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Diss Factsheets

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

Referenceopen allclose all

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
Transient reduced body weight gain and food consumption were observed in high dose males and females. Sedative effects were observed in the high dose group (lower response to auditory stimulus during exposure); these effects were not evident 1 hour after exposure. No reproductive toxicity was observed at any dose level.
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
Transient reduced body weight gain and food consumption were observed in high dose males and females. Sedative effects were observed in the high dose group (lower response to auditory stimulus during exposure); these effects were not evident 1 hour after exposure. No reproductive toxicity was observed at any dose level.
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
Mean pup body weights, sex ratios, live litter sizes, numbers of dead pups on lactation day 0 and viability indices were unaffected by exposure to the test article. Various indicators of physical development, as well as behavioural responses, of the FI pups were comparable to the control group values. No test article-related internal findings were noted in the F1 pups that died or were euthanised, or at the scheduled necropsies. Necropsy findings, organ weights and microscopic findings for the selected F1 weanling pups did not suggest any effects of exposure to the test article. There were no effects on live litter sizes, number of dead pups and viability.
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
Mean pup body weights, sex ratios, live litter sizes, numbers of dead pups on lactation day 0 and viability indices were unaffected by exposure to the test article. There were no effects on live litter sizes, number of dead pups and viability.
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

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

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
Body weight gain was depressed at 3.0% (4571 - 5089 mg/kg/day) secondary butanol, but efficient food utilisation was not affected, indicating the effect was due to depressed appetite.

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.
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
Fetotoxicity as measured by a significant reduction in pup viability at birth, a reduced birthweight, and reduced survival to day 21 was seen at 3.0% SBA in the F1a generation. No treatment-related effects were seen on corpora lutea or resorptions.

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.
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

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  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
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).

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
Reference
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
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