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EC number: 201-159-0 | CAS number: 78-93-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
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- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
In a two-generation inhalation study with methyl isobutyl ketone (MIBK), the NOAEL for reproductive toxicity was considered to be 2000 ppm (8177 mg/m³), the highest dose tested.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Justification for type of information:
- September 24, 1998 to December 2, 1998.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: (F0) 46 days; (F1) 49 days
- Weight at study initiation: (F0) Males: 259-552 g; Females: 235-371 g; (F1) Males: 362-538 g; Females: 218-339 g
- Housing: individually is suspended wire-mesh cages
- Diet: PMI Nutrition International Certified Rodent LabDiet® 5002, ad libitum
- Water: municipal water treated on-site by reverse osmosis, ad libitum
- Acclimation period: 23 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30 to 70%
- Air changes per hour: 10 during acclimation, 12 to 15 during exposure
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: August 3, 1998 To: May 1999 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 2.0 m³ stainless steel and glass whole body inhalation chamber
- Method of holding animals in test chamber: cage
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: not applicable
- Temperature, humidity, pressure in air chamber: 22 ± 2°C and 30 to 70%, respectively
- Air flow rate: 12 to 15 air changes per hour
- Air change rate: 12 to 15 per hour
- Method of particle size determination: not applicable
- Treatment of exhaust air: not reported
TEST ATMOSPHERE
- Brief description of analytical method used: exposure concentrations were measured 9 to 10 times during each daily exposure by a validated gas chromatographic method. Samples were also taken from exposure containers before and after use, to check stability. Compound structure was verified using GC-MS.
- Samples taken from breathing zone: yes - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: presence of copulatory plug or of sperm in vaginal smear, referred to as day 0 of gestation
- After 14 days of unsuccessful pairing, females were placed in a maternity cage with nesting material.
- Further mating after two unsuccessful attempts: no
- After successful mating each pregnant female was caged individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Exposure concentrations were measured 9 to 10 times (approximately every 35 minutes) during each daily exposure by a validated gas chromatographic method.
- Duration of treatment / exposure:
- F0 and F1 males: at least 70 days prior to mating until 1 day prior to euthanasia
F0 and F1 females: at least 70 days prior to mating until gestational day 20; then from PND day 5 until 1 day prior to euthanasia
F1 litters were potentially exposed in utero and during PND days 0-21, and were intentionally exposed from weaning PND 22 and continued.
F2 animals were potentially exposed in utero and during lactation day 0 to 21 (but were not exposed in exposure chambers). - Frequency of treatment:
- 6 hours/day, 7 days/week
- Details on study schedule:
- - F1 parental animals not mated until 10 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 4 days of age.
- Age at mating of the mated animals in the study: 13 weeks - Dose / conc.:
- 500 ppm
- Remarks:
- Target concentration. Analytical concentrations were 491 ppm (F0) and 506 ppm (F1), equivalent to 2011 mg/m³ and 2073 mg/m³ respectively.
- Dose / conc.:
- 1 000 ppm
- Remarks:
- Target concentration. Analytical concentrations were 999 ppm (F0) and 1002 ppm (F1), equivalent to 4092 mg/m³ and 4105 mg/m³ respectively.
- Dose / conc.:
- 2 000 ppm
- Remarks:
- Target concentration. Analytical concentrations were 1996 ppm (F0) and 2006 ppm (F1), equivalent to 8177 mg/m³ and 8217 mg/m³ respectively
- No. of animals per sex per dose:
- 30
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale:
on the basis of previous studies with test article
- Rationale for animal assignment: random
- Fasting period before blood sampling for clinical biochemistry: not applicable - Positive control:
- No
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: appearance, behaviour, pharmacotoxic signs within one hour after completion of exposure, moribundity and mortality. In addition, at the approximate midpoint of each day’s exposure, a Striker device was used to produce a loud noise (novel stimulus) directly on the front glass of the exposure chamber. The animals in accessible cages were observed each day for a reaction to the stimulus, and the findings were recorded.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
- Oestrous cyclicity (parental animals):
- The oestrous stage of each female F0 and F1 was determined by daily preparation of vaginal smears beginning 21 days before pairing and continuing until evidence of mating was present or the end of the mating period. The oestrous stage of each female was also determined on the day of euthanasia.
- Sperm parameters (parental animals):
- Sperm motility and morphology for each F0 and F1 male was determined immediately following euthanasia. Homogenization-resistant spermatid and sperm production rates were also determined.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4 sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, and physical abnormalities.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities. - Postmortem examinations (parental animals):
- SACRIFICE
- All surviving F0 animals were euthanized upon selection of the F1 generation, and all surviving F1 animals were euthanized following weaning of the F2 generation
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues/organs were prepared for microscopic examination: adrenals (2), aorta, bone with marrow (sternebrae), brain (forebrain, midbrain, hindbrain), coagulating gland, eyes with optic nerve (2), gastrointestinal tract (oesophagus, stomach, duodenum, ileum, jejunum, cecum, colon, rectum), heart, kidneys (2), liver (sections of 2 lobes), lungs (including bronchi, fixed by inflation with fixative), lymph node (mesenteric), ovaries and oviduct, pancreas, peripheral nerve (sciatic), pituitary, prostate, salivary gland (submaxillary; 2), seminal vesicles (2), skeletal muscle (vastus medialis), skin with mammary gland, spinal cord (cervical), spleen, testes with epididymis (1) and vas deferens, thymus, thyroids (with parathyroids if present; 2), trachea, urinary bladder, uterus with vagina, and all gross lesions; in addition the following organs were weighed: adrenals, brain, epididymis (total and cauda), kidneys, liver, ovaries, pituitary, prostate, seminal vesicles with coagulating glands (with accessory fluids), spleen, testes, thymus, and uterus with oviducts and cervix.
Microscopic evaluations of the following tissues were performed for parental (10/sex/group) animals who were found dead or euthanized due to morbidity: adrenals, brain, epididymides (right; caput, corpus, and cauda), cervix, coagulating gland, kidneys, liver, lung, ovaries, oviducts, pituitary, prostate, seminal vesicles, spleen, testes (right), thymus, uterus, vagina, vas deferens, and all gross internal lesions. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: brain, spleen, and thymus weights for 1 pup/sex/litter. The morphology of developmental and reproductive systems was assessed and all lesions retained for examination.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. - Statistics:
- All analyses conducted using 2-tailed tests, with minimum significance set at 5%.
The following statistical tests were used:
Chi-square, one-way ANOVA with Dunnett’s test, Kruskal-Wallis test with Mann-Whitney U-test, Kolmogorov-Smirnov test (one-tailed), and ANCOVA (with litter size as covariant) and Student’s t-test. - Reproductive indices:
- Mating and fertility
- Offspring viability indices:
- Survival
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female in the mid dose group died during parturition; clinical findings for two days before death indicated dystocia. One male was euthanised in extremis due to mechanical injury to nose. Neither death was attributed to treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Transient reductions in mean body weight gains were observed in the high dose group F0 females during weeks 0-1 and 1-2. No effects were observed in F1 females at these intervals. Mean body weights were unaffected in F0 mid and low dose groups, and in all F0 males at all exposure levels.
- Food efficiency:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- There was an increase in the number of observations of male and female rats having no reaction to an auditory startle stimulus in the mid and high dose groups.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No significant effects were observed.
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Individual variation in the oestrous cycle occurred in all study groups. The regularity and duration of oestrus were not affected by exposure.
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEC
- Remarks:
- parental systemic toxicity
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOAEC
- Remarks:
- reproductive toxicity
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed at any dose level.
- Critical effects observed:
- no
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Exposure-related clinical signs, including rocking, lurching or swaying while walking, half-closed eyelids, bilateral lacrimation and red material around the nose and mouth, were observed in the 2000 ppm group F1 (P1) males and females. As a result of this mortality and the clinical signs observed, exposure was suspended to PND 27. After exposure was resumed, these clinical signs were observed in 6 out of 30 high dose group males, but not in females. The predominant clinical sign observed for F1 parental (P1) males consisted of hair loss on the forelimbs.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One F1 (P1) male in the high dose group died after one day of exposure, on PND 22, and was replaced by another weanling. No further mortality occurred.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight gains were reduced in the 2000 ppm group F1 parental (P1) males and females during week 17-18 (the first week of exposure following selection) and in the 2000 ppm group F1 parental (P1) males during week 18-19. 19. Mean body weights in the 2000 ppm group F1 parental (P1) females were slightly reduced throughout the pre-breeding and post-lactational phases. These transient reductions, although slight, were attributed to test article exposure. Mean body weights and body weight gains were unaffected by test article exposure throughout gestation and lactation for F1 parental (P1) females at all exposure levels evaluated.
- Food efficiency:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- A dose-related increase in the numbers of animals of both sexes with no response to an auditory startle stimulus was observed in the mid and high dose groups.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Exposure-related increases in mean absolute and relative (to final body weight) liver weights were observed for F1 parental (P1) males and females at the 2000 ppm level; relative liver weights were also increased for F1 parental (P1) males at the 1000 ppm level. Correlating exposure-related centrilobular hepatocellular hypertrophy was observed - this is considered an adaptive response and not indicative of systemic toxicity.
Exposure-related increases in mean absolute and relative (to final body weight) kidney weights were observed for F1 parental (P1) males and females in all exposure groups. Microscopic changes were observed in basophilic tubules for all dose groups, with corresponding acidophilic hyaline inclusions consistent with alpha 2µ globulin formation observed at all exposure levels. This is known to be a male rat specific effect. - Gross pathological findings:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEC
- Remarks:
- F1 parental (P1) systemic toxicity
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Dose descriptor:
- NOAEC
- Remarks:
- reproductive toxicity
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed at any dose level
- Critical effects observed:
- no
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Dose descriptor:
- NOAEC
- Remarks:
- neonatal toxicity
- Generation:
- F1
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effect observed in F1 pups which were not subsequently exposed to the test material
- Critical effects observed:
- no
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Dose descriptor:
- NOAEC
- Remarks:
- neonatal toxicity
- Generation:
- F2
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Conclusions:
- Methyl isobutyl ketone (MIBK) has been tested in a whole-body inhalation study. Male and female Sprague-Dawley rats were exposed to 0, 500, 1000 or 2000 ppm MIBK, 6 hours/day, 7 days/week for 70 days premating and from mating through gestation day 20 and from postnatal day 5 for F0 and F1 females. The NOAEC for parental systemic toxicity and neonatal toxicity was considered to be 1000 ppm. The NOAEC for reproductive toxicity was considered to be 2000 ppm, the highest dose tested.
- Executive summary:
The reproductive toxicity of methyl isobutyl ketone (MIBK) has tested in a two-generation toxicity study in Crj: CD(SD) rats conducted according to a protocol similar to OECD TG 416 and in compliance with GLP. Rats were administered MIBK at target concentrations of 0, 500, 1000 and 2000 ppm by whole body inhalation. Mean measured concentrations for the F0 generation were 0, 491, 999, and 1996 ppm, equivalent to 0, 2011, 4092, and 8177 mg/m³; for the F1 generation mean measured concentrations were 0, 506, 1002 and 2006, equivalent to 0, 2073, 4105 and 8217mg/m³. Parental (F0 and F1) findings included transient decreased body weight during the first 2 weeks of exposure at the 2000 ppm dose concentration and increases in absolute and relative liver weights at 2000 ppm. Significant increases in parental F0 and F1 mean absolute and relative kidney weights were observed for males in all MIBK-treated groups relative to the control group; however, mean kidney weights of female rats were unaffected. These increases in mean kidney weight were attributed to an alpha2µ-mediated mechanism and are not considered relevant to human risk identification. Offspring findings included a single mortality and signs of CNS depression in the F1 parental group following MIBK exposure on postnatal day (PND) 22 to 25. As a result, F1 MIBK exposure was suspended until PND 27. CNS depressive effects were observed until PND 31, but not after. F1 parental animals in the 1000 and 2000 ppm groups showed reduced reactivity to novel stimulus during exposure, which was attributed to a sedative effect. There were no effects on reproductive parameters reported. Based on these findings the NOAEC for parental systemic toxicity and neonatal toxicity was considered to be 1000 ppm. The NOAEC for reproductive toxicity was considered to be 2000 ppm, the highest dose tested.
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1975
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Study was performed prior to GLP or OECD guidelines and followed rats for two-generations through to weaning. The F2 pups were not necropsied but instead placed into a chronic, carcinogenicity study. F1b generation was produced for teratologic examination. For read-across substance
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- F2 pups were not necropsied
- Principles of method if other than guideline:
- The P animals were re-mated and F1b fetuses were produced and examined in a teratology study. The F2 pups were produced and followed through weaning, but not necropsied. F1a pups were reared and mated and then necropsied as adults. The F1b fetuses were necropsied for a complete teratological examination.
- GLP compliance:
- no
- Remarks:
- study was prior to GLP
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Rats (30/sex/group) were housed individually in mesh-bottom cages in an air-conditioned room and provided food and water ad libitum. Food and fluid intake, and body weights were measured on a weekly basis.
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- Animals were provided with drinking water via stainless steel sipper tubes containing 0.3, 1.0, or 3.0% (approximately 538, 1644, or 5089 mg/kg/dayfor males; and 594, 1771, and 4571 mg/kg/day for females) secondary butanol. On day 10 post-partum of the F1 pups, the top dose was lowered to 2.0% (approximately 3000 mg/kg/day) due to clear loss in body weight of the dams and lower birthweight of the pups.
The average daily intake in mg/kg/day at the 2% exposure level was not reported by the study investigators, but was reported by the USEPA in their 2003 IRIS assessment of MEK as average daily intakes of 3,384 mg/kg/day in males and 3,122 mg/kg/day in females based on a linear regression analysis of the reported average intakes for males and females at drinking water concentrations of 0, 0.3, 1, and 3%.
Negative controls were provided with tap water. - Details on mating procedure:
- For the P1 mating, after 9 weeks on test, one male was co-housed with one female until a vaginal sperm plug was observed or sperm were evident in a vaginal smear. Females were transferred to separate cages on gestation day 17 or 18, and allowed to carry their litters to term. Dams having more than 8 pups had the number of pups randomly culled to a maximum litter size of 8. Pup and dam weights were recorded on day 4 and 21 of lactation.
For the P2 mating, after separation from their weaned F1 litters, dams were allowed a two-week rest interval (no treatment), then placed back on treatment and re-mated as before until the first 20 dams showed evidence of pregnancy.
For the F1 mating, at 12 weeks of age, matings were accomplished as per the P1 method described above. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Not applicable
- Duration of treatment / exposure:
- F0 animals: 9 weeks premating exposure, 18 days gestation, 21 days lactation
F1 animals: 21 days lactation, 8 weeks premating exposure, 18 days gestation, 21 days lactation
F2 animals: 21 days lactation.
Second mating of the P-generation:
Two-week "rest period" then remating. Exposure through day 20 gestation. - Frequency of treatment:
- Continuous (P, F1)
A two week rest interval occurred between the first and the second matings of the P generation. - Details on study schedule:
- Rats (30/sex/group) were exposed continuously via drinking water to SBA concentrations of 0, 0.3, 1.0, or 3.0% for 9 weeks and then mated until evidence of pregnancy achieved. After the birth of the F1a generation, on day 10 of lactation, the top dose was lowered to 2.0% for all subsequent stages of the study. The F1a pups were reared to day 28, and then transferred to individual cages and continued on treatment until 12 weeks of age, when they were mated to form an F2 generation, which was brought to term and followed through day 21 weaning.
P animals were re-mated (20 dams/group) to generate F1b fetuses which were necropsied for teratological examination. - Remarks:
- Doses / Concentrations:
Controls
Basis:
nominal in water
0 - Remarks:
- Doses / Concentrations:
Low dose
Basis:
nominal in water
0.3 % (538 - 594 mg/kg/day) - Remarks:
- Doses / Concentrations:
Mid dose
Basis:
nominal in water
1.0 % (1644 - 1771 mg/kg/day) - Remarks:
- Doses / Concentrations:
High dose - P1 generation only
Basis:
nominal in water
3.0 % (5089 - 4571 mg/kg/day) - Remarks:
- Doses / Concentrations:
High dose - P2 and F1 generations only
Basis:
nominal in water
2.0 % (approximately 3000 mg/kg/day) - No. of animals per sex per dose:
- 30 dams + 30 males (reproduction)
20 dams (teratology) - Control animals:
- yes
- Details on study design:
- An F1b generation was produced in a second mating of 20 of the dams/group from the P generation, exposed to secondary butanol at concentrations of 0, 0.3, 1.0, or 2.0 %. This F1b generation was necropsied for teratological evaluation (1/3 of the pups for visceral, and 2/3 of the pups for skeletal examinations).
F1a Litters were weaned at 21 days and housed together for an additional 6 days under the same treatment as the dams. Pups from these litters (30 males and females aged 28 days) were selected for the F1 mating. - Positive control:
- Not applicable
- Parental animals: Observations and examinations:
- Body weight (weekly) and daily food and water consumption up to 8 weeks.
Calculated test material intake. - Oestrous cyclicity (parental animals):
- No data
- Sperm parameters (parental animals):
- No data
- Litter observations:
- % viable at birth, 4 days, and 21 days. (viability and lactation indices)
Body weight day 4 and day 21.
Number of live/dead pups were ascertained as soon as possible following delivery, and completed by day 4. - Postmortem examinations (parental animals):
- All animals received a gross necropsy. Uteri were examined. Ten animals per sex/group received histopathological evaluations and organ weight measurements on spleen, adrenals, pituitary, gonads, and heart. Twenty animals/sex/group were examined histologically for lesions and organ weights measured for the liver and kidney. Any gross lesions noted were examined histologically.
Teratology portion reproductive parameters:
* Corpora lutea
* Implant sites
* Resorptions
* Live fetuses
* Dead fetuses
Clinical Chemistry: fasting blood sugar, urea nitrogen, serum glutamic oxaloacetic transaminase (SGOT), serum alkaline phosphatase, serum ornithine carbamyl transferase (SOCT), total serum proteins.
Haematology: hematocrit, hemoglobin, erythrocyte count, total and differential leucocyte counts, and prothrombin time.
Urinalysis: Semi-quantitative for sugar, protein, ketone bodies, specific gravity, and microscopic characterization of the centrifuged sediment. - Postmortem examinations (offspring):
- * Live/dead fetuses
* Sex of live fetuses
Teratology:
1) Soft tissue (visceral) examination:
2) Skeletal examination:
* Sternebrae
* ribs
* vertebrae
* extremities
* skull
* hyoid - Statistics:
- Not reported
- Reproductive indices:
- Fertility
Gestation - Offspring viability indices:
- Viability
Lactation - Clinical signs:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Dose descriptor:
- NOAEL
- Effect level:
- 10 000 mg/L drinking water
- Sex:
- male/female
- Basis for effect level:
- other: No changes in clinical signs, organ weights, histopathology, or fertility indices. Equivalent to 1644 and 1771 mg/kg/day for males and females, respectively.
- Dose descriptor:
- LOAEL
- Effect level:
- 20 000 mg/L drinking water
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 10 000 mg/L drinking water
- Sex:
- male/female
- Basis for effect level:
- other: Based on no observed fetotoxicity, viability or teratogenicity. Equates to 1644 and 1771 mg/kg/day for males and females, respectively
- Dose descriptor:
- LOAEL
- Generation:
- F1b
- Effect level:
- 20 000 mg/L drinking water
- Sex:
- male/female
- Basis for effect level:
- other: Decreased foetal weights
- Reproductive effects observed:
- not specified
- Conclusions:
- Secondary butyl alcohol, administered in drinking water to rats over two generations did not affect reproductive parameters or cause fetotoxicity up to a concentration of 1.0% (approximately 1700 mg/kg/day). A decrease in pup viability was seen at 3.0% and a slight decrease in fetal body weight was seen at 2.0% (3122 mg/kg/day in females). Kidney pathology in adult rats exposed to the highest doses of 3.0 and 2.0% were typical of kidney lesions seen in rats with aging.
- Executive summary:
Secondary butyl alcohol, administered in drinking water to rats over two generations did not affect reproductive performance or cause developmental toxicity up to a concentration of 1.0% (1644 mg/kg/day). Adult rats exposed to 2.0% SBA (3122 mg/kg/day) showed significant kidney histopathology in the form of renal tubular degeneration/regeneration, renal tubular casts, microcysts on the tip of the papilla. Pup viability was reduced at 3.0% (4571 mg/kg/day). Fetal body weights were slightly lower at 2.0%. The NOAEL in the study for general systemic, reproductive, and fetotoxic effects was 10000 mg/L (1644 mg/kg/day).
Referenceopen allclose all
Parameter |
0 ppm |
500 ppm |
1000 ppm |
2000 ppm |
F0 |
||||
Male mating index |
100% |
100% |
90% |
100% |
Female mating index |
100% |
100% |
90% |
100% |
Male fertility index |
93.3% |
96.7% |
86.7% |
93.1% |
Female fertility index |
93.3% |
96.7% |
86.7% |
93.3% |
Mean pre-coital interval (days) |
2.2 ± 1.21 |
2.5 ± 1.20 |
2.7 ± 1.11 |
3.0 ± 1.66 |
Gestation length (days) |
21.8 ± 0.44 |
22.2 ± 0.62* |
21.7 ± 0.46 |
22.0 0.19 |
Testicular sperm numbers (left; million sperm/g tissue) |
87.3 ± 9.90 |
91.9 ± 13.48 |
91.7 ± 17.26 |
86.0 ± 15.35 |
Epididymal sperm numbers (left; million sperm/g tissue) |
343.6 ± 92.66 |
310.1 ± 77.60 |
355.5 ± 81.06 |
380.2 ± 92.44 |
Sperm production rate (million sperm/g tissue/day; left testis) |
14.3 ± 1.63 |
15.1 ± 2.21 |
15.0 ± 2.83 |
14.1 ± 2.50 |
Sperm motility (% motile) |
80.0 ± 14.45 |
78.4 ± 16.38 |
82.9 ± 9.68 |
78.3 ± 17.89 |
Morphologically normal sperm (%) |
99.0 ± 1.31 |
99.0 ± 1.12 |
99.3 ± 1.42 |
99.0 ± 1.02 |
F1 |
||||
Number born |
13.0 ± 2.28 |
12.5 ± 2.91 |
13.3 ± 2.22 |
14.0 ± 2.31 |
Sex at birth (% male) |
52.1 ± 17.53 |
45.6 ± 19.46 |
47.9 ± 17.83 |
54.1 ± 12.99 |
Live litter size (PND 0) |
13.0 ± 2.35 |
12.4 ± 2.99 |
13.1 ± 2.18 |
13.8 ± 2.25 |
Mean body weight on PND 1 (g) |
6.9 ± 0.60 |
7.1 ± 0.70 |
6.9 ± 0.50 |
7.1 ± 0.49 |
Male mating index |
100% |
93.3% |
93.3% |
100% |
Female mating index |
100% |
93.3% |
93.3% |
100% |
Male fertility index |
96.7 |
90.0 |
80.0 |
93.3 |
Female fertility index |
96.7 |
90.0 |
80.0 |
93.3 |
Mean pre-coital interval (days) |
3.5 ± 2.73 |
3.2 ± 2.03 |
3.5 ± 2.66 |
3.2 ± 2.28 |
Gestation length (days) |
21.7 ± 0.53 |
21.7 ± 0.54 |
21.6 ± 0.58 |
21.6 ± 0.49 |
Testicular sperm numbers (left; million sperm/g tissue) |
86.6 ± 20.21 |
89.3 ± 12.24 |
82.6 ± 18.69 |
81.3 ± 10.86 |
Epididymal sperm numbers (left; million sperm/g tissue) |
517.5 ± 124.37 |
507.1 ± 106.48 |
550.3 ± 141.39 |
540.9 ± 93.27 |
Sperm production rate (million sperm/g tissue/day; left testis) |
14.2 ± 3.31 |
14.6 ± 2.01 |
13.5 ± 3.06 |
12.9 ± 3.00 |
Sperm motility (% motile) |
80.8 ± 13.29 |
82.2 ± 10.52 |
84.4 ± 10.30 |
83.9 ± 9.94 |
Morphologically normal sperm (%) |
98.7 ± 4.07 |
99.0 ± 1.21 |
99.0 ± 0.82 |
98.9 ± 0.82 |
F2 |
||||
Number born |
13.4 ± 2.86 |
13.8 ± 1.96 |
13.5 ± 2.36 |
14.2 ± 1.87 |
Sex at birth (% male) |
48.6 ± 14.54 |
49.9 ± 14.06 |
45.8 ± 12.02 |
50.2 ± 10.51 |
Live litter size (PND 0) |
13.1 ± 2.82 |
13.6 ± 2.19 |
13.5 ± 2.36 |
14.0 ± 1.89 |
Mean body weight on PND 1 (g) |
6.9 ± 0.59 |
6.8 ± 0.65 |
6.8 ±0 .64 |
6.6 ± 0.48 |
Fertility rate for the P animals treated with 3.0% SBA was 73%, which is below historical norms for the rat colony. After lowering the top dose to 2.0% secondary butanol (3384 and 3122 mg/kg/day in males and females, respectively), no effect on fertility was observed in the F1 matings.
No hematologic, urinary, or clinical biochemical alterations were seen in the sacrificed adult animals of either generation.
Males had slightly elevated liver and kidney weights, and females had elevated liver weights at 2.0% secondary butanol, but these increases were not statistically significant using a t-test.
In all dose groups, a high rate of respiratory and renal disease were noted upon microscopic evaluation. These findings were assessed as being typical of rat colonies not barrier maintained.
In the lungs of animals in all groups, a progressive hypertrophy of lymphoid tissue around bronchi, bronchioles, and often blood vessels, and in the mucosa of the trachea and bronchi were typically seen. Later changes include chronic interstitial inflammation of the alveolar walls, and loci of acute and subacute inflammation of the bronchial and tracheal mucosa, which precedes the development of bronchiectasis and abscess formation or atelectasis.
A low incidence of worms and the parasite (Trichosomoides crassicauda) was found in the renal pelvis of two animals (not related to treatment).
All of the above changes were considered to be expected findings in rat colonies from this era and not treatment-related.
Findings that were unexpected, and potentially treatment-related included the following four:
i) Nonreactive tubular degeneration in the outer medullary zone, probably involving mainly the thick ascending limb of the loop of Henle. The
epithelium shows loci of pycnosis, cytoplasmic granulation, increased eosinophilia, and, sometimes, desquamation with downstream
intraluminal clusters of free cells. In this study the change observed in female animals showed equal extent and intensity in animals of all groups. However, among the males, the change is two to three times more prominent in the high level test group (2% secondary butanol) than in the water control.
2) Tubular casts were found in five of the 2% group only. This excludes (a) the marked scarring and cast formation in the two animals with polyarteritis nodosa; and (b) a solitary small cast that might be seen in an occasional animal of any group.
3) Foci of tubular regeneration to a notable extent in eight 2% secondary butanol animals, and in only one water control animal, one low dose secondary butanol animal and in two mid dose secondary butanol animals. Some of these foci apparently are regenerating epithelium, and others have recently regenerated.
4) Microcysts in the tip of the renal papilla were found in 2% secondary butanol animals but in no water controls. These presumbably are dilatations of collecting ducts just before they open into the renal pelvis. Some of these "cysts" were empty, others were more or less filled with homogeneous eosinophilic material that resembles plasma, and may have been fluid during life, with component proteins that were fixed in place by formalin.
Of the above unexpected renal findings, none were regarded as having clear pathologic significance.
Compared to water, 2% secondary butanol evoked changes in kidneys of rats (males more than females) including an accelerated
appearance of tubular casts and focal tubular regeneration, development of microcysts in the apices of renal papillae, and
possibly epithelial degeneration in tubules in the outer medullary zone.
No skeletal or soft tissue abnormalities or terata were observed with SBA treatment. Fetotoxicity as reduced birthweight was also seen in the F2 pups exposed to 2.0% SBA.
Table 1. Summary of Reproduction Parameters in the P/F1b generation
Parameter | Water | 0.3% SBA | 1.0% SBA | 2.0% SBA |
Number of pregnancies | 29 | 28 | 30 | 29 |
Number of pregnancies to term | 29 | 28 | 30 | 29 |
Corpora lutea (total) | 392 | 357 | 422 | 383 |
Corpora lutea (per dam) | 13.1 | 11.9 | 14.1 | 12.8 |
Live litters (total) | 29 | 27 | 30 | 29 |
Implant sites (total) | 344 | 312 | 372 | 322 |
Implant sites (per dam) | 11.9 | 11.1 | 12.4 | 11.1 |
Resorptions (total) | 5 | 11 | 1 | 10 |
Resorptions (1 or more per dam) | 5 | 8 | 1 | 6 |
Resorptions (complete litter) | 0 | 0 | 0 | 0 |
% partial resorptions | 17.2 | 28.6 | 3.33 | 20.7 |
Live fetuses (total) | 339 | 300 | 371 | 312 |
Live fetuses (per dam) | 11.7 | 10.7 | 12.4 | 10.8 |
Sex ratio (M/F) | 0.99 | 1.08 | 0.91 | 0.89 |
Dead fetuses (total) | 0 | 1 | 0 | 0 |
Dams with all dead fetuses | 0 | 1 | 0 | 0 |
% all dead | 0 | 3.57 | 0 | 0 |
Average fetal weight (g) | 4.14 | 4.16 | 4.38 | 3.74 |
Net body weight gain (P males) | 269 | 274 | 261 | 229 |
Net body weight gain (P females) | 154 | 158 | 155 | 130 |
Table 2. Summary of Reproduction and Lactation Parameters (P generation)
Parameter | Water | 0.3% SBA | 1.0% SBA | 3.0% SBA |
Number of matings | 30 | 30 | 30 | 30 |
Number of pregnancies | 29 | 27 | 29 | 27 |
Number of litters: | ||||
Born alive | 29 | 27 | 29 | 26 |
Alive at 4 days | 29 | 27 | 29 | 25 |
Alive at 21 days | 28 | 24 | 29 | 23 |
Number of pups: | ||||
Born alive | 300 | 289 | 311 | 220 |
Born dead | 2 | 6 | 3 | 23 |
Number of pups: | ||||
Alive at 4 days | 300 | 283 | 309 | 203 |
Alive at 21 days | 215 | 180 | 225 | 153 |
Number of pups/litter: | ||||
Born alive | 10.3 | 10.7 | 10.7 | 8.5 |
Alive at 4 days | 10.3 | 10.5 | 10.7 | 8.1 |
Culled to at 4 days | 7.8 | 7.6 | 7.9 | 6.8 |
Alive at 21 days | 7.7 | 7.5 | 7.8 | 6.8 |
Mean pup body weight: | ||||
at 4 days | 10.3 | 10.2 | 10.0 | 8.2 |
at 21 days | 49.5 | 47.2 | 44.4 | 28.4 |
Indices: | ||||
Fertility | 96.7 | 90.0 | 96.7 | 90.0 |
Gestation | 100.0 | 100.0 | 100.0 | 96.3 |
Viability | 100.0 | 97.9 | 99.4 | 92.3 |
Lactation | 95.6 | 88.2 | 97.8 | 89.5 |
Table 3. Summary of Reproduction and Lactation Parameters (F1/F2 generation)
Parameter | Water | 0.3% | 1.0% | 2.0% |
Number of matings | 30 | 30 | 30 | 30 |
Number of pregnancies | 29 | 29 | 28 | 27 |
Number of litters: | ||||
Born alive | 29 | 29 | 28 | 27 |
Alive at 4 days | 28 | 28 | 27 | 24 |
Alive at 21 days | 27 | 28 | 25 | 23 |
Number of pups: | ||||
Born alive | 296 | 302 | 267 | 272 |
Born dead | 4 | 3 | 2 | 4 |
Number of pups: | ||||
Alive at 4 days | 282 | 293 | 236 | 241 |
Alive at 21 days | 200 | 209 | 170 | 166 |
Number of pups/litter: | ||||
Born alive | 10.2 | 10.4 | 9.54 | 10.1 |
Alive at 4 days | 10.1 | 10.5 | 8.74 | 10.0 |
Culled to at 4 days | 7.54 | 8.00 | 7.00 | 7.46 |
Alive at 21 days | 7.41 | 7.46 | 6.80 | 7.22 |
Mean pup body weight (g) | ||||
At 4 days | 10.0 | 9.74 | 9.56 | 9.48 |
At 21 days | 40.1 | 39.2 | 39.1 | 34.9 |
Indices: | ||||
Fertility | 96.7 | 96.7 | 93.3 | 90.0 |
Gestation | 100 | 100 | 100 | 100 |
Viability | 95.3 | 97.0 | 88.7 | 88.6 |
Lactation | 94.8 | 93.3 | 90.0 | 92.7 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 3 122 mg/kg bw/day
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 8 177 mg/m³
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Information on the reproductive toxicity of methyl ethyl ketone is read across from a study conducted with methyl isobutyl ketone (MIBK) which has been tested in a two-generation toxicity study in Crj: CD(SD) rats conducted according to a protocol similar to OECD TG 416 and in compliance with GLP (WIL, 200; Nemec et al, 2004). Rats were administered MIBK at target concentrations of 0, 500, 1000 and 2000 ppm by whole body inhalation. Mean measured concentrations for the F0 generation were 0, 491, 999, and 1996 ppm, equivalent to 0, 2011, 4092, and 8177 mg/m³; for the F1 generation mean measured concentrations were 0, 506, 1002 and 2006, equivalent to 0, 2073, 4105 and 8217 mg/m³. Parental (F0 and F1) findings included transient decreased body weight during the first 2 weeks of exposure at the 2000 ppm dose concentration and increases in absolute and relative liver weights at 2000 ppm. Significant increases in parental F0 and F1 mean absolute and relative kidney weights were observed for males in all MIBK-treated groups relative to the control group; however, mean kidney weights of female rats were unaffected. These increases in mean kidney weight were attributed to an alpha2µ-mediated mechanism and are not considered relevant to human risk identification. Offspring findings included a single mortality and signs of CNS depression in the F1 parental group following MIBK exposure on postnatal day (PND) 22 to 25. As a result, F1 MIBK exposure was suspended until PND 27. CNS depressive effects were observed until PND 31, but not after. F1 parental animals in the 1000 and 2000 ppm groups showed reduced reactivity to novel stimulus during exposure, which was attributed to a sedative effect. There were no effects on reproductive parameters reported. Based on these findings the NOAEL for parental systemic toxicity and neonatal toxicity was considered to be 1000 ppm. The NOAEL for reproductive toxicity was considered to be 1996 ppm, 8177 mg/m³ the highest dose tested.
Supporting 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 (sBA). Metabolic data demonstrate that sBA 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 sBA 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 foetal 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 general systemic toxicity in the study was 1644 mg/kg/day; the NOAEL for fertility effects was 3122 mg/kg/day. This study was conducted prior to the introduction of GLP and was similar to OECD test guideline 416.
Please refer to the documents attached to Section 13 for further information and justification of read across.
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 Test 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 (3003 mg/m³). 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. No embryotoxic or teratogenic effects were reported in either of these studies.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From Apr. 21, 1979 to May 24, 1979
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well documented, according to accepted guidelines
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Spartan Research Animals, Haslett, Michigan
- Age at study initiation: Reported as adult
- Weight at study initiation: 250 g
- Fasting period before study: None
- Housing: Individuall housed in stainless steel, wire-bottom cages. (group housed in exposure chambers for 7 hours/day during exposure period)
- Diet (e.g. ad libitum): Commercial laboratory chow (Ralston Purina company).
- Water (e.g. ad libitum): ad libitum when not in exposure chamber
- Acclimation period: not reported
ENVIRONMENTAL CONDITIONS
- Temperature (F): 70 ± 3 F
- Humidity (%): 45 ± 5%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: Not reported - Route of administration:
- inhalation
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: airstream
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:exposure cage
- Method of holding animals in test chamber: cage
- Source and rate of air: filtered air
- Method of conditioning air: Not reported
- System of generating particulates/aerosols: Not aplicable
- Temperature, humidity, pressure in air chamber: Not reported
- Air flow rate: Not reported
- Air change rate: Not reported
- Method of particle size determination: Not aplicable
- Treatment of exhaust air: Not reported
TEST ATMOSPHERE
- Brief description of analytical method used:
- Samples taken from breathing zone: yes
VEHICLE (if applicable)
- Justification for use and choice of vehicle:Filtered air
- Composition of vehicle:Filtered air
- Type and concentration of dispersant aid (if powder): Not applicable
- Concentration of test material in vehicle: 400, 1000, or 3000 ppm
- Lot/batch no. of vehicle (if required): Not applicable
- Purity of vehicle:not reported - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Chamber concentrations monitored 15 min/hr/chamber using Miran I Variable Filter Infrared Analyzer.
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
- If cohoused:not reported (bred by supplier)
- M/F ratio per cage: not reported (bred by supplier)
- Length of cohabitation: not reported (bred by supplier)
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not reported (bred by supplier)
- Further matings after two unsuccessful attempts: not reported (bred by supplier)
- Verification of same strain and source of both sexes: not reported (bred by supplier)
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 6 through day 15 of gestation
- Frequency of treatment:
- Daily, 7 hours/day
- Duration of test:
- 18 days
- No. of animals per sex per dose:
- 25 females/group, 35 females/control group
- Control animals:
- other: Filtered room air
- Details on study design:
- - Dose selection rationale: Based on previous teratologic studies
- Rationale for animal assignment (if not random): Random - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At day 21 of gestation
BODY WEIGHT: Yes
- Time schedule for examinations: Day 6, 8, 10, 16 and 21 of gestation
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Not a feeding study
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not a drinking water study
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Liver - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Number of early resorptions: only in non-pregnant animals.
- Number of late resorptions: Not specified - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: 1/3 per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: 1/3 per litter - Statistics:
- The frequency of alterations and resorptions among litters and the fetal population was evaluated by the Wilcoxon test. Other incidence data were analyzed by the Fisher exact probability test. Analysis of body weights, liver weights and body measurements were made by analysis of variance. Group means were compared to control values using Dunnett's test.
- Indices:
- Not reported
- Historical control data:
- Not reported
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Maternal body weights were significantly decreased on day 16 and a decrease in maternal body weight gain occured on days 10 through 15 in rats exposed to 3000 ppm of MEK. Water consumption of rats exposed to the high dose level of MEK was significantly increased on days 15 through 17 of gestation - Dose descriptor:
- NOAEC
- Effect level:
- ca. 1 002 ppm (analytical)
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Significant decrease in delayed ossification of interparietal bones and significant increase in the incidence of extra lumbar ribs at 3000 ppm. - Dose descriptor:
- NOAEC
- Effect level:
- ca. 1 002 ppm (analytical)
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 3 003 mg/m³
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
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. Foetal 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 foetal 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/m³ at 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 foetal 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 foetal 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/m³).
Information on the developmental toxicity of MIBK is included in support the read across of reproductive toxicity data from MIBK to MEK. The developmental toxicity of MIBK was evaluated in an inhalation GLP-Prenatal Developmental Toxicity Study equivalent or similar to OECD Guideline 414 (Tyl et al., 1987). Pregnant Fischer 344 rats and pregnant CD-1 mice were exposed to MIBK concentrations of 0, 300, 1000, or 3000 ppm (0, 1229, 1416 and 12277 mg/m³) MIBK for 6 hrs/day on gestation days 6 through 15. Maternal toxicity and fetotoxicity were seen at 3000 ppm (12292 mg/m³). Effects in the dams included decreased body weight gain, increased liver and kidney weights, decreased food consumption, and in mice, maternal deaths. Reduced foetal body weights and delayed ossification were noted in both species and increased resorptions were noted for mice. 1000 ppm (4106 mg/m³) was considered to be the NOAEC for toxicity in both maternal animals and offspring, and the NOAEC for teratogencity was considered to be 3000 ppm (12277 mg/m³).
Information on the developmental toxicity of sBA is included in support the read across of reproductive toxicity data from sBA to MEK. Groups of 15 to 20 sperm-positive rats were exposed to secondary butanol at concentrations of 0, 3500, 5000, or 7000 ppm, 7 hours/day, throughout gestation. No treatment-related malformations were observed at any dose. Maternal food consumption was reduced in all treatment groups. Maternal body weights were significantly reduced at the mid- and high-doses only. Foetal body weights were reduced at the mid- and high-dose level. Resorptions were increased at the highest concentration and the number of live foetuses per litter was reduced also at the highest concentration. The NOAEC for developmental toxicity in this study was 3500 ppm, and the LOAEL for maternal toxicity was 3500 ppm.
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 reproductive or developmental toxicity, as set out in Regulation (EC) No. 1272/2008.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.