subacute toxicity study (Bayer, 1984) Propargyl alcohol (99% a.i.) was diluted in water and administered to groups of 10 male and 10 female Wistar rats orally by gavage at dose levels of 0, 5, 15, 45 mg/kg bw/day. No animals died during the study period. Significant and dosedependent increases in relative liver and kidney weights were seen in all treated groups. At 15 and 45 mg/kg bw, significantly decreased red blood cell counts and haemoglobin and haematocrit levels were observed in both sexes. Reticulocyte counts were increased in males. At 45 mg/kg bw, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) were decreased in males. The authors concluded these changes to be indicative of hypochromic anaemia. No changes were observed in leukocyte numbers, thrombocyte numbers, and differential counts. In addition to the haematological and organ weight effects, a dose of 45 mg/kg retarded body weight gain and increased ALAT, ALP, and glutamate dehydrogenase (GLDH) activities in male rats. Furthermore, plasma cholinesterase activity was significantly decreased (by 60%) in females and plasma creatinine levels were significantly decreased in both sexes. Histopathological changes indicative of a treatmant related liver cell damage were noted in male animals treated with 45 mg/kg propynol. No changes were noted at microscopic examination of the kidneys and in urinalysis.

 

In a second study described in the same report, the suggested direct action of propynol on microsomal liver enzymes was addressed in a 4-week gavage study in Bor:WISW (SPF:Cpb) rats. Fifteen animals/sex were daily administered 60 mg/kg bw Propargyl alcohol (= propynol). Because of the occurrence of marked symptoms of toxicity (apathy, atonia, bloody salivation) and the death of one of the 15 treated male rats, the daily dose was lowered to 50 mg/kg bw from day 4 to 21. From day 22 to 28, animals were given 60 mg/kg bw propynol again. After 28 days, the treated animals displayed decreased body weight, increased relative liver and kidney weights, and haematological changes comparable to the first experiment. No effects were noted in urinalysis. Clinical chemistry analysis indicated increased plasma activities of ALAT, GLDH, ALP, and γ-glutamyl transferase in both sexes and of aspartate aminotransferase in males. Plasma cholinesterase activity was decreased in females. Creatinine levels were decreased in both sexes, whereas urea nitrogen levels were increased in females. In liver tissue, the activities of N-demethylase (both sexes), O-demethylase (males), and cytochrome P450 (both sexes) were significantly decreased. Triglyceride levels were not affected in liver tissue. In addition, macroscopic changes were noted in the liver of males, whereas microscopic changes (e.g., focal necrosis, increased mitotic rates in liver parenchyma, and unusual mitotic figures) were noted in all treated animals.

 

Based on these results the authors concluded that Propargyl alcohol has a specific effect on liver mixed function oxidases and induces liver cell damage. Other effects were on red blood cells and the kidneys. Because the changes in relative liver and kidney weights at 5 mg/kg bw were not accompanied by clinical chemistry or histological changes, the authors considered this dose level to be a threshold dose (NOAEL).

 

Male and female Crl:CD(SD)BR rats (n=20/sex/group) were dosed orally (gavage) with 0, 5, 15 or 50 mg/kg bw of Propargyl alcohol (purity: >99%) (at 10 mL/kg in deionised water) daily for 13 weeks (US EPA, 1987). Rats were sacrificed on days 91 or 92 after dosing. Parameters examined included clinical signs, body and organ weight changes, food consumption, ophthalmology, haematology, blood chemistry and histological evaluations. Treatment-related mortality was reported for 4/20 males in the high-dose group. The most prevalent clinical sign was salivation, occurring mainly at 50 mg/kg bw. Body weights were significantly lower in the high-dose animals. Haematological changes observed in the high-dose animals comprised decreased haemoglobin, MCV (also at 15 mg/kg bw), MCH, and mean corpuscular haemoglobin concentration (MCHC) values. Enzyme changes characteristic of liver damage were seen in the mid- and high-dose animals. These changes included significantly increased ALAT, ASAT, LDH, and ALP serum activities. Moreover, decreased glucose, sodium, total cholesterol, total protein, albumin, globulin, and creatinine serum levels were seen, whereas inorganic phosphate and total bilirubin serum levels were significantly higher. The haematological and blood chemistry changes were considered to be treatment-related. Absolute and relative liver and kidney weights were significantly increased in males and/or females at 15 and 50 mg/kg bw/day. At 5 mg/kg bw, mean absolute and relative liver weights were higher compared to controls, but statistical significance was not reached. Macroscopic findings were confined to the liver (15 and 50 mg/kg bw) and the stomach (50 mg/kg bw). Hepatocytic megalocytosis with a less prominent proliferation of the bile ducts and cytoplasmic vacuolation of hepatocytes was observed in the majority of rats in the mid- and high-dose groups. In the low-dose group, megalocytosis was seen only in one rat treated for 3 months. Karyomegaly of renal tubular epithelial cells was reported to occur in a dose-response fashion in the mid- and high-dose groups, but not in the low-dose group. Treatment-related effects at 15 mg/kg bw included increased liver weights in both genders, increased kidney weights in females, and megalocytosis of the liver after 13 weeks of dosing. The daily oral administration of 5 mg/kg bw/day of propynol produced no apparent treatment-related effects and hence this dose level was considered a NOAEL for subchronic oral exposure to Propargyl alcohol.

supporting information on a structural analoge (2-butyne-1,4-diol; CAS no. 110-65-6) used for read across to cover the endpoint reprotoxicity:

2-Butyne-1,4-diol was given to male and female Wistar Imp:DAK rats by oral gavage for 28 consecutive days in daily doses of 1, 10, or 50 mg/kg/day (Jedrychowski et al, 1992). After 28 days all animals were necropsied, blood samples were obtained and selected organs were weighed and prepared for histological examination. Treatment-related effects in the high-dose group consisted of: fatality in both sexes; decreased body weight gain in males; increase of absolute and/or relative weights of liver and kidneys in both sexes; depressed red blood cell count, haematocrit value and haemoglobin concentration in female rats; elevated reticulocyte count and leukocyte count in both sexes; increased total serum protein content in females; elevated glucose concentration in males and higher activity of sorbital dehydrogenase in both sexes; histopathological evidence of hepatotoxicity and nephrotoxicity in decedents; and hepatic and splenic changes in survivors. Minor hepatic, splenic, and erythrocyte changes were also found in some females given the middle dose. The dose of 1 mg/kg/day was considered to the NOAEL, and 10 mg/kg/day the LOAEL.

Repeated dose toxicity: dermal

 

In a subchronic dermal toxicity study (DOW-OTS0510181), Propargyl alcohol was applied as aqueous solution (0.1, 0.3 and 1-percent Propargyl alcohol in distilled water) to the intact and abraded skin of 2 - 3 male and female albino rabbits at dose levels of 0, 1, 3 and 10 mg/kg bw/day, 8 hours/day for 5 days/week during a 91-day period, beginning on day 63, the top dose was increased to 20 mg/kg bw/day. Body weight gain changes and biochemical and haematological parameters did not differ significantly from those of the control group. No substance-related gross or microscopic tissue changes were observed. Application of Propargyl alcohol to the intact or abraded skin in daily doses of 1 or 3 mg/kg bw/day over a 90-day period, or 10 mg/kg bw/day for day 1-62 and subsequently 20 mg/kg bw/day for day 63-90 produced no systemic effects (including body weight gain, haematology, and histology). Furthermore, no local effects were seen. The NOAEL derived from this study is 10 – 20 mg/kg bw/day.

 

Repeated dose toxicity: inhalation

Swiss mice (10/group) were exposed to propargyl alcohol (99% a.s.) at concentrations (analytical) of 88 ppm (81.0 - 104.0 ppm) or 25.3 ppm (22.0 - 31.0 ppm) 6 hours/day for 4, 9, or 14 days (Zissu, 1995). Concentrations were chosen according to the RD value, which corresponds to the concentration that induced a 50% decrease in respiratory rate (nominal: 85 ppm) and RD50 x 0.3 (nominal: 25.5 ppm). Vapour concentrations were analytically determined by collection of chamber air samples with a solid adsorbent (silica gel), which were analyzed further by gas-liquid chromatography. Breathing rates were monitored during exposure. There were no significant toxic effects at the lower exposure. Respiratory epithelium and olfactory epithelium lesions were observed after repeated exposure to 88 ppm Propargylalcohol. Lesions were of greatest severity at 4 days of exposure and did not increase in severity following 14 days of exposure. Neither the trachea nor the lungs were affected from all irritant exposed mice. Exposure of mice to 25.3 ppm for 6 hrs/day for 4 days resulted in no histological changes in the respiratory tract. Thus, 25.3 ppm for 6 hours can be considered as NOAEC for histopathologic changes of the respiratory tract of mice.

In a 14-d dose range finding study (according to OECD TG 412 and GLP; BASF Toxiclogy Department, 1990) to a 90-d inhalation study (see below) groups of 5 Wistar rats/sex were exposed 5 days/week for 6 hours/day to Propargyl alcohol concentrations of 0, 10, 50 and 200 ppm (eq. to 22, 115 and 456 mg/m³). At 200 ppm apathy, closed eyes, reddish nasal discharge and irregular breathing occurred during the exposures. The signs did not subside between the exposures. In addition, there was deterioration in general condition. One female animal of this group died. No clinical sings were seen at the lower concentration levels. Changes in blood chemistry parameters associated with liver lesions occurred at 50 and 200 ppm and consisted of increased alanine aminotransferase (ALAT) and alkaline phosphatase (ALP) serum activities, increased thromboplastin times, increased bilirubin serum levels, decreased total protein, triglyceride and cholesterol serum levels. Male rats at 200 ppm had significantly higher relative liver weights, males and females at 50 and 200 ppm had significantly increased kidney weights. Histopathological examination revealed lesions in the nasal mucosa and the liver (hepatocelluar hypertrophy and cytoplasmatic granulation, parenchymal single cell necrosis at 200 ppm and, due to an irritating effect, changes of the respiratory epithelial cells of the nasal mucosa were in the form of inflammatory processes (at 200 ppm) as well as metaplastic changes (at 50 and 200 ppm). A NOAEC of 10 ppm (23 mg/m³) can be derived.

 

In a subchronic inhalation toxicity study according to OECD TG 409 and GLP (BASF Toxicology Department, 1992) Propargyl alcohol was administered to 10 Wistar rats/sex/concentration by whole body exposure at concentrations of 0, 1 ppm (0.002 mg/L), 5 ppm (0.011 mg/L), 25 ppm (0.058 mg/L) for 6 hours per day, 5 days/week for a total of 90 days (65 exposures). At 5 and 1 ppm no treatment-related effects were observed. In the males of the 25 ppm group the body weight gain was retarded especially during the first 2 weeks of exposure; the relative kidney and liver weights were increased. In females the absolute and relative kidney weights were increased and cholinesterase activity was decreased. No further treatment-related effects were found regarding clinical and opthalmological examinations, hematology, clotting time analysis and clinicochemical analysis; especially no morphological and no histopathological findings were found which could be related to the observed effects. Based on the results, the NOEC is 5 ppm (0.011 mg/L). This subchronic inhalation toxicity study in the rat is acceptable and satisfies in general the guideline requirement for a subchronic inhalation study OECD 413 in the rat.

 

In a subchronic inhalation toxicity study (Dow, 1964), Propargyl alcohol was administered to 12 male rats and 12 female rats by whole body exposure at a concentration of 80 ppm (183 mg/m³ air). Exposures were 7 hours per day, 5 days/week. 59 exposures were given in a 89 day period. After the first exposure the eyes appeared sore and the animals were slow moving, subsequently they apparently became acclimated to the test substance. In the treated rats of both sexes white blood cell count and serum glutamic-pyruvic transaminase activity were elevated; relative liver weight was elevated in both sexes and relative kidney weight only in females. Microscopically males showed slight pneumonitis, mild degenerative changes in the epithelial lining of the kidneys and rather extensive changes in the livers: degeneration in the central parts of the lobule, varying from focal necrosis to hydropic degeneration associated with cellular infiltration, as well as fatty changes mostly seen in the midzonal area and the periphery of the lobule. In females changes were of the same type but slightly more pronounced.

 

In a 3 -month inhalation toxicity study, groups of 10 male and 10 female Fischer 344 rats were whole body exposed to Propargyl alcohol vapor at concentrations of 0, 4, 8, 16, 32 or 64 ppm, for 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. Propargyl alcohol (>99 % a.i.) was used. All rats survived to the end of the study. Mean body weights of all exposed groups were similar to those of the chamber control groups. An exposure concentration- and time-related decrease in serum cholinesterase activity occurred in exposed male (32 ppm and higher) and female rats (8 ppm and higher). Absolute liver weight was significantly increased in 64 ppm males. Relative liver and kidney weights were significantly increased in 64 ppm males and females and in 32 ppm males, and relative liver weight was significantly increased in 16 ppm males. The incidences of minimal to mild hyperplasia of respiratory epithelium of the nose were significantly increased in all exposed groups except 8 ppm males and 4 ppm females. Squamous metaplasia of the respiratory epithelium was noted in a few males and most females exposed to 64 ppm. Necrosis of olfactory epithelium was present in half of the males and females exposed to 64 ppm and in a few males and females exposed to 32 ppm. Based on these results, the NOAEC for females was 4 ppm. For males, the significantly increased incidences of minimal to mild hyperplasia of respiratory epithelium of the nose at 4 ppm are not judged as a clearly substance related effect, because at 8 ppm the incidence was not significantly different from the control males and a clear dose response was only present at 16 ppm and higher. Thus, a NOAEC of 8 ppm can be derived for the male rat.

 

In a 3 -month inhalation toxicity study, groups of 10 male and 10 female mice were whole body exposed to Propargyl alcohol vapor at concentrations of 0, 4, 8, 16, 32, or 64 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of males exposed to 8 ppm or greater and 32 and 64 ppm females were significantly less than those of the chamber control groups. Histopathologic changes occurred in the nasal cavity of mice and involved both the respiratory and olfactory epithelium in groups exposed to 16 ppm or greater. Lesions included minimal to moderate suppurative inflammation, minimal to moderate squamous metaplasia of the respiratory epithelium, minimal to mild hyaline degeneration (accumulation) in the respiratory epithelium, minimal to moderate olfactory epithelial atrophy, minimal to moderate hyperplasia of glands in the olfactory region, minimal necrosis of olfactory epithelium, and minimal to moderate turbinate atrophy. There were no biologically significant differences in organ weights between exposed and chamber control groups. Reproductive tissue parameters of exposed males were similar to those of the chamber controls. Only 2/9 female mice in the 64 ppm group exhibited regular estrous cyclicity compared to 6/10 in the controls. Females exposed to 16 ppm differed from chamber controls in the relative time in the estrous stages, and 64 ppm females had a significantly increased probability of extended estrus. No gross lesions were observed at necropsy. Based on these results, the NOAEC for males was 4 ppm due to the reduced mean body weights observed when exposed to 8 ppm Propargyl alcohol or greater. Since histopathologic changes occurred in the nasal cavity at 16 ppm Propargyl alcohol or greater in mice and females exposed to 16 ppm differed from chamber controls in the relative time in the estrous stages, for females a NOAEC of 8 ppm can be derived.

In a 2-year carcinogenicity whole body inhalation study (NIH, 2008) groups of 50 male and 50 female rats were exposed to propargyl alcohol vapor at concentrations of 0, 16, 32, or 64 ppm, 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. 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 (for further details see section “carcinogenicity”).

 

In a 2 -year whole body exposure carcinogenicity study (NIH, 2008) groups of 50 male and 50 female mice were exposed to Propargyl alcohol vapor at concentrations of 0, 8, 16, or 32 ppm, 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 nose was the primary target organ. 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 for further details see section “carcinogenicity”). 

Justification for classification or non-classification

Propargyl alcohol is listed in Annex VI to Regulation 1272/2008/EC. The classification does not include a classification for repeated dose or specific target organ toxicity.

However, based on these results propargyl alcohol should be classified with STOT RE, Category 2 according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.