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Key value for chemical safety assessment

Effects on fertility

Additional information

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 10,000 mg acetone/L drinking water (1%) for 4 weeks, or 0 or 5,000 mg acetone/L drinking water (0.5%) for 9 weeks (corresponding to doses of 1,300 or 650 mg/kg bw/d). Weights and histopathology of the male reproductive organs (testes, epididymis, seminal vescicles) 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 recognised 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 10,000 mg/L) although there were indications of systemic toxicity (Dalgaard et al., 2000).

Male Wistar rats were exposed to 0.5% acetone in drinking water for 6 weeks corresponding to 5,000 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 foetuses. Additionally, 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, whereas 0.5% hexanedione in drinking water had a distinct testis-injuring effect (Larsen et al., 1991).

In the course of a 13-week repeated dose toxicity drinking water study, sperm parameters and vaginal cytology were investigated additionally (Dietz et al., 1991; NTP, 1991). 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.

Male and female Fischer 344 rats were exposed to concentrations of 2,500, 10,000, and 50,000 ppm in drinking water resulting in actual dosages of 200, 900 and 3,400 mg/kg bw/d in male rats and 300, 1,200 and 3,100 mg/kg bw/d in female rats.

A mild toxic effect on spermatogenesis with a LOAEL of 3,400 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 20,000 ppm corresponding to a dose of 1,700 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 50,000 ppm or 3,100 mg/kg bw/d.

In the study with B6C3F1 mice, water concentrations were 1,250, 5,000 and 20,000 ppm for males resulting in dosages of 380, 1,353 and 4,858 mg/kg bw/d. Females consumed water with 2,500, 10,000 and 50,000 ppm acetone resulting in actual dosages of 892, 4,156 and 11,298 mg/kg bw/d. There was no indication of reproductive toxicity up to the highest tested doses of 20,000 ppm for male mice (NOEL 4,858 mg/kg bw/d) or of 50,000 ppm for female mice (NOEL 11,298 mg/kg bw/d). Systemic toxicity was indicated in female mice at 11,298 mg/kg bw/d (systemic LOAEL).

In summary, there are no indications on an impairment of fertility up to 3,100 mg/kg bw/d in female rats, up to ca. 5,000 mg/kg bw/d in male mice and up to ca. 11,000 mg/kg bw/d in female mice. In male rats, no indications of an of impairment of fertility were found at 900 mg/kg bw/d. As mild changes of sperm parameters and of weights of the cauda epididymis and the epididymis occurred only at the highest tested dose of 3,400 mg/kg bw/d, but systemic toxicity was indicated at the kidneys and the hemopoetic system already at 1,700 mg/kg bw/d, it is questionable if there is a specific reproductive effect. There is a high probability that the observed changes of male reproductive parameters are also an expression of generalized toxicity. Additionally, the daily levels of acetone exposure of 3,400 mg/kg bw/d reached dose levels reported to induce severe acute intoxication symptoms in humans after oral uptake (e.g. single dose of 2,500 mg/kg bw; see Section 7.10.3).

There are no studies available covering the test conditions and endpoints of a guideline study on toxicity to reproduction.

As there was no indication of a specific effect on male or female fertility up to daily doses of 3,400 mg/kg bw/d (see above) whereas generalized toxicity was seen with a LOAEL of 1,700 mg/kg bw/d, the tolerance to acetone exposure principally is high. Additionally, it is known that pregnancy and lactation, as well as perinatal development and postnatal growth represent physiological states during which ketogenesis and the endogenous levels of acetonecan be appreciably increased both in the mother and in the offspring up to 20fold above normal due to the ketogenesis from their higher energy requirements (see Section 7.1.1). Acetone was detected both in human milk and cord blood. Consequently, acetone exposure of the foetus or the pups can be increased from endogenous sources and is obviously tolerated. Excretion of exogenous acetone was shown to be fast. Based on these observations as a whole, the performance of a one-generation or two-generation reproductive toxicity study is waived as no signs of reproductive or developmental toxicity are expected to occur in the offspring of exposed parent animals at exposure scenarios relevant for human exposure.

Short description of key information:
Drinking water study, male rat, 4 w: NOEL male fertility 1,300 mg/kg bw/d
Drinking water study, male rat, 9 w: NOEL male fertility 650 mg/kg bw/d
Drinking water study, rat, 13 w: NOAEL male fertility 900 mg/kg bw/d, LOAEL 3,400 mg/kg bw/d; LOAEL systemic toxicity 1,700 mg/kg bw/d
NOAEL female fertility 3,100 mg/kg bw/d
Drinking water study, mouse, 13 w: NOAEL male fertility 4,858 mg/kg bw/d
NOAEL female fertility 11,298 mg/kg bw/d

Effects on developmental toxicity

Description of key information
Inhalation study, rat, GD 6-19:        LOAELs foetotoxicity and maternal toxicity 11,000 ppm acetone (26,500 mg/m3)
NOAELs foetotoxicity and maternal toxicity 2,200 ppm acetone (5,300 mg/m3)
Inhalation study, mouse, GD 6-17: LOAELs foetotoxicity and maternal toxicity 6,600 ppm acetone (15,900 mg/m3)
NOAELs foetotoxicity and maternal toxicity 2,200 ppm acetone (5,300 mg/m3)
Effect on developmental toxicity: via inhalation route
Dose descriptor:
5 300 mg/m³
Additional information

The potential to cause developmental toxicity was assessed in pregnant rats and mice exposed to acetone vapours. The test protocol was comparable to OECD Guideline 414 (Key study: 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 11,000 ppm acetone (1,060, 5,300, 26,500 mg/m3) for Sprague-Dawley rats, and 0, 440, 2,200 and 6,600 ppm (1,060, 5,300, 15,900 mg/m3) for CD-1 mice. As a dose level of 11,000 ppm induced narcosis in mice within several hours, the high-dose level was reduced to 6,600 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 there 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 11,000 -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 ot 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 are not interpreted as an indication of a substance-specific teratogenic potential of acetone. Plasma acetone levels were increased at 30 min but dropped to control levels within 17 h post exposure except for a slight increase in the 11000 -ppm group. However, no accumulation of acetone was found over the entire exposure period and there was no increase of the other ketone bodies (data from Group B).

Pregnant mice ((N=33/dose level, Group A) were exposed from gestation days 6 to 17 (6 h/d, 7 d/w). For comparison, toxicity and body weight development was observed in a second group, Group B, with 10 virgin females per dose level.

The only sign of maternal toxicity was a statistically significant increase in the mean absolute or relative liver weights at 6,600 ppm. Developmental toxicity was observed in the 6,600 -ppm group as a statistically significant reduction of foetal weights and a slight, but statistically significant increase in the percent incidence of late resorptions. The incidence ot foetal malformations or variations was not altered in mice (NTP, 1988).

In summary, in both species indications of developmental toxicity (reduction of fetal weights, increase of late resorptions) were only observed at exposure concentrations that induced significant maternal toxicity, so that a classification is not justified according to EC Directive 1272/2008. The NOAEC was 2,200 ppm or 5,300 mg/m3 for both species concerning both reproductive toxicity and maternal toxicity.

Justification for classification or non-classification

Male and female fertility: no indication of adverse effects in absence of generalized toxicity, so that a classification is not justified according to EC regulation 1272/2008.

Indications of developmental toxicity in mice and rats (reduction of fetal weights, increase of late resorptions) were only observed at exposure concentrations that induced significant maternal toxicity, so that a classification is not justified according to EC regulation 1272/2008.

Additional information