Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
3 122 mg/kg bw/day
Additional information

Information on the effects of methyl ethyl ketone on fertility were obtained by reading across to a study conducted with the read-across substance, secondary butanol. Metabolic data demonstrate that s-butanol is rapidly and extensively converted to methyl ethyl ketone via oxidation of the alcohol functional group by alcohol dehydrogenase in the liver. Thus, methyl ethyl ketone may be used as an appropriate surrogate for s-butanol and vice versa considering that exposure to either substance would essentially result in exposure to methyl ethyl ketone.

Secondary butanol, in a modified two-generation reproductive toxicity study in rats, produced a reduction in fertility when administered at 3% in drinking water, a concentration which clearly exceeded the maximum tolerated dose level, causing significant maternal toxicity and reduced pup survival (US EPA). The non-specific systemic effects on the dams and pups noted at 3% (4571 mg/kg/day) included significant maternal body weight loss, kidney and liver histopathology, reduced fetal body weight and pup survival and reduced fertility. When the highest concentration was lowered to 2% (equivalent to 3384 and 3122 mg/kg/day for males and females, respectively) for 2 subsequent matings (P and F1), no effect on fertility or reproduction was observed. Adult rats exposed to 2.0% SBA showed significant kidney histopathology; however, no adverse systemic effects were found at a dose of 1% (equivalent to 1644 and 1771 mg/kg/day for males and females, respectively). Thus, the overall NOAEL for the study was 1644 mg/kg/day. This study was conducted prior to the GLPs and was similar to OECD test guideline 416.

Please refer to the documents attached to Section 13 for additional data and justification of read across.


Short description of key information:
Information on the effects of methyl ethyl ketone on fertility were obtained by reading across to a study conducted with secondary butanol. Secondary butanol has been studied for effects on fertility through two generations in rats, and through a second P mating leading to a teratology study via drinking water exposures up to 3% (approximately 4571 - 5089 mg/kg/day). A number of non-specific systemic effects on the dams and pups were noted at 3% (4571 mg/kg/day), including significant maternal body weight loss, kidney and liver histopathology, reduced fetal body weight and pup survival and reduced fertility. No evidence for specific reproductive impairment was seen at a concentration of 2% (3122 mg/kg/day). Adult rats exposed to 2.0% SBA showed significant kidney histopathology; however, no adverse systemic effects were found at a dose of 1% (equivalent to 1644 and 1771 mg/kg/day for males and females, respectively). The overall NOAEL for the study was 1644 mg/kg/day.
There are no selective effects on offspring during the lactational phase at dose levels which are not also maternally toxic.

Effects on developmental toxicity

Description of key information
The developmental toxicity of methyl ethyl ketone (MEK) was evaluated in a non-GLP inhalation study in rats similar in design to OECD Guideline 414.  Slight fetotoxicity and maternal toxicity were noted at 3,000 ppm, the highest dose level tested.  There were no teratogenic or embryotoxic effects noted at any dose level.  As such, the NOAEC for both maternal and fetal toxicity was considered to be 1002 ppm.  
Supportive information was provided by 2 other inhalational studies involving mice and rats. In both of these studies, maternal and fetal toxicity were noted at 3000 ppm. There were no maternal-toxic or fetal-toxic effects noted at 1000 ppm. In both of these studies, there were no embryotoxic or teratogenic effects reported.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
3 003 mg/m³
Additional information

The developmental toxicity of methyl ethyl ketone (MEK) was evaluated in an inhalational non-GLP prenatal development toxicity study similar to OECD Guideline 414 (Pilny, 1979). Sprague-Dawley rats were exposed to MEK concentrations of 0 (filtered room air control), 400, 1000, or 3000 ppm daily for 7 hours/day from gestation days 6 through 15. Maternal toxicity, evidenced by decreased body weight gain and increased water consumption was noted at the 3000 ppm dose level. Fetal effects included a slight increase in variations such as delayed ossification of the cervical centrum and extra lumbar ribs at 3000 ppm. MEK was considered to not be teratogenic or embryotoxic at any dose level tested in the study. While the authors did not specifically identify a NOAEC, the NOAEC for maternal and fetal toxicity in this study is considered to be 1002 ppm (analytical result) on the basis of findings noted at 3000 ppm. The NOAEC is equivalent to 3000 mg/m3at 20 °C.

Supportive information is provided by an inhalational prenatal developmental toxicity study of MEK in rats (Saillenfait et al., 2006). Decreased maternal weight gain and food consumption was noted at 3000 ppm and decreased fetal body weights were noted at 3000 ppm. There were no treatment-related malformations or anomalies at any concentration tested.

Supportive information on the developmental toxicity potential of MEK was provided by an inhalation teratology study in Swiss mice by Schwetz et al., (1991). Slight maternal toxicity in form of increased relative liver and kidney weights and fetotoxicity in form of reduced male fetal weights and increased incidence of the variation misaligned vertebrae were noted at 3000 ppm. Some additional variations and malformations occurred in the study that were not normally encountered in contemporary controls, but there was no clear dose-response relationship for these findings. The NOAEC for fetotoxic and maternal toxicity in this study was 1000 ppm (2940 mg/m^3).

 

Overall, the data from these studies indicate that MEK is not embryotoxic or teratogenic.  MEK does not cause fetotoxicity at doses that do not also cause maternal toxicity.

Please refer to the documents attached to Section 13 for further information.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) No. 1272/2008.