Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
In addition to standard parameters, several newer paramaters (e.g. sperm analysis, developmental landmarks, estrous cycling, weanling organ weights) were also evaluated.
GLP compliance:
yes
Remarks:
US
Limit test:
no

Test material

Constituent 1
Reference substance name:
1-methoxypropan-2-ol
EC Number:
203-539-1
EC Name:
1-methoxypropan-2-ol
Cas Number:
107-98-2
IUPAC Name:
1-methoxypropan-2-ol
Details on test material:
1-methoxypropan-2-ol is a close structural analogue of the submission substance, 1-ethoxypropan-2-ol.

- Name of test material (as cited in study report): Propylene glycol monomethyl ether (PGME)
- Impurities (identity and concentrations): none present at greater than 0.1%
- Isomers composition: 97.99-98.07% 1-methoxy-2-propanol; 1.86-1.90% 2-methoxy-1-propanol
- Stability under test conditions: The test material was characterized by gas chromatography with flame ionization detection and infared spectroscopy prior to the start of the study and periodically during the course of the study.
- Other: Supplied by Dow Chemical Company

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rats (except pups) were identified with uniquely coded ear tags.

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, NY
- Age at study initiation: Approximately 4 wks upon receipt
- Housing: Individually in wire mesh, stainless-steel cages during and after inhalation exposure. Females were housed in plastic nesting boxes with ground corn cob bedding during late gestation and lactation.
- Diet: Purina certified rodent chow No.5002 (Purina Mills Inc., Stl Louis, MO) ad libitum except during the 6-h/day exposures when feed was withheld
- Water: ad libitum
- Acclimation period: Approximately 2 wks

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 22 degrees C
- Humidity: Approximately 40-60%
- Air changes: 12-15 changes/hr
- Photoperiod: 12hr light/12hr dark cycle

Administration / exposure

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: Liquid PGME was metered into the glass J-tube assembly using a fluid-metering pump. Compressed air(up to 100 lpm) was passed through the J-tube simultaneously to volatilize the test material. The air was heated with a heat gun(FT-4, Master Appliance Corporation, Racine, WI) to the minimum extent necessary to facilitate complete vaporization of the test material. The PGME vapors were diluted and mixed with room air to achieve a total flow rate of approximately 2900 Lpm and the desired concentration. Exposures were conducted in 14.5 m3 chambers.
- Temperature, humidity, pressure in air chamber: 22 +/- 2 degress C; 40-60% relative humidity; chambers were operated at slightly negative pressure relative to the surrounding area. Chamber temperature and relative humidity were recorded hourly during exposures.
- Air flow rate: 2900 litres per min. Airflow through each chamber was recorded hourly during exposures.

TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of PGME in the breathing zone of the animals in each chamber was measured at least once per hour using a MIRAN 1A infrared spectrophotometer at a wavelength of 10.2 microns. In addition, the amount of PGME used each day was recorded and the nominal concentration of PGME calculated.
- Samples taken from breathing zone: yes
Details on mating procedure:
Breeding of P1 and P2 adults commenced after approximately 10 weeks of treatment. Each female was placed with a single male from the same exposure group until pregnancy occurred or 2 weeks had elapsed. During each breeding period, daily vaginal lavage samples were evaluated for the presence of sperm, as an indication of mating. The day on which sperm was detected or a vaginal plug was observed in situ was considered day 0 of gestation. If mating did not occur during the 2 weeks, the animals were separated without further opportunity for mating. For the P2 mating, cohabitation of littermates was avoided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No further data
Duration of treatment / exposure:
See details on study schedule below
Frequency of treatment:
Continuous during treatment
Details on study schedule:
Animals were exposed 6 hours/day, 5 days/ week for 10 weeks prior to mating, and 6 hours/day, 7 days/week during mating, gestation and lactation. Maternal rats were not exposed from gestation day 20 until lactation day 4 in order to allow for parturition and initiation of lactation. During the lactation period, pups were not placed in the exposure chambers, but remained in the nesting boxes on lactation days 5 through 21.
Doses / concentrationsopen allclose all
Dose / conc.:
300 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
3 000 ppm
No. of animals per sex per dose:
30
Control animals:
yes, sham-exposed
Details on study design:
In order to confirm findings noted in the F1a litters, the P1 animals were mated a second time (1 week after weaning the last F1a litter) to produce the F1b litters. Initially, 30 males and 30 females from each treatment group were randomly selected from the F1a litters and assigned to treatment groups to become the second generation (P2) parents. However, 1-3 days after exposure of the F1a weanlings commenced on postnatal day 22, it became apparent that the weanlings were too small to tolerate an absence of feed during the 6-hours of inhalation exposure. Therefore, exposures were temporarily discontinued until postnatal day 28 and then continued until evalution of vaginal openings and preputial separation, after which these animals were sacrificed. Due to this modification, parents for the second generation were randomly chosen from the F1b litters. These litters were weaned on postnatal day 21, but exposure was not initiated until postnatal day 28.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All adult rats were observed daily for changes in behaviour, demeanor, or overt indications of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: P1 and P2 rats were weighed weekly during pre-breeding treatment period. Following the pre-breeding period, male body weights continued to be recorded weekly. Females exhibiting evidence of mating were weighted on days 0, 7, 14, and 21 of gestations and those with litters were weighed on days 1, 4, 7, 14, 21 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Not measured in this study.
Oestrous cyclicity (parental animals):
Estrous cycle length and normality were evaluated daily by vaginal lavage for all P1 and P2 females starting 3 weeks prior to the F1a and F2 matings only, and continued throughout cohabitation.
Sperm parameters (parental animals):
Sperm count and motility were determined at necropsy after completion of the mating period for the adult P1 and P2 males.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes, litters with fewer than 8 pups were not culled.
- 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 recorded for each litter: total litter size on the day parturition was initiated (day 0 ), the number of live and dead pups on day 0, 1, 4, 7, 14, and 21 postpartum, and the sex and weight of each pup on days 1, 4, 7, 14, and 21 of lactation. Any visible physical abnormalities or demeanor changes in the neomates were recorded during the lactation period.

GROSS EXAMINATION OF DEAD PUPS:
Yes, to the extent possible for defects and/or cause of death. Pups were preserved in neutral, phosphate-buffered 10% formalin.
Postmortem examinations (parental animals):
SACRIFICE
Animals were fasted overnight, anesthetized with methoxyflurane, and euthanized by decapitation.

GROSS NECROPSY
The eyes were visually examined in situ through a moistened glass slide gently pressed against the cornea. Tissue sections from all major organ systems were preserved. The lungs were infused with formalin, and the nasal cavity flushed with formalin to ensure rapid fixation.

ORGAN WEIGHTS
1st ten P1 and P2 animals sacrificed in each group: Ovaries or testes, left epididymis (total and cauda), seminal vesicles (with coagulating glands and their fluids), prostate, brain, liver, kidneys, lungs, adrenal glands, spleen, and thymus.

HISTOPATHOLOGY
All rats in control and high dose groups: Cervix, coagulating glands, epididymides, kidneys, mammary gland, nasal tissues, ovaries, oviducts, pituitary, prostate, seminal vesicles, testes, thymus, uterus, vagina, and any gross lesions.
Low and middle dose groups: Liver, ovaries - as these organs showed histologic changes at the high dose group.
Postmortem examinations (offspring):
SACRIFICE
Pups were anesthetized with methoxyflurane and euthanized by decapitation.
Terminal body weights were recorded.

GROSS NECROPSY
A complete gross necropsy on one pup/sex/exposure concentration from the first ten F1 and F2 litters was conducted on postnatal day 22. Gross examination and preservation of tissues were performed as described above for parental animals.

HISTOPATHOLOGY / ORGAN WEIGHTS
The ovaries or testes, brain, heart, liver, kidneys, adrenal glands, spleen and thymus of necropsied pups were weighed. The kidneys, liver, spleen, thymus, and testes were examined microscopically in the control and high concentration groups.
Statistics:
Body weights, gestation/lactation body weight gains, organ weights, sperm count per gram of cauda epididymis, percent motile sperm, pup body weight (litter mean), and anogennital distance (litter mean) were first evaluated by Bartlett's test (alpha 0.01) for equality of variances (Winer, 1971). Based upon the outcome of Barlett's test, either a parametric or nonparametric anlysis of variance was performed (alpha = 0.10). If ANOVA was significant, a two-sided dunnett's test, or the Wilcozon Rank-Sum test with Bonferroni's correction was performed (alpha = 0.05). Gestation lenth, average time to mating, litter size, age at vaginal opening, and age at preputial separation were analyzed using a nonparametric ANOVA. If the AONOVA was significant, the Wilcoxon Rank-cum test with Bonferroni's correction was performed. Statistical outliers were identified by the method of Grubbs (1969), but were only excluded from analysis for documented, scientifically sound reasons. Fertility idices wer analyzed by the Fisher exact probabilitytest (alpha = 0.05) and bonferroni's correction was used for multiple testing of groups in comparison to a single control. Evaluation of the neonatal sex ratio was performed by the binomial distribution test. Survival indices and other incidence data among neonates were analyzed, using the litter as the experimental unit by the Wilcoxon test (alpha = 0.05) as modified by Haseman and Hoel (1974).
Reproductive indices:
No data
Offspring viability indices:
No data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Exposure to 3000 ppm resulted in sedation, as evidence by incoordination and decreased activity, which was observed during the 6-hour exposure period and for various lengths of time after exposure. In all cases the sedation resolved by the next exposure day. This sedation was apparent in P0 adults during the first 3-5 weeks of exposure. Sedation was not observed thereafter in the 3000 ppm rats nor in any rats exposed to 300 or 1000 ppm at any time during the study.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Of the 480 adult rats on test, one control, one 300 ppm, four 1000 ppm and one 3000 ppm group rats were found dead. The causes of death of these rats were generally incidental and considered unrelated to treatment with PGME.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights of 3000 ppm males and females were significantly decreased during the pre-mating, gestation, and early lacatation periods relative to control body weights. Among the 1000 ppm group female rats, body weights were significantly lower than controls during a limited portion of the pre-mating phase, but not during gestation or lactation. No significant effects on body weight were observed in 1000 ppm group males nor in 300 ppm group males or females at any time during the study.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histologically, an increased incidence of ovarian atrophy (consistent with decreased ovarian weight) was observed among the 3000 ppm PGME females. Typical atrophic ovaries had fewer, or no, corpora lutea, and multiple large cstic and atretic follicles. There was no apparent increase in follicular atresia (identified by apoptotic granulosa cells) among developing follicles. Primordial and all subsequent stages in follicular maturation were evaluated qualitatively; they appeared to be present in normal numbers and were of normal appearance. the severity of ovarian atrophy was classified either as very slight, slight, or moderate. Moderate ovarian atrophy was observed in 8/30 females in the 3000 ppm group, as compared to a control incidence of 1/30. There were no treatment-related histopathological changes noted among the P1 or P2 adults exposed to 300 or 1000 ppm of PGME.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
Females exposed to 3000 ppm PGME exhibited an increase in the mean number of days epr estrous cycle as well as a resultant decrease in the mean number of estrous cycles during the period of evaluation. This effect on estrous cyclicity did not achieve statistical significance but was considered to be biologically significant. Also, 4 out of 10 high-exposure females exhibited atypical vaginal cytology. No effects on mean number of days per cycle or number of cycles per dam were noted for the 300 or 1000 ppm group dams.
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
Sperm count and motility was determined at necropsy after completion of the mating period. No treatment-related differences in sperm counts or motility were observed for an exposure concentration tested. A significant increase in the number of progressively motile sperm obtained from 3000 ppm PGME males was considered spurious and not of toxicological significance
Reproductive performance:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on gestation survival index, pup sex ratios, gestation length, or time to mating at any exposure concentration for the mating/litters. However, decreases in F1b and F2 male and female conception and fertility indices were observed among the 3000 ppm group animals. These decreases were not always statistically identified, but were usually outside of historical control ranges and were considered treatment-related. No treatment-related effects were observed on any index of reproduction or fertility, gestation survival (% liveborn pups), pup survival, pup sex ratios, gestation length, or time to mating at 300 or 1000 pm PGME.

Effect levels (P0)

open allclose all
Dose descriptor:
NOEC
Effect level:
300 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEC
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive performance

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Exposure to 3000 ppm resulted in sedation, as evidence by incoordination and decreased activity, which was observed during the 6-hour exposure period and for various lengths of time after exposure. In all cases the sedation resolved by the next exposure day. This sedation was apparent in postnatal day 28 rats selected as P2 parents during the first 2 weeks of exposure. Sedation was not observed thereafter in the 3000 ppm rats nor in any rats exposed to 300 or 1000 ppm at any time during the study. No other treatment-related changes in behaviour or demeanor were observed in P1 adults at any exposure concentration during any phase of the study..
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Of the 480 adult rats on test, one control, one 300 ppm, four 1000 ppm and one 3000 ppm group rats were found dead. The causes of death of these rats were generally incidental and considered unrelated to treatment with PGME.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights of 3000 ppm males and females were significantly decreased during the pre-mating, gestation, and early lacatation periods relative to control body weights. These body weight decreases were especially marked in the P1 generation, with mean body weights as much as 21% lower than controls. Among the 1000 ppm group female rats, body weights were significantly lower than controls during a limited portion of the pre-mating phase, but not during gestation or lactation. No significant effects on body weight were observed in 1000 ppm group males nor in 300 ppm group males or females at any time during the study.
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Among P1 males, significant increases in relative liver, lung, and seminal vesicle weights were observed in the 3000ppm group, while P1 females similarly exposed had significantly decreased brain (absolute) and ovary (absolute and relative) weights relative to controls. There were no treatment-related differences in organ weights of males or females exposed to 300 or 1000 ppm PGME.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histologically, an increased incidence of ovarian atrophy (consistent with decreased ovarian weight) was observed among the 3000 ppm PGME females. Typical atrophic ovaries had fewer, or no, corpora lutea, and multiple large cstic and atretic follicles. There was no apparent increase in follicular atresia (identified by apoptotic granulosa cells) among developing follicles. Primordial and all subsequent stages in follicular maturation were evaluated qualitatively; they appeared to be present in normal numbers and were of normal appearance. the severity of ovarian atrophy was classified either as very slight, slight, or moderate. Moderate ovarian atrophy was observed in 10/30 females in the 3000 ppm group, as compared to a control incidence of 0/30. Among females in the 3000 ppm, an increased incidence of slight ovarian atrophy also occurred (4/30 bs. 0/30 for controls). Note that the incidence of slight or very slight ovarian atropy was similar among all groups in the P0 generation, probably reflecting an increased background incidence of reproductive senescence of the P1 females (8 months old) vs. the P2 females (5.6 months old). There were no treatment-related histopathological changes noted among the P1 or P2 adults exposed to 300 or 1000 ppm of PGME.
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
Females exposed to 3000 ppm PGME exhibited an increase in the mean number of days epr estrous cycle as well as a resultant decrease in the mean number of estrous cycles during the period of evaluation. This effect on estrous cyclicity achieved statistical significance. Also, 4 out of 10 high-exposure females exhibited atypical vaginal cytology. No effects on mean number of days per cycle or number of cycles per dam were noted for the 300 or 1000 ppm group dams.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Sperm count and motility was determined at necropsy after completion of the mating period. No treatment-related differences in sperm counts or motility were observed for an exposure concentration tested.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
No treatment-related effects were observed on gestation survival index, pup sex ratios, gestation length, or time to mating at any exposure concentration for the mating/litters. However, decreases in F1b and F2 male and female conception and fertility indices were observed among the 3000 ppm group animals. These decreases were not always statistically identified, but were usually outside of historical control ranges and were considered treatment-related. No treatment-related effects were observed on any index of reproduction or fertility, gestation survival (% liveborn pups), pup survival, pup sex ratios, gestation length, or time to mating at 300 or 1000 pm PGME.

Effect levels (P1)

open allclose all
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEC
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical observations or physical alterations were observed for any pups from any of the exposure groups.
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Decreased pup survival was noted during the lactation phase for the litters of the 3000 ppm PGME group. No treatment-related effects were observed on gestation survival (% liveborn pups), pup survival, pup sex ratios at 300 or 1000 pm PGME. Decreased litter size was noted in the high-exposure group also. These were reflective of significant decreases in pup survival during lactation, as mentioned above. No effects on mean litter size were observed for any of the 300 or 1000 ppm PGME group litters at any time during their respective lactation periods.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreased pup body weights were noted in the litters of the high-exposure group.
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
effects observed, treatment-related
Description (incidence and severity):
Offspring from the 3000 ppm group exhibited statistically significant delays in age at vaginal opening (F1a and F1b) and age at preputial separation (F1 only). In females, vaginal opening was delayed by >2.6 days, while in males, a delay of 3.1 days was observed for preputial separation. Both the male and female F1b rats in the 3000 ppm group weighed significantly less than controls at the time these markers of puberty were achieved. No effects on developmental these developmental markers were noted for the 300 or 1000 ppm groups.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
High concentration male and female weanlings generally exhibited decreased absolute weights of the kidneys, liver, spleen, testes, thymus and brain, and increased relative brain weights (data not shown). Although these changes were not always statistically identified, the trends in these organs appeared fairly consistent across the litters. No significant treatment-related organ weight changes were identified among the 300 or 1000 ppm PGME weanlings.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions identified at the weanling necropsy that were associated with PGME exposure.
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Histologically, the livers of F3000 ppm PGME weanlings often lacked the normal degree of glycogen vacuolation and exhibited thymic single-cell necrosis. No significant treatment-related histopathological changes were identified among the 300 or 1000 ppm PGME weanlings.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Dose descriptor:
NOAEC
Generation:
F1
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical observations or physical alterations were observed for any pups from any of the exposure groups.
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Decreased pup survival was noted during the lactation phase for the litters of the 3000 ppm PGME group. No treatment-related effects were observed on gestation survival (% liveborn pups), pup survival, pup sex ratios at 300 or 1000 pm PGME. Decreased litter size was noted in the high-exposure group also. These were reflective of significant decreases in pup survival during lactation, as mentioned above. No effects on mean litter size were observed for any of the 300 or 1000 ppm PGME group litters at any time during their respective lactation periods.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreased pup body weights were noted in the litters of the high-exposure group.
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
no effects observed
Description (incidence and severity):
No significant effects were noted on anogenital distance for F2 male or female pups at any exposure concentration tested
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
High concentration male and female weanlings generally exhibited decreased absolute weights of the kidneys, liver, spleen, testes, thymus and brain, and increased relative brain weights (data not shown). Although these changes were not always statistically identified, the trends in these organs appeared fairly consistent across the litters.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross lesions identified at the weanling necropsy that were associated with PGME exposure.
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Histologically, the livers of F3000 ppm PGME weanlings often lacked the normal degree of glycogen vacuolation and exhibited thymic single-cell necrosis. No significant treatment-related organ weight, gross pathological, histopathological changes were identified among the 300 or 1000 ppm PGME weanlings.

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Effect levels (F2)

Dose descriptor:
NOAEC
Generation:
F2
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Inhalation exposure of male and female Sprague-Dawley rats for two generations resulted in reproductive and neonatal efects at 3000 ppm, while no reproductive or neonatal effects were seen at 1000 or 300 ppm. The reproductive effects appeared to affect only the female, and consisted mainly of lenthened estrous cycles, ovarian histological changes, and reduced fertility. The neonatal effects primarily involved decreased body weights, reduced survival and litter size, slight delays in puberty onset, histologic liver glycogen depletion, and thymic single-cell necrosis. These reproductive and neonatal effects occurred only at maximal concentrations and were most likely secondary to the markedly decreased parental body weights and sedation noted at this concentration. The NOEL for fertility and reproductive effects in this two-generation inhalation reproduction study was 1000 ppm PGME, while the NOEL for parental toxicity was 300 ppm.
Executive summary:

In a guideline and GLP study, the reproductive toxicity of methoxypropanol was studied in male and female SD rats exposed by inhalation to 0, 300 1,000 or 3,000 ppm vapours for 10 days prior to mating and 7 d/wk during mating, gestation and lactation for 2 generations. Marked parental toxicity was seen at 3,000 ppm, as evidenced by changes in various organ and body weights (relative/absolute) of the first and second generation males and females, in particular of the testes and ovaries. In females, toxicity was accompanied by decreased fertility, lengthened oestrous cycle, decreased ovarian weight and histopathological ovarian atrophy. Embryotoxicity and foetotoxicity occurred only at maternally toxic doses. No reproductive/neonatal effects were observed at 1000 ppm, a concentration which caused less marked , but significant body weight effects without sedation. Based on these findings the NOEL for reproductive/neonatal effects was 1000 ppm, and that for parental toxicity was 300 ppm.