Pentan-3-one

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no reproduction toxicity study available for diethyl ketone (DEK). Therefore, existing data for the structural similar aliphatic ketones dimethyl ketone (DMK, CAS 67-64-1) and methylethyl ketone (MEK, CAS 78-93-3) were used for a read across/weight of evidence approach. DEK, DMK and MEK are structurally very similar low molecular weight aliphatic ketones, which differ only in the alkyl chain length by one or two methyl groups. They are volatile and flammable organic solvents with similar specific gravity and a logPOW value between -0.21 and 0.85. Moreover, a comparison of the available toxicity data shows a similar toxicological profile: all substances exhibiting narcotic properties at high vapour concentrations and are of low toxicity by the oral, dermal and inhalative route of exposure (i.e. LD50/LC50 values above the regulatory threshold laid down in Regulation 1272/2008/EC (CLP)), they do not cause skin irritation but skin dryness after repeated dermal exposure and have a potential for eye and upper respiratory tract irritation in humans. Furthermore, these ketones share common metabolic pathways such as reduction to secondary alcohols and oxidation to hydroxyketones and finally carbon dioxide.

Dimethyl ketone (DMK, Acetone, CAS 67 -64 -1)

A weight of evidence approach is possible based on several studies investigating parameters that are indicators of an impairment of male and female fertility. Effects on male fertility were assessed in Wistar rats exposed to 0 or 10000 mg DMK/L drinking water (1%) for 4 weeks, or 0 or 5000 mg DMK/L drinking water (0.5%) for 9 weeks (corresponding to doses of 1300 or 650 mg/kg bw/d). Weights and histopathology of the male reproductive organs (testes, epididymis, seminal vesicles) were examined. In the last week of the 4 -week study, each male was mated with an untreated female rat to investigate reproductive performance (number of males without recognized mating, number of pregnant females, number of implantations, number of dead or retarded fetuses). Expression of the cell structure protein vimentin was analyzed via immunohistochemistry in the testes in Sertoli cells, the surrounding basal lamina propria and in interstitial cells. No adverse effect on male fertility was found (NOEL 10000 mg/L) although there were indications of systemic toxicity.(Dalgaard et al., 2000)

In another study male Wistar rats were exposed to 0.5% DMK in drinking water for 6 weeks corresponding to 5000 mg/L followed by a 10-week recovery period for half of the males. After mating with untreated female rats (mating ratio 1:1) both in the last weeks of treatment and of recovery, effects on fertility were assessed by determination of numbers of pregnant females and numbers of fetuses. In addition, testis weights, microscopic changes of testes and seminiferous tubular diameters were examined both at the end of dosing and of recovery. There were no indications of an adverse effect of 0.5% acetone treatment on any of the investigated parameters of male fertility.(Larsen et al., 1991)

In the course of a 13-week repeated dose toxicity drinking water study with rats and mice, sperm parameters and vaginal cytology were investigated additionally. Investigations in male animals included weights of right testis, of cauda epididymal, and of right epididymis as well as the histopathology of epididymis, seminal vesicles, prostate, and testes, and changes of sperm morphology, density and motility. In female animals, ovaries and uterus were examined histopathologically as well as stage and length of estrous cycle via vaginal cytology. In this study male and female Fischer 344 rats were exposed to concentrations of 2500, 10000, and 50000 ppm in drinking water resulting in actual dosages of 200, 900 and 3400 mg/kg bw/d in male rats and 300, 1200 and 3100 mg/kg bw/d in female rats.

A mild toxic effect on spermatogenesis with a LOAEL of 3400 mg/kg bw/d was indicated by significantly depressed sperm motility, by a significantly increased incidence of abnormal sperm, and by significantly depressed weights of the cauda epididymis and the epididymis. For male rats the minimal toxic concentration (LOAEL) for systemic toxicity was 20000 ppm corresponding to a dose of 1700 mg/kg bw/d with the kidneys, and hematopoetic system as most sensitive target organs. No relevant toxicological findings including investigated reproductive endpoints were observed in female rats up to the highest dose leading to a NOAEL of 50000 ppm or 3100 mg/kg bw/d.

In the study with B6C3F1 mice, water concentrations were 1250, 5000 and 20000 ppm for males resulting in dosages of 380, 1353 and 4858 mg/kg bw/d. Females consumed water with 2500, 10000 and 50000 ppm acetone resulting in actual dosages of 892, 4156 and 11298 mg/kg bw/d. There was no indication of reproductive toxicity up to the highest tested doses of 20000 ppm for male mice (NOEL 4858 mg/kg bw/d) or of 50000 ppm for female mice (NOEL 11298 mg/kg bw/d). Systemic toxicity (LOAEL for centrilobular hepatocellular hypertrophy) was indicated in female mice at 11298 mg/kg bw/d. (Dietz et al., 1991; NTP, 1991)

Methylethyl ketone (MEK, CAS 78 -93 -3)

A reproductive toxicity study has been conducted on 2 butanol, which can be used as a surrogate for MEK. There are several animal studies indicating that 2 butanol is readily absorbed and metabolized to MEK:

Saito (1975) administered 2 ml/kg 2-butanol (approximately 1.6 g/kg) orally to rabbits and blood samples were collected and analyzed by gas chromatography. Approximately 1 mg/ml 2-butanol was found in blood after 1 hour, with 0.7 mg/ml present after 7 hours, and only trace amounts after 10 hours. 2-butanol was metabolized via alcohol dehydrogenase to MEK, which was detected in the blood, reaching its maximum level in the blood after 6 hours. 2-butanol was excreted via exhalation (3.3% of the original dose) and urine (2.6%), but more of the original 2-butanol was excreted as its metabolite MEK. MEK excretion via exhalation and urine were 22.3% and 4.1% of the original dose, respectively. (Saito, 1975)

In another study, 14% of an 8 mmol/kg [approximately 600 mg/kg] oral dose of 2-butanol in rabbits was excreted in the urine as a glucuronic acid conjugate. Majority of the remaining dose was metabolized to MEK. (Kamil et al., 1952)

In rats, Traiger and Bruckner (1976) found a blood elimination half-life of 2.5 hours (after an oral dose of 2.2 ml/kg). One hour after administration, a maximum blood 2-butanol level of 800 mg/l was found; the MEK level at that time point was 430 mg/l and rose to a maximum of 1050 mg/l 4 hours after the 2-butanol administration.(Traiger and Bruckner, 1976)

DiVincenzo et al. (1976) examined the metabolism and clearance of MEK, the primary 2-butanol metabolite, in serum of male guinea pigs following a single i.p. dose 450 mg/kg MEK as a 25% solution in corn oil. Metabolites were identified in serum by gas chromatography-mass spectrometry. The serum half-life of MEK was determined to be 270 minutes, and the clearance time was 12 hours. 2 butanol, 3-hydroxy-2-butanone and 2,3-butanediol were identified as the serum metabolites of MEK. Reduction at the carbonyl group led to the formation of 2-butanol from MEK. The 2-butanol is then likely eliminated in urine as o-sulfates or o-glucuronide or may enter the intermediary metabolism to be eliminated as CO₂or incorporated into tissues. Oxidation of MEK appeared to proceed by hydroxylation of the ω-1 carbon to form 3-hydroxy-2-butanone, which is further reduced to 2,3-butanediol.(DiVincenco et al., 1976)

 

A two-generation reproductive toxicity study with 2-butanol was conducted in rats at concentrations of 0.3, 1.0, and 3.0% in drinking water. The animals were treated for eight weeks before mating. The pups were weaned at 21 days. Toxicity was observed in the first generation (F0) parent rats at 3.0%. Therefore, 2.0% was selected as the highest dose for the second generation study (F1). Thirty pups per sex per treatment group were selected as the F1 generation. These rats were treated with either 0.3, 1.0, or 2.0% 2-butanol in the drinking water, since some signs of toxicity were seen in the parental animals at 3.0% 2-butanol. At both the 0.3% and 1.0% level 2-butanol was not toxic in terms of growth and reproduction efficiency; however, at 2.0%, 2-butanol caused a slight but not statistically significant depression in growth of weanling rats. The F1 generation animals were raised to maturity, mated to produce one set of litters, and then sacrificed for gross and microscopic evaluation. Gross and microscopic pathologic findings were negative for the two lower dose levels, being limited to those frequently seen in untreated rat colonies. The 2.0% level resulted in a series of mild changes in the rat kidney which, while not suggestive of overt toxicity, appeared to represent responses to stress. No other findings of note were seen. 2-butanol produced no effects when administered to rats in the drinking water up to the level of 1% (equivalent to approximately 1500 mg/kg/day). The 2% dose level caused effects suggesting mild toxicity and/or stress reactions. There was no observed reproductive toxicity in parental animals. The 2.0% group offspring had a significant depression in growth of weaning rats. 2-Butanol was somewhat fetotoxic at the 2.0% dose level, as shown by decreased mean pup weights. This was a minimal response as shown by the fact that none of the other parameters (nidation, early or late fetal deaths) were detectably affected. Skeletal abnormalities seen in the 2-butanol groups were consistent in type and frequency with the spontaneous incidence observed in this rat colony. There were no significant soft tissue findings in the 2% treated group. All findings with 2-butanol at both 0.3 and 1.0% were negative with respect to signs of toxicity in terms of growth, gross and microscopic pathological evaluations, and reproductive efficiency. However, at 2.0%, 2-butanol caused a significant depression in the growth of weaning rats. On the basis of this study, 2-butanol produced no effects when administered to rats in the drinking water at concentrations up to 1.0% (approximately 1500 mg/kg/day). The NOEL in this study was 1.0%. The administration of 2.0% 2 butanol produced maternal effects which were suggestive of mild toxicity and/or stress reactions (LOEL = 2.0%). (Cox et al., 1975; Gallo et al., 1977; cited in OECD SIDS)

References:

Saito. (1975). The metabolism of lower alcohols. Nippon Ishi, 34:569-58.

Kamil, I.A., Smith, J.N., and Williams, R.T. (1952). The metabolism of aliphatic alcohols. The glucuronic acid conjugation of acyclic aliphatic alcohols. Biochem., 53:129-136.

Traiger, G.J. and Bruckner, J.V. (1976). The participation of 2-butanone in 2-butanol-induced potentiation of carbon tetrachloride hepatotoxicity. J. Pharmacol. Exp. Ther. 196:493-500.

DiVincenzo, G.D., Kaplan, C.J. and Dedinas, J. (1976). Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butylketone, and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol. Appl. Pharm., 36:511 -522. Cox, G.E., Bailey, D.E., and Morgareidge, K. (1975). Toxicity studies in rats with 2-butanol including growth, reproduction, and teratologic observation. Food and Drug Research Laboratories. LaB No. 2093. Astra Nutrition, Molndal Sweden [with TSCE 8(e) cover note dated May 11, 1992 by Shell Oil, Houston, TX, USA] Gallo, M.A., Oser, B.L., Cox, G.E. and Bailey, D.E. (1977). Studies on the long-term toxicity of 2-butanol. Toxicol. Appl. Pharmacol., 41:135.

Short description of key information:
There is no reproductive toxicity study available for diethyl ketone (DEK). Therefore, existing data for the structural similar aliphatic ketones dimethyl ketone (DMK, CAS 67-64-1) and methylethyl ketone (MEK, CAS 78-93-3) were used for a read across/weight of evidence approach. Based on the available data for DMK and MEK, there is no reproductive toxicity expected for DEK.

Effects on developmental toxicity

Description of key information

There is no developmental toxicity study available for diethyl ketone (DEK). Therefore, existing data for the structural similar aliphatic ketones dimethyl ketone (DMK, CAS 67-64-1) and methylethyl ketone (MEK, CAS 78-93-3) were used for a read across/weight of evidence approach. Based on the available data for DMK and MEK, there is no developmental toxicity expected for DEK.

Additional information

There is no developmental toxicity study available for diethyl ketone (DEK). Therefore, existing data for the structural similar aliphatic ketones dimethyl ketone (DMK, CAS 67-64-1) and methylethyl ketone (MEK, CAS 78-93-3) were used for a read across/weight of evidence approach. DEK, DMK and MEK are structurally very similar low molecular weight aliphatic ketones, which differ only in the alkyl chain length by one or two methyl groups. They are volatile and flammable organic solvents with similar specific gravity and a logPOW value between -0.21 and 0.85. Moreover, a comparison of the available toxicity data shows a similar toxicological profile: all substances exhibiting narcotic properties at high vapour concentrations and are of low toxicity by the oral, dermal and inhalative route of exposure (i.e. LD50/LC50 values above the regulatory threshold laid down in Regulation 1272/2008/EC (CLP)), they do not cause skin irritation but skin dryness after repeated dermal exposure and have a potential for eye and upper respiratory tract irritation in humans. Furthermore, these ketones share common metabolic pathways such as reduction to secondary alcohols and oxidation to hydroxyketones and finally carbon dioxide.

Methylethyl ketone (MEK, CAS 78 -93 -3)

 

In a developmental toxicity study (Schwetz et al., 1974) similar to OECD Guideline 414, methylethyl ketone was administered to female Sprague-Dawley rats by inhalation at dose levels of 0 and 1000 (1126±61 measured) ppm or 0 and 3000 (2618±26 measured) ppm for 7 hours a day from days 6 through 15 of gestation. The NOAEC for maternal toxicity was considered to be 3000 ppm, since only minimal maternally toxicity occurred. At 1000 ppm the total number of litters containing fetuses with anomalous skeletons was significantly increased compared to controls. This observation is biologically not relevant as it was not seen at 3000 ppm. Moreover, there was no increase of specific skeletal anomalies. Sternebral variations occurred at an increased incidence among litters of dams exposed to 3000 ppm methyl ethyl ketone when compared to the concurrent control group, but not when compared to the control group which was run concurrently to the 1000 ppm exposure group. Therefore, it is questionable if this increase represents a treatment related effect. As there was no single soft tissue anomaly which occurred at an increased incidence, the significantly greater total number of litters containing fetuses with soft tissue anomalies is biologically not relevant. Among 4 litters of dams exposed to 3000 ppm methyl ethyl ketone, there were 2 acaudate fetuses with an imperforate anus and 2 brachygnathous fetuses. Considered collectively, these anomalous fetuses accounted for a significantly increased number of the fetal population and litters having gross anomalies compared to the incidence among the controls. In this study some effects occurred at the high concentration of 3000 ppm which might indicate a slight fetotoxic and/or teratogenic potential of methyl ethyl ketone. Therefore, a second study was conducted to determine the repeatability of the effects.

In this developmental toxicity study, also similar to OECD Guideline 414, methyl ethyl ketone was administered to female Sprague-Dawley rats by inhalation at dose levels of 0, 400, 1000 or 3000 ppm for 7 hours a day from days 6 through 15 of gestation (Deacon et al., 1981). Slight maternal toxicity, as evidenced by temporarily decreased weight gain and increased water consumption, was observed among rats exposed to 3000 ppm MEK. No embryotoxic effects were noted. The only effect observed in fetuses was a slightly but statistically significantly increased incidence of two minor skeletal variants (extra ribs and delayed ossification cervical centra) among litters from animals exposed to 3000 ppm MEK. In summary, MEK did neither cause an embryotoxic nor a teratogenic response in rats at exposure levels up to concentration of 3000 ppm. The increased incidence of gross anomalies seen in the first study could not be repeated. Slight fetal toxicity noticed as an increase of skeletal variations (which was also seen in the first study at 3000 ppm) and maternal toxicity was seen at 3000 ppm. Based on the results of both studies, 1000 ppm represents the NOAEC for maternal toxicity and fetotoxicity and 3000 ppm the NOAEC for embryotoxicity and teratogenicity in the rat.

 

To assess the potential of methyl ethyl ketone to cause developmental toxicity in rodents, groups of mice were exposed to 0, 400, 1000, or 3000 ppm MEK vapors 7 hr/day on days 6–15 of gestation (Schwetz et al., 1991). Groups consisted of about 30 bred females each. Exposure of pregnant mice to these concentrations of MEK resulted in a treatment-related increase in relative liver weight which was statistically significant in the 3000 ppm group. In the 3000 ppm group mean fetal body weight of males and females was 5.1 % and 3.8 %, respectively, less than in the respective control group fetuses, reaching statistical significance in males only. There was no increase in the incidence of resorptions or the number of litters with resorptions among mice exposed to MEK. There was no significant increase in the incidence of any single malformation. There was a significant trend, but not a significant increase at any concentration in comparison to control, for increased incidence of misaligned sternebrae, a developmental variation. In summary, pregnant mice were relatively insensitive to MEK at the inhaled concentrations used in this study. Dams of the 3000 ppm group had significantly elevated relative liver weight, indicating minor maternal toxicity at this exposure level. The offspring of the mice exhibited minor signs of developmental toxicity (slightly reduced fetal weight and a significant trend for increased incidence of misaligned sternebrae) at 3000 ppm. No toxicity was observed at 1000 ppm MEK or below. Thus, a NOAEC of 3000 ppm is derived for embryotoxicity and teratogenicity and the NOAEC of 1000 ppm for maternal toxicity and fetotoxicity.

Dimethylketone (DMK, Acetone, CAS 67 -64 -1)

The potential to cause developmental toxicity was assessed in pregnant rats and mice exposed to acetone vapors. The test protocol was comparable to OECD Guideline 414. (NTP, 1988)

During whole-body exposure in an exposure chamber for 6 h/d on 7 d/w, exposure concentrations were 0, 440, 2,200 and 11000 ppm acetone (1060, 5300, 26500 mg/m³) for Sprague-Dawley rats, and 0, 440, 2200 and 6600 ppm (1060, 5300, 15900 mg/m³) for CD-1 mice. As a dose level of 11000 ppm induced narcosis in mice within several hours, the high-dose level was reduced to 6600 ppm from the second day of exposure. The highest dose for rats can be calculated to be 6125 mg/kg bw/d, and for mice to be 8400 mg/kg bw/d, assuming 100% absorption.

Pregnant rats (N=31/dose level, group A) were exposed from gestation days 6 to 19. In 7 additional dams/dose level (group B), plasma levels of ketone bodies (acetone, acetoacetate and ß-hydroxybutyrate) were analyzed on gestation days 7, 14 and 19, both 30 min and 17 h post exposure. These dams and their fetuses were subjected to the same examinations as group A except for an evaluation of malformations (only gross examination for external effects). For comparison, toxicity and body weight development was observed in a third group (group C) with 10 virgin females per dose level.

Pregnant rats (groups A and B) exhibited overt signs of maternal toxicity in the 11000 ppm group as statistically significant reductions of body weight, of cumulative weight gain from gestation day 14 onwards, of uterine weight and extragestational weight gain. Mean body weights of treated virgins (group C) were also reduced, but not significantly. At the same exposure concentration, fetal toxicity was indicated by a significant reduction of fetal weights (groups A and B). The incidence of fetal malformations was not significantly increased, although the percent of litters with at least one pup exhibiting malformations was greater for the 11000 ppm group than for the control group (11.5 % vs. 3.8%). The diversity of malformations was greater than that found in the lower dose groups or the controls. These changes were not interpreted as an indication of a substance-specific teratogenic potential of acetone.

Pregnant mice ((N=33/dose level) were exposed from gestation days 6 to 17 (6 h/d, 7 d/wk). For comparison, toxicity and body weight development was observed in a control group. There was a statistically significant increase in the mean absolute or relative liver weights of maternal animals at 6600 ppm. Developmental toxicity was observed in the 6600 ppm group as a statistically significant reduction of fetal weights and a slight, but statistically significant increase in the percent incidence of late resorptions. The incidence of fetal malformations or variations was not altered in mice.

Justification for classification or non-classification

Based on the read-across to data on methyl ethyl ketone and dimethyl ketone, diethyl ketone is not subject for classification and labelling according to Directive 67/548/EEC and Regulation 1272/2008/EC.