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EC number: 203-550-1 | CAS number: 108-10-1
- 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
- Nanomaterial porosity
- 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
Effects on fertility
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2000
- 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 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- 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 (e.g. ad libitum): Standard rodent chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 23 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 30 to 70%
- Air changes per hour: 12 to 15
- 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 reported
- Temperature, humidity, pressure in air chamber: 22 ± 2°C and 30 to 70%, respectively
- Air flow rate: 12 to 15 air changes/hour
- Air change rate: 12 to 15 /hour
- Method of particle size determination: not reported
- Treatment of exhaust air:not reported
TEST ATMOSPHERE
- Brief description of analytical method used: measured 9 to 10 times during each daily exposure by a validated gas chromatographic method
- 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: copulatory plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Yes. Air in exposure chambers was sampled approximately every 35 minutes during exposure, and MIBK concentration verified using gas chromatography.
- Duration of treatment / exposure:
- F0 and F1 males: =70 days prior to mating until 1 day prior to euthanasia
F0 and F1 females: =70 days prior to mating until gestational day 20; PND 5 until 1 day prior to euthanasia
Exposure for F1 animals began on PND 22.
F2 animals were potentially exposed in utero and during PND 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 - Remarks:
- Doses / Concentrations:
500, 1000, or 2000 ppm
Basis:
other: target concentrations - Remarks:
- Doses / Concentrations:
491, 999, and 1996 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
2012, 4093 or 8178 mg/m3
Basis:
analytical conc.
F0 generation - Remarks:
- Doses / Concentrations:
2073, 4105 or 8219 mg/m3
Basis:
analytical conc.
F1 generation - No. of animals per sex per dose:
- 30
- Control animals:
- yes, sham-exposed
- Details on study design:
- - Dose selection rationale: on the basis of results of previous studies using MIBK
- Positive control:
- No
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly - Oestrous cyclicity (parental animals):
- To determine the estrous stage of each female F0 and F1, vaginal smears were prepared daily beginning 21 days before pairing and continuing until evidence of mating was present or the end of the mating period. The estrous 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 (esophagus, 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. Morphology of developmental and reproductive systems 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
- 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:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- parental systemic toxicity
- Effect level:
- 1 000 ppm (analytical)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- other: Transient reduced body weight gain and food consumption (systemic toxicity apart from alpha 2µ globulin-mediated nephropathy), increases in liver and kidney weights
- Remarks on result:
- other: Generation not specified (migrated information)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- neonatal toxicity
- Effect level:
- 1 000 ppm (analytical)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- other: Based on observed acute changes on PND 22 and 28 (single mortality and anesthetic CNS effects observed during exposure only).
- Remarks on result:
- other: Generation not specified (migrated information)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- 2 000 ppm (analytical)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- other: No effects observed at highest dose tested
- Remarks on result:
- other: Generation not specified (migrated information)
- Clinical signs:
- no effects observed
- 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
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 000 ppm (analytical)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: No significant effects.
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 ppm (analytical)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: No significant effects.
- Reproductive effects observed:
- not specified
- Conclusions:
- Although reproductive/developmental parameters were not affected by inhalation of MIBK at concentrations up to 2000 ppm, over 2 generations in rats, adverse liver and kidney effects in adult rats were apparent. THE NOAEL for parental systemic toxicity and neonatal toxicity was considered to be 1000 ppm. The NOAEL for reproductive toxicity was considered to be 2000 ppm.
- Executive summary:
The reproductive toxicity of methyl isobutyl ketone (MIBK) was evaluated in a GLP-compliant multi-generation toxicity study in Crj: CD(SD) rats. The study design was equivalent to OECD test guideline 416. Rats were administered MIBK at target concentrations of 0, 500, 1000 and 2000 ppm (mean measured concentrations were 0, 491, 999, and 1996 ppm or 0, 2012, 4093, and 8178 mg/m3) by whole body inhalation. Parental (F0) 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 (see Section 7.9.3). Offspring findings included a single mortality and signs of CNS depression in the F1 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 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 2000 ppm, the highest dose tested.
Reference
No significant effects
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Statistically significant differences between the 0 and 2000 ppm exposure groups were observed for body weight gains for weeks 0 to 1 and 1 to 2 (considered to be exposure-related).
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No significant effects
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No significant effects
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No significant effects
ORGAN WEIGHTS (PARENTAL ANIMALS)
Significant increases in mean liver weights (absolute and relative) were observed in the 2000 ppm group males and females. Significant increases in mean absolute and relative kidney weights were observed for males in all exposure groups relative to the control group; however, mean kiney weights of female rats were unaffected.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No significant effects
HISTOPATHOLOGY (PARENTAL ANIMALS)
No significant effects
No significant effects.
CLINICAL SIGNS (OFFSPRING)
No significant effects
BODY WEIGHT (OFFSPRING)
No significant effects
ORGAN WEIGHTS (OFFSPRING)
No significant effects
GROSS PATHOLOGY (OFFSPRING)
No significant effects
HISTOPATHOLOGY (OFFSPRING)
No significant effects
OTHER FINDINGS (OFFSPRING)
A single mortality and signs of CNS depression were observed in 18 animals in the 2000 ppm F1 group (7 males and 11 females) following exposure on PND 22 to 25. Due to this observation, exposure in all groups of F1 weanlings was suspended until PND 27. CNS depressive effects were observed in 6 males in the 2000 pm group again on PND 23 to 31, but not again thereafter. Animals in the 1000 and 2000 ppm groups showed reduced reactivity to novel stimulus during exposure.
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 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 4 093 mg/m³
- Species:
- rat
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The reproductive toxicity of methyl isobutyl ketone (MIBK) was evaluated in a GLP-compliant multi-generation toxicity study in Crj: CD(SD) rats (Nemec, 2000; Nemec et al., 2004). The study design was equivalent to OECD test guideline 416. Rats were administered MIBK at target concentrations of 0, 500, 1000 and 2000 ppm (mean measured concentrations were 0, 491, 999, and 1996 ppm or 0, 2012, 4093, and 8178 mg/m3) by whole body inhalation. Parental (F0) 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 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 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 (4093 mg/m3). The NOAEL for reproductive toxicity was considered to be 2000 ppm (8178 mg/m3), the highest dose tested.
Short description of key information:
A GLP inhalation multi-generation study in rats, equivalent to OECD Guideline 416, reported a parental and neonatal toxicity of 1000 ppm (4093 mg/m3 at 20 °C), and a reproductive toxicity of 2000 ppm (8330 mg/m3 at 20 °C; the highest dose tested). Reproductive tests in other species, or by the dermal or oral dose route, were not conducted.
Justification for selection of Effect on fertility via inhalation route:
Key study
Effects on developmental toxicity
Description of key information
In inhalation developmental toxicity studies in rats and mice, maternal toxicity and fetotoxicity were seen at 3000ppm (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 fetal body weights and delayed ossification were noted in both species and increased resorptions were noted for mice. 1000ppm (4106 mg/m3) was considered to be the NOEL for both maternal animals and offspring.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 4 106 mg/m³
- Species:
- other: rat and mouse
Additional information
Developmental and maternal toxicity were evaluated in groups of 35 pregnant Fischer 344 rats and 30 pregnant CD-1 mice exposed by inhalation to 0, 300, 1000, or 3000 ppm (0, 1229, 4106, 12,292 mg/m3) MIBK for 6 hrs/day on gestation days 6 through 15 (Tyl, 1984; Tyl et al., 1987). Animals were sacrificed on gestation day 21 (rats) or 18 (mice). Dams were evaluated for exposure-related changes in clinical signs, body weight, food consumption, organ weights (kidney, liver, and gravid uterus), and reproductive parameters; fetuses were evaluated for exposure-related changes in body weight and viability, and for external, skeletal, and thoracic and peritoneal visceral alterations. Maternal mean body weight, weight gain, and food consumption were significantly decreased in rats exposed to 12,292 mg/m3(but not to 4106 mg/m3 or lower) during the exposure period, but they had recovered to control levels by the day of sacrifice; maternal body weight was not affected in mice. Maternal clinical signs observed in rats or mice included coordination loss, hindlimb weakness, paresis, irregular gait, hypoactivity, ataxia, unkempt fur, negative tail or toe pinch, piloerection, lacrimation, or red perioral encrustation. These clinical signs were observed only during the exposure period and only at 12,292 mg/m3. Three maternal deaths (12% of the animals in the group) occurred in mice exposed to 12,292 mg/m3after the first exposure on gestation day 6; no further deaths occurred in that group, and no exposure-related deaths occurred in the other mouse or rat exposure groups. Neonates from those dams were not considered in the final evaluation. Statistical analyses by the authors were per dam or per litter. No exposure-related effects were observed in rats or mice with respect to numbers of corpora lutea, total implants, percent implantation loss, live fetuses per litter, nonviable implants per litter, percent live fetuses, and sex ratio. In mice, there was an increased mean number of dead fetuses per litter at 12,292 mg/m3(0.6 per litter compared to 0.1 in controls). Fetal body weights (litter weight, male weight per litter, and female weight per litter) were significantly reduced in rats exposed to 1229 (the mean by 3%) and 12,292 mg/m3(the mean by 6%) but not to 4106 mg/m3; and in mice, fetal body weights were statistically significantly reduced at 12,292 mg/m3(the mean by 13%) but not at 4106 mg/m3or below. The authors indicated that the reduction in rat fetal body weight was confounded by a skewed distribution of litter size, whereby higher doses had very small litters and smaller litters had varied mean weights across dose, while lower-dosed dams appeared to have larger litters and larger litters showed a dose-dependence in mean weight. There was no statistically significant increase in the number of rat or mouse fetuses per litter. The authors decided the reductions in rat fetal body weight was not treatment-related. No exposure-related change in the incidence of malformations of any type were observed in rat and mouse fetuses. The number of litters with observations indicating retarded skeletal ossification was significantly increased to various degrees in both rats and mice at 12,292 mg/m3relative to controls for a variety of skeletal endpoints, with scattered increases in litters with retarded ossification at lower exposure levels that were not considered to be exposure-exposure-related.
Justification for selection of Effect on developmental toxicity: via inhalation route:
Reliable inhalation developmental toxicity studies are available in rats and mice.
Justification for classification or non-classification
The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.
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.
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