3-methylbutanone

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

40-57 days

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to GLPs and OECD 421 and OPPTS 870.3550 guidelines.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3550

Deviations:

yes

Principles of method if other than guideline:

Protocols were written in accordance with the above guidelines. Several minor protocol and standard operating procedure deviations occurred during the study, but they did not impact the integrity or quality of the study. There were no significant guideline deviations.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-methyl-2-butanone

IUPAC Name:

3-methyl-2-butanone

Constituent 2

Reference substance name:

3-methylbutanone

EC Number:

209-264-3

EC Name:

3-methylbutanone

Cas Number:

563-80-4

Molecular formula:

C5H10O

IUPAC Name:

3-methylbutan-2-one

Constituent 3

Reference substance name:

methylbutanone; methyl isopropyl ketone; MIPK

IUPAC Name:

methylbutanone; methyl isopropyl ketone; MIPK

Details on test material:

Test substance:
-Test substance (as cited in the report): Methyl isopropyl ketone (MIPK, 5-methylbutan-2-one)
-Physical state and appearance: Clear, colorless liquid
-Source of test substance: Eastman Chemical Company, Kingsport, TN
-Purity by GC/FID (prior to study initiation): 99.6%
-Purity by GC/FID (study termination): 99.3%
-Structure confirmed using mass spectrometry
-Stability: based on purity analysis before and after the study, the test material is considered to be stable.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Strain: Crl:CD(SD)IGS BR (Charles River Laboratories, Stone Ridge (Kingston), NY)
-Age (study start): 61 days
-Body weight (study start): Males 301.24 ± 12.39 g; Females 208.12 ± 11.59 g
-Acclimation: 5 days
-Housing: Single housed in stainless-steel wire-mesh cages during non-exposure period; housing was washed once a week, cage papers changed daily; exposure cages were washed daily
-Feed: Purina Rodent Chow #5002, meal (PMI Feed, Inc. Richmond, IN) ad libitum except during exposure; feed containers were cleaned and refilled at least 1X/wk
-Water: Rochester, NY local water system ad libitum except during exposure
-Identification: uniquely-numbered metal ear tags
-Randomization: Animals were chosen using a stratified randomization program based on body weight; body weights did not vary more than 20% from the mean for each sex.

Environmental conditions:
-Temperature (°C) 21.4-27.5
-Humidity (%): 34.9-59.7
-Photoperiod (hrs dark/ hrs light): 12 hrs light/dark

Study dates:
-Study initiation date: March 12, 2001
-Experimental start date: March 26, 2001
-Experimental completion date: September 25, 2001

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: filtered air

Details on exposure:

Selection of exposure concentrations:
Exposure concentrations were selected by the Sponsor based on data from a 4-week inhalation toxicity study.

Exposure:
Inhalation exposures were conducted in 590 L stainless-steel and glass inhalation chambers at target concentrations of 5.0, 2.5, 1.0 and 0.0 mg/L. Animals were singly housed during the 6-hour exposure and, at least once a week, the animals were rotated to a new cage position within the chamber. The exposure chambers were maintained under negative pressure relative to room air. Airflow, temperature and humidity were recorded approximately every 30 minutes. Chamber vapor concentrations were recorded at least once each hour.

Exposure atmosphere generation:
The test atmosphere was generated by metering the test substance into glass distillation columns packed with glass beads and passing filtered compressed air through the column to evaporate the test substance. The test substance delivery rate and air flow rate were adjusted to produce the desired chamber target vapor concentrations. The resultant vapor was directed to a tee upstream of the inhalation chamber where it was mixed with filtered, conditioned outside air to produce airflow resulting in 12-16 air changes per hour.

Particle size analysis:
A particle counter (Micro Laser Particle Counter, model µLPC-301, Particle Measuring Systems, Inc., Boulder, CO) was used to measure the number and size of particulates in the chamber. The results indicate that an aerosol of the test substance was not present.

Chamber vapor homogeneity:
Prior to study initiation, the test substance concentration in the air from the breathing zones of 8 different cage positions was compared to the concentration at a fixed reference position within the inhalation chamber. Based on the data, the test atmosphere was considered homogeneous.

Air flow measurement:
Total chamber air flow was a combination of compressed air and dilution air. The compressed air was used to vaporize the test substance and carry it from the generation system to the inhalation chamber. The compressed air flow was continuously monitored using a flowmeter. The dilution air flow was adjusted throughout exposure using an Omega Air Velocity Transducer (FMA-602-V-S) and Ratemeter (DPF66-RS232).

Oxygen level:
During pre-study tests, the oxygen content of the chamber exposure atmosphere was measured from a reference position using a MAS MiniOX Monitor (MAS Instruments Division, Pittsburgh, PA), and the oxygen content was ≥ 20%.

Chamber temperature and humidity:
Chamber temperature and humidity were measured using wet/dry bulb hygrometers and were recorded approximately every 30 minutes during exposure.

Details on mating procedure:

Male and female rats were paired 1:1 within the same dose group for 1-14 days. Copulation was verified through identification of sperm in vaginal smears or by appearance of a copulatory plug. The morning of the day copulation was verified was considered Gestation Day 0. Following copulation, animals were separated and housed individually until study termination.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Purity, structure, and stability determination:
-Purity was measured using GC/FID at study initiation (99.6%) and study termination (99.3%).
-Based on the purity determinations, the test substance was considered stable over the test period.
-Structure of the test substance was determined by mass spectrometry and the results were consistent with MIPK.

Weekly GC/FID vapor concentration determination:
Once a week, samples of the chamber test atmosphere were collected in Tedlar bags and analyzed by GC/FID.

Daily GC/TCD vapor concentration determination:
Daily chamber vapor concentrations were monitored with a multipositional air sampling and analysis system and analyzed by GC/TCD. The system consisted of a Micro Gas Chromatograph CP 9002 and Chrompack CP-Maître I/II Chromatography Data System (Chrompack International B.V., Middelburg, Netherlands). Chamber vapor samples were sampled from each chamber at least once an hour.

Daily MIRAN vapor concentration determination:
On study days 3-50, chamber vapor concentrations were monitored with a single MIRAN IA infrared gas analyzer (Wilks Foxboro Analytical, South Norwalk, CT) and a computer-operated four-port sampling valve. Chamber vapor samples were analyzed from each chamber at least once an hour.

Nominal concentration determination:
Nominal concentration was calculated by dividing the amount of test substance consumed from the chamber reservoir by the total chamber air flow.

Duration of treatment / exposure:

6 hours/day

Frequency of treatment:

7 days/week

Details on study schedule:

The study consisted of four phases: pre-mating (14 days), mating (1-14 days), gestation (21-23 days), and early lactation (4-6 days). The females were exposed 6 hours/day, through Gestation Day 19 (35-41 consecutive exposures). Females that delivered a litter and their offspring were euthanized on Lactation Day 4, 5, or 6. Females that showed evidence of copulation but did not deliver a litter were euthanized on Day 23 of gestation. Males were exposed 6 hr/day throughout the entire study (until all dams had littered or were euthanized due to non-delivery) for a total of 51 consecutive daily exposures. All males were euthanized on the day following the last exposure.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1.0 mg/L
Basis:
other: target concentration

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2.5 mg/L
Basis:
other: target concentration

Doses / concentrations 3

Remarks:

Doses / Concentrations:
5.0 mg/L
Basis:
other: target concentration

No. of animals per sex per dose:

12 animals/sex/group

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

Clinical examinations (hands-on):
Clinical observations included, but were not limited to, inspection of the hair, skin, eyes, mucous membranes, motor activity, feces, urine, respiratory system, circulatory system, autonomic nervous system, central nervous system, and behavior patterns. During inhalation exposure, rats visible through the chamber windows were observed for clinical signs. Tapping sounds were made on the outside of the chamber to assess the animals’ activity levels. Clinical examinations were conducted after each exposure and in the morning prior to necropsy. The animals were observed for signs of moribundity and mortality including examination of urine and feces prior to exposure. Beginning on Gestation Day 20 (during the non-exposure period), all female rats had a clinical examination each morning and a moribundity and mortality check each afternoon.

Body weight:
Body weights for male rats were measured prior to exposure on Days 0, 7, and weekly thereafter. Terminal body weights for males were measured after exsanguination, but prior to necropsy. For female rats, body weights were measured prior to exposure on Days 0, 7, 14, 21, 28 (premating and mating), Gestation Days 0, 7, 14, and 20, and Lactation Days 0 and 4.

Feed consumption:
Feed consumption was measured for males between Days 0-7, 7-14, 28-35, 35-42, and 42-49. Male rats were fasted overnight prior to necropsy. Feed consumption was measured for females between Days 0-7 and 7-14 (premating), Gestation Days 0-7, 7-14, and 14-20, and Lactation Days 0-4.

Oestrous cyclicity (parental animals):

Not determined in the study

Sperm parameters (parental animals):

Motility Evaluation:
Motility was determined for sperm in the right epididymis; the epididymis was placed in a petri dish containing 1% bovine serum albumin (BSA) in phosphate buffered saline (PBS) warmed to ~38 °C. The epididymis was pierced three times with a scalpel, and the sperm were allowed to swim out (3 minutes). A sample of the mixture was loaded onto a pre-warmed stage of a Hamilton Thorne IVOS automated sperm analyzer. Five fields were automatically selected, each motion image was recorded and stored, and the percent motility was determined for each animal.

Testicular Spermatid Head Counts:
Homogenization-resistant spermatid head counts were performed on the frozen left testes. The tissue was thawed, the tunica removed, tissue was weighed, homogenized, and vortexed; then a 100 µL sample was transferred to a reaction vial containing a dye that uniquely stained the head of the sperm. A sample of the stained sperm was placed into a 20 µm deep glass slide and was loaded onto the Hamilton Thorne IVOS automated sperm analyzer. Twenty fields were automatically selected and total sperm counts were determined. Head counts were reported on an absolute and relative (to testis weight) basis.

Epididymal Spermatozoan Counts:
Homogenization-resistant spermatozoan counts were performed on the frozen left epididymides. The tissue was processed in a similar manner as the testicular tissue except the left epididymis was used. Head counts were reported on an absolute and relative (to epididymal weight) basis.

Litter observations:

Clinical Observations:
All pups were observed for clinical abnormalities.

Body weight:
For live pups, body weights were measured as a group, by sex, on Postnatal Days 0 and 4.

Postmortem examinations (parental animals):

Euthanasia:
Male rats were fasted overnight beginning after the last inhalation exposure; the next day, they were anesthetized with carbon dioxide and euthanatized by exsanguination. The male rats were necropsied in a random order based on a computer-generated list. The adult females were euthanatized with carbon dioxide. Females showing evidence of copulation, but which did not deliver a litter, were euthanatized on Gestation Day 23. All other females were euthanatized on Day 4, 5, or 6 post-partum.

Necropsy:
All adult animals were subjected to a necropsy and gross examination. Special attention was paid to the organs of the reproductive system. The uteri from all adult females were examined, and implantation sites were counted. Corpora lutea were counted at the time of necropsy.

The following tissues were collected and fixed in 10% buffered formalin: ovaries, uterus, Fallopian tubes, seminal vesicles, coagulating gland, prostate gland, and gross lesions. The right testis and right epididymis (after motility analysis) were fixed in Bouin’s fixative. After approximately 2 hours, the polar ends of the testis were trimmed to facilitate fixation and 24 hours later they were rinsed in 50% ethyl alcohol and stored in 70% ethyl alcohol. For long-term storage the right testis and epididymis were stored in 10% buffered formalin. The left testis and epididymis were placed into individual containers, frozen with dry ice, and stored at -70 °C.

Organ weights:
The testes and epididymides were weighed separately.

Histopathology:
The ovaries, right testis, and right epididymis (including sections of the caput, corpus, and cauda) were embedded in paraffin and sectioned at approximately 4 µm for the control and 5.0 mg/L groups. Gross lesions were examined from all animals. The resulting tissue sections were stained with hematoxylin and eosin; duplicate sections of the testicular tissue were stained using the periodic acid-Schiff procedure.

Postmortem examinations (offspring):

Euthanasia: The pups were euthanatized with carbon dioxide.

Statistics:

Mean values were calculated for time-weighted average atmospheric concentration, chamber temperature, chamber relative humidity, chamber airflow, chamber nominal concentration, adult body weight and body weight change, male pup and female pup body weight and body weight change, feed consumption, feed utilization, organ weights, organ-to-body weight ratios, gestation duration, fertility index, fecundity index, precoital interval, implantation counts, post-implantation loss, litter size, and pup percent survival. Homogeneity of adult body weight, body weight change, male and female pup body weight, pup body weight change, feed consumption, feed utilization, organ weight, organ-to-body weight ratio, precoital interval, gestation period, numbers of implants and corpora lutea, pre- and post-implantaion loss, numbers of live, dead, male, and female pups, percent of male pups, and pup percent survival data were evaluated using Bartlett’s test (p ≤ 0.01), one-way analysis of variance (ANOVA) (p ≤ 0.05) and Dunnett’s t-test (p ≤ 0.05) to indicate statistical significance (MINITAB Statistical Software, State College, PA). When the variances of the means were not considered equal by the Bartlett’s test (p ≤ 0.01), the data were evaluated using a Kruskal-Wallis H-test (p ≤ 0.05) followed by a Mann-Whitney U-test (p ≤ 0.05) (MINITAB Statistical Software).

Reproductive performance of dams and fertility and fecundity indices were evaluated in contingency tables using a Chi-square test (p ≤ 0.05). Total number of pups per litter (live and dead) and total number of live pups per litter were evaluated using a linear regression model (p ≤ 0.05). Precoital interval, gestation period, numbers of implants and corpora lutea, and numbers of live, dead, male, and female pups were evaluated using Kruskal-Wallis H-test (p ≤ 0.05) followed by Mann-Whitney U-test (p ≤ 0.05) and total live and dead pups per group were evaluated in contingency tables using a Chi-square test (p ≤ 0.05).

Reproductive indices:

Fertility index = (Number of pregnant females)(100) ÷ (Number of cohabited pairs)

Fecundity index = (Number of pregnant females)(100) ÷ (Number of mated pairs with copulatory plug or sperm)

Precoital interval = Date of insemination-Date of first cohabitation

Gestation duration = Date delivery begins-Date of insemination

Post-implantation loss = (Number of implantation sites-Number of pups in the litter)(100) ÷ (Number of implantation sites)

Pre-implantation loss = (Number of corpora lutea-Number of implantation sites)(100) ÷ (Number of corpora lutea)

Offspring viability indices:

No data were provided in the study report.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

Mortality:
No mortality occurred during the study.

Clinical observations:
During inhalation exposure, a concentration-dependent reduction in activity level (defined as less movement, decreased alertness, and slower response to tapping on the chamber wall compared to controls) was observed for all MIPK-exposure groups. In addition, saliva soaked perioral hair and partially closed eyes were observed occasionally in the 2.5 and frequently in the 5.0 mg/L groups. Immediately following exposure, unkempt hair and saliva soaked perioral hair was observed in some rats in all MIPK-exposure groups at varying times throughout the study. Porphyrin discharges from the eyes and/or noses were observed in controls and in all exposure groups except the 1.0 mg/L group.

Body weight:
For male rats, mean body weight was significantly lower on Day 7 (5.0 mg/L group), Day 14 (2.5 and 5.0 mg/L groups), and Day 21 (2.5 mg/L group) when compared to controls. Mean body weight gain was significantly lower on Days 7 (2.5 and 5.0 mg/L groups), 14 (1.0, 2.5, and 5.0 mg/L groups), and 35 (1.0 mg/L group) when compared to controls. For female rats, mean body weight was significantly lower on Day 14 (5.0 mg/L group) (pre-mating) and Gestation Day 20 (5.0 mg/L group) when compared to controls. Mean body weight gain was significantly lower on Days 7 (5.0 mg/L group) and 14 (2.5 and 5.0 mg/L groups) (pre-mating) when compared to controls.

Food Consumption:
For male rats, mean food consumption was significantly lower on Day 7 (2.5 and 5.0 mg/L groups), and mean feed utilization was significantly lower on Days 7 and 14 (2.5 and 5.0 mg/L groups) and Days 14 and 35 (1.0 mg/L group) when compared to controls. For female rats, mean food consumption was significantly lower on Days 7 (2.5 and 5.0 mg/L groups) and 14 (5.0 mg/L group) (pre-mating), and Gestation Day 7 (5.0 mg/L group), but significantly higher on Gestation Day 14 (1.0 mg/L group) when compared to controls. Mean food utilization was significantly lower on Days 7 (5.0 mg/L group) and 14 (2.5 and 5.0 mg/L groups) (pre-mating) when compared to controls.

Organ weights:
MIPK male rat mean organ weights were comparable to controls.

Gross pathology and Histology:
No test substance-related changes were observed.

Sperm morphology and development:
No test substance-related effects on sperm motility, epididymal spermatozoa count, or testicular sperm count were observed.

Effect levels (P0)

1

Dose descriptor:

other: NOEC for Systemic Toxicity

Effect level:

< 1 other: mg/L air (target)

Sex:

male/female

Basis for effect level:

other: The overall NOEC for systemic toxicity in the parental generation is considered to be <1.0 mg/L based on reduced activity in all animals of both sexes at the lowest concentration used in the study.

2

Dose descriptor:

other: NOEC for Developmental Toxicity

Effect level:

1 other: mg/L air (target)

Sex:

male/female

Basis for effect level:

other: For dams exposed to 2.5 mg/L MIPK from pre-mating through Gestation Day 19, there was an increase in the number of dead pups on Postnatal Day 0.

3

Dose descriptor:

other: NOEC for Reproductive toxicity

Effect level:

5 other: mg/L air (target)

Sex:

male/female

Basis for effect level:

other: No evidence of reproductive toxicity was observed in this study.

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Details on results (F1)

Litter data:
The mean number of live pups per litter was significantly lower for the 5.0 mg/L group on Day 0, the number of dead pups per litter was significantly higher for the 2.5 mg/L group on Day 0, and the number of pups per litter that died between Day 0 and 4 was higher for the 5.0 mg/L group when compared to controls. The mean litter weights were significantly lower on Days 0 and 4 for the 5.0 mg/L group when compared to controls. However, upon examination of the individual data, this effect was primarily due to a single 5.0 mg/L litter with only four pups; when this litter was removed from statistical analysis, the mean litter weights were comparable among the groups on both days.

All other examined parameters, in test-substance-exposed groups (reproductive performance; fertility and fecundity indexes; precoital interval; gestation duration; pre and post-implantation loss; pup survival; numbers of implants; numbers of corpora lutea; ratio of male to female pups; pup body weight and pup body weight change), were comparable to controls.

Neonatal observations:
One pup from the 5.0 mg/L group had fluid-filled loose skin, hypothermia, and swollen hind limbs. Other clinical abnormalities such as hematomas, bruises, and lack of milk in stomachs occurred with similar frequencies between pups from MIPK-treated dams and controls.

Body weights:
No test-substance related changes were observed in pup body weights.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Exposure Conditions:

-Weekly mean analytical (GC/FID) concentrations of test material in air test atmospheres were 5.17 ± 0.156, 2.51 ± 0.144, and 1.05 ± 0.046 mg/L compared with target concentrations of 5.0, 2.5, 1.0 mg/L, respectively.

-Mean daily (GC/TCD) concentrations for each exposure level were 5.11 ± 0.16, 2.59 ± 0.13, and 1.03 ± 0.07 mg/L compared with target concentrations of 5.0, 2.5, 1.0 mg/L, respectively. 

-Mean daily (MIRAN) concentrations for each exposure were 4.91 ± 0.11, 2.48 ± 0.10, and 1.01 ± 0.06 mg/L compared with target concentrations of 5.0, 2.5, 1.0 mg/L, respectively. The mean analytical GC/FID concentration and the mean daily time-weighted average (MIRAN) and GC/TCD concentrations were within 10% of the target concentrations.

-Nominal concentrations were 5.21 ± 0.23, 2.65 ± 0.13, and 1.03 ± 0.06 mg/L compared with target concentrations of 5.0, 2.5, 1.0 mg/L, respectively.

-No test substance was detected in the control chamber.

-Mean chamber temperatures for the 5.0, 2.5, 1.0, and 0.0 mg/L groups were, respectively, 22.4 ± 0.8, 22.5 ± 0.9, 22.7 ± 1.0, and 22.5 ± 0.9 °C.

-Mean chamber relative humidity concentrations for the 5.0, 2.5, 1.0, and 0.0 mg/L groups were, respectively, 58.0 ± 5.8, 59.0 ± 4.4, 59.5 ± 3.4, and 58.5 ± 3.7%.

Applicant's summary and conclusion

Conclusions:

There were no adverse effects on mating performance, fertility, reproductive organs, or any other reproductive indices in a reproduction and developmental toxicity screening study in which male and female Sprague-Dawley rats were exposed via whole body inhalation to up to 5.0 mg/L methyl isopropyl ketone 6 hr/day, 7 days/wk from the start of pre-mating through Day 19 of gestation (35-41 consecutive exposures for females; 51 consecutive exposures for males). Developmental toxicity was evidenced by reduced numbers of live pups and increases in postnatal pup death for litters from the 2.5 and 5.0 mg/L exposure groups. Toxicity, including CNS effects, decreased body weight and body weight gain, and decreased food consumption and feed utilization was observed in adult males and females at these exposure levels. Signs of reduced activity were also observed in the 1.0 mg/L parental-exposure group. Based on the severity of effects observed in the 5.0 mg/L exposure group, this exposure concentration was considered to be at the maximum tolerated dose. The no-observed-effect level (NOEC) for systemic toxicity in the parental generation was less than 1.0 mg/L based on dose-dependent CNS effects observed at all exposure levels. The NOEC for developmental toxicity was considered to be 1.0 mg/L while the NOEC for reproductive toxicity was 5.0 mg/L.

In a well-conducted reproductive and developmental toxicity screening study in rats, there was no clear evidence of an adverse effect on sexual function, fertility, reproductive organs, or any other reproductive parameter even in the presence of maternal/paternal toxicity. Fetotoxicity in the 5.0 mg/L exposure group was evidenced by a reduction in mean number of live pups per litter on Postnatal Day 0 and an increase in the number of pups per litter that died between Postnatal Days 0 and 4; in the 2.5 mg/L exposure group, there was a significant increase in the number of dead pups per litter on Postnatal Day 0. At these dose levels, systemic toxicity, including reversible CNS effects, reduced feed consumption and food utilization, and decreased body weights and body weight gains, was observed in both sexes of the parental generation. Based on this information, methyl isopropyl ketone is not a reproductive toxicant and is not selectively toxic to the developing fetus. Methyl isopropyl ketone is not classified for “Developmental or Reproductive Toxicity” according to GHS guidelines.

Executive summary:

In a reproductive and developmental toxicity screening study, methyl isopropyl ketone (MIPK) was administered to 12 Sprague-Dawley (Crl:CD(SD)IGS BR) rats/sex/dose via whole-body inhalation at exposure concentrations of 0, 1.0, 2.5 or 5.0 mg/L for 6 hr/day, 7 days/wk. Females were exposed to the test substance until Gestation Day 19 (35-41 total exposures) and males were exposed for 51 days. There were no adverse effects on any reproductive parameters including fertility index, gestation duration, precoital interval, and fecundity index. 

 

For dams exposed to 5.0 mg/L MIPK from the start of pre-mating through Gestation Day 19, there was a significant reduction in number of live pups per litter on Postnatal Day 0, an increase in number of pups per litter dying between Postnatal Days 0 and 4, and clinical abnormalities noted in a single pup. Signs of developmental toxicity noted in offspring from the 2.5 mg/L group consisted of an increased number of dead pups on Postnatal Day 0. At these exposure levels, systemic toxicity including reversible CNS effects, decreased body weight and body weight gain, and decreased food consumption and feed utilization was observed in both sexes in the parental generation. Mild CNS effects were also observed at 1.0 mg/L, the lowest exposure concentration used in this study.

 

Based on these findings, the NOEC for overall toxicity was < 1.0 mg/L. The NOEC for reproductive toxicity was 5.0 mg/L and the NOEC for developmental toxicity was 1.0 mg/L.