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Effects on fertility

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Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, published in peer-reviewed literature, minor restrictions in design and reporting, but otherwise adequate for assessment.
Qualifier:
according to
Guideline:
other: NTP Reproductive Assessment by Continuous Breeding (RACB)
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, NY.
- Age at study initiation: 6 weeks
- Housing: group housed by sex in solid-bottom polypropylene or polycarbonate cages with stainless-steel wire lids, during the quarantine and the 1-week premating periods. subsequently, the animals were housed as breeding pairs or individually
- Diet (e.g. ad libitum): ground rodent chow, ad libitum
- Water (e.g. ad libitum): deionized/filtered water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Photoperiod (hrs dark / hrs light): 14/10

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Each concentration was mixed separately at periodic intervals.

VEHICLE
Water
- Concentration in vehicle: 1.00, 2.50 and 5.00%
Details on mating procedure:
In the continuous breeding study mice were exposed to the test substance for 7-day premating period, and were then randomly grouped as mating pairs and cohabited and treated continuously for 98 days. Data were collected on all newborns during this period within 12 hours of birth, after which each litter was discarded. After the 98-day cohabitation, the pairs were separated but continued on treatments. During the next 21 days, any final litters were delivered and kept for at least 21 days (weaning). The mother was dosed through weaning and F1 mice were dosed until mated at 74 ± 10 days of age. For this, male offspring were mated to female off-spring from the same treatment group (n = 20/group/sex) and the F2 litters were examined for litter size, sex and pup weight.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 days in the dose range-finding study; 7 days pre-mating period, 98 days (14 weeks) cohabitation, 21 days post-cohabitation. Any litters delivered during these 21 days (second generation animals) were kept for at least 21 days (weaning) and continued receiving the chemical treatment initially through lactation (mother was dosed throughout) and then through drinking water. Second generation animals were mated at 74 ± 10 days of age.
Frequency of treatment:
Daily
Details on study schedule:
Other: A 14-day dose-setting study utilized one control group and 5 groups of dosed animals (8/sex/dose). The endpoints for this study were clinical signs, mortality, body weight gain and consumption of food and water.
In the main study, the litters were removed and examined as soon as possible after delivery was completed. The offsprings were sexed, weighed and killed so that the female may be impregnated immediately. This approach maximized the number of litters which could be produced in the 14-week breeding phase.
Remarks:
Doses / Concentrations:
0, 1.82, 4.80 and 10.10 g/kg bw/day (main study)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0, 0.5, 1.0, 2.5, 5.0 and 10% in water (dose-range finding study)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
5% in water (second generation animals)
Basis:
nominal in water
No. of animals per sex per dose:
Dose range-finding study: 8/sex/dose
Main study: 20/sex/dose in each treatment group; 40/sex/dose in the control group
Second generation animals: 20/sex/dose (only the highest dose (5% in water) was tested).
Control animals:
yes
Details on study design:
- Dose selection rationale: based on a 14-day dose-selecting study
- Rationale for animal assignment: stratified randomization procedure based on body weights.

Other: when significant adverse effects on fertility were observed in the continuous breeding phase a crossover mating trial was usually performed to determine whether F0 males or females were more sensitive to the effects. High-dose animals of each sex were mated to control mice of the opposite sex to determine the affected sex. The high dose animals were selected to increase the possibility of detecting effects in the crossover mating. There were three conbinations of control and treated mice: control males with control females, high-dose males with control females, and control males with high-dose females. The offspring of the crossover matings were analyzed as in Task 4, and the parents were necropsied. Results of mating high-dose mice with control group partners were compared to matings within the control group to determine which sex was adversely affected. The crossover mating was not done if significant reproductive effects were not observed in the continuous breeding phase.
Necropsies were performed in this series of studies, usually on only F0 mice involved in th crossover mating trial, when there was evidence of an effect on reproduction or, at the least, in the second generation even if there was no effects on the F0 mice. Endpoints examined for the females included selected organ weights and histology. At necropsy, the endpoints of male reproductive function included selected organ weights and histology, percentage motile sperm, epididymal sperm concentration, and percentage abnormal sperm. These multiple measured of fertility (whole animal, organ) were designed to increase the sensitivity of the RACB protocol.

Positive control:
Diethylstilbestrol and ethylene glycol monoethyl ether
Parental animals: Observations and examinations:
Clinical signs, mortality, body weight gain and consumption of food and water were assessed during the 14-day dose-setting study.
Oestrous cyclicity (parental animals):
Not performed.
Sperm parameters (parental animals):
As no adverse effects on fertility were observed in the continuous breeding study, the subsequent substudy (crossover mating with subsequent examination of male reproductive function in F0 animals) was not performed.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
mean No. litters per pair, mean No. live pups per pair, mean No. live male pups per litter, mean No. live female pups per litter, proportion of pups born alive, sex of pups born alive, mean live pup weight per litter, mean live male pup weight per litter, mean live female pup weight per litter; adjusted mean live pup weight per litter; adjusted mean live male pup weight per litter; adjusted mean live female pup weight per litter, body weight.



Postmortem examinations (parental animals):
As no adverse effects on fertility were observed during the continious breeding study, subsequent crossover mating with subsequent necropsies of F0 animals was not performed.
Postmortem examinations (offspring):
Not performed.
Statistics:
Dose-related trend in fertility: the Cochran-Armitage test (Armitage, 1971)
Pairwise comparisons involving mating and fertility indices: Fisher's exact test
Overall differences in number of litters, number of live pups, proportion of live pups and the sex ratio for dose group means: Kruskal-Wallis test (Conover 1980)
Ordered differences in number of litters, number of live pups, proportion of live pups and the sex ratio for dose group means: Jonckheere's test (Jonckheere, 1954)
Pairwise comparisons of treatment group means: Wilcoxon-Mann-Whitney U test
Average pup weight: Kruskal-Wallis test
Treatment differences in average pup weight: analysis of covariance (Neter and Wasserman, 1974)
Pairwise comparisons: two-sided t test
Organ weights: analysis of covariance F test (overall equality) and t test (pairwise equality)
Reproductive indices:
Fertility index was determined as (No. fertile/No.cohabited) x 100
Mating index was determined as No. females with plugs/No. cohabited
Offspring viability indices:
No data.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
effects observed, treatment-related
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No chemical-related deaths were observed in either a dose-range finding study or during the 14 weeks cohabitation period in the main study. No significant chemical related clinical signs of toxicity were noted during the main study cohabitation phase.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In the dose-range finding study, the untreated males, on the average, gained 5% of their original body weight. The correspoding value for animals in the 10.0% propylene glycol was 7%. The female CD-1 mice in the control and 10% dose groups gained 8 and 15% of their initial body weight, respectively. The comparison of average daily water consumption values revealed that animals in the 10.0% propylene glycol group consumed nearly 60% more than the control group.
In the main study, male mice in the control, 1.0, 2.5 and 5.0% dose groups gained an average of 8, 7, 10 and 7% of their original body weight after 14 weeks of treatment. Female mice responded similarly; group mean body weights for the females varied with the gestation phase. Dam weights at delivery were essentially the same for animals in the control and 3 treatment groups.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
In the dose-range finding study water consumption was greatly increased in the 10.0% group. It was suspected that treatment at 10.0% may result in significantly altered fluid balances and increased body weight realtive to the control group.
In the main study, the average daily consumption of dosed water by animals in the 3 treatment groups was consistently higher than the control values, especially in the highest dose group.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
For the second generation animals, estrual cyclicity was not sensitive to propylene glycol under the present experimental condition except a small decrease in the percent estrus phase in treated animals.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
For the second generation animals, sperm studies illustrated that propylene glycol treatment at the 5.0% dose level does not significantly affect (p > 0.05) sperm motility, sperm density (sperm count per g caudal tissue), or the incidence of abnormal sperm.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
All breeding pairs in the main study delivered at least 1 litter after 14 weeks of cohabitation. Propylene glycol administered in drinking water at up to the 5.0% level had no significant effect (p > 0.05) on any of the reproductive parameters. These included the number of litters per pair, the number of live pups per litter, the proportion of pups born alive, the sex ratio and both the absolute and adjusted live pup weights.
The cumulative number of days to litter were also uneffected by propylene glycol treatment.
For the second generation animals, the mating index (percent of plug positive/no. cohabited) for the control and treated animals was 85%. The fertility index (percent of no. fertile/no. cohabited) values for the control and treated pairs was 75 and 80%, respectively. No significant differences (p > 0.05) were noted with respect to litter size, proportion of pups born alive, sex ratio, as well as absolute and adjusted pup weights.

Dose descriptor:
NOAEL
Remarks:
toxicity
Effect level:
10 100 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No effects reported at the highest dose tested.
Clinical signs:
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not examined
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
Propylene glycol had no apparent effect on pup survival.

BODY WEIGHT (OFFSPRING)
Propylene glycol had no apparent effect on pup body weight gain. For the second generation animals treated with 5% solution of propylene glycol, there was no significant difference (p > 0.05) in the body weight between the treated and control animals.

ORGAN WEIGHTS (OFFSPRING)
For the second generation animals, the absolute as well as adjusted organ weights for the liver, kidney, seminal vesicles, right cauda, prostate, right testis and right epididymis were not affected by propylene glycol treatment.
Dose descriptor:
NOAEL
Remarks:
fertility
Generation:
F1
Effect level:
10 100 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No effects on fertility of F1 generation were observed at the highest dose.
Dose descriptor:
NOAEL
Remarks:
developmental effects
Generation:
F2
Effect level:
10 100 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No effects on litter size, sex and pup weight in F2 pups were observed at the highest dose.
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 100 mg/kg bw/day
Species:
mouse
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A continuous breeding study with mice, performed within the frame of the National Toxicology Program, was available for assessment (Morrissey, 1989; National Toxicology Program, 1985), comparable to OECD guidelines for multi-generation studies (i.e. OECD 416) with respect to the assessment of fertility parameters. Mice were exposed to the test substance for 7-day premating period, and were then randomly grouped as mating pairs and cohabited and treated continuously for 98 days. Data were collected on all newborns during this period within 12 hours of birth, after which each litter was discarded. After the 98-day cohabitation, the pairs were separated but continued on treatments. During the next 21 days, any final litters were delivered and kept for at least 21 days (weaning). The mother was dosed through weaning and F1 mice were dosed until mated at 74 ± 10 days of age. For this, male offspring were mated to female off-spring from the same treatment group (n = 20/group/sex) and the F2 litters were examined for litter size, sex and pup weight.

No data on maternal toxicity were reported. No effects on fertility were observed in P animals.

No effects on fertility index or mating index were observed in F1 animals.

No differences were found between control and test P animals in the mean No. litters per pair, mean No. live pups per pair, mean No. live male pups per litter, mean No. live female pups per litter; proportion of pups born alive; sex of pups born alive; mean live pup weight per litter; mean live male pup weight per litter; mean live female pup weight per litter; adjusted mean live pup weight per litter; adjusted mean live male pup weight per litter; adjusted mean live female pup weight per litter.

No differences were found between control and F1 animals in mean No. live pups per litter; mean No. liver male pups per litter; mean No. live female pups per litter; proportion of pups born alive and sex of pups born alive.

The NOAEL for effects on fertility was established to be 10100 mg/kg bw/day (the highest dose tested).

Available data on reproductive toxicity of monopropylene glycol have been assessed and evaluated by the expert panel of the NTP CERHR (National Toxicology Program, 2004a). No human data were identified. Based on the data reported in the continuous breeding study by Morrissey (Morrissey, 1989; NTP, 1985) the Panel concluded that propylene glycol is not a reproductive toxicant in males or females or in their progeny under the conditions of this study. These data were assumed by the Panel to be relevant for assessing human hazard. Based on these findings, the Panel concluded that current estimated exposures to monopropylene glycol are of negligible concern for reproductive toxicity in humans.


Short description of key information:
No adverse effects on fertility were found in a continuous breeding study with mice, administered monopropylene glycol at levels up to 10100 mg/kg bw/day for 7 days pre-mating period, followed by cohabitation and continuous treatment for 98 days. The NOAEL for reproductive toxicity was established to exceed 10100 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

No adverse effects on development were noted in the developmental toxicity study with mice, administered monopropylene glycol at dose levels up to 10400 mg/kg bw/day on gestation days 6 to 15. Based on these data, monopropylene glycol is considered to be not a developmental toxicant.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant well-conducted and documented study, available as unpublished report, no restrictions, fully adequate for assessment.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (St. Constant, Canada)
- Age at study initiation: males 49 days old upon arrival, females 46 days old upon arrival
- Weight at study initiation: males 26-28 g, females 25-28 g upon arrival
- Housing: males were housed singly in stainless steel, wire mesh cages (23.5 x 40.0 x 18.0 cm); females were housed 2 to a gage in a stainless steel, wire mesh cages (23.5 x 20.0 x 18.0 cm) during acclimation.
- Diet (e.g. ad libitum): Ground, certified Rodent Chow #5002 (Purina Mills, Inc.) was available ad libitum during most of the acclimation period, and then powedered, certified AGWAY PROLAB animal Diet Rat, Mouse, Hamster 3200 (Agway Inc.) was available ad libitum for the duration of the study.
- Water: tap water (Municipal Authority of Westmoreland County, Greensburg, PA), ad libitum
- Acclimation period: ca. 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-77
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Propylene glycol was administered undiluted.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: January 30 - February 3, 1991
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal and dropped copulation plug, referred to as day 0 of pregnancy
Duration of treatment / exposure:
On gestation days 6 through 15
Frequency of treatment:
Daily
Duration of test:
18 days
Dose / conc.:
520 mg/kg bw/day (actual dose received)
Remarks:
administerd as 0.5 ml/kgb w/day.
Dose / conc.:
5 200 mg/kg bw/day (actual dose received)
Remarks:
administerd as 5 ml/kgb w/day.
Dose / conc.:
10 400 mg/kg bw/day (actual dose received)
Remarks:
administerd as 10 ml/kgb w/day.
No. of animals per sex per dose:
30 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a range-finding gavage study with propylene glycol in CD-1 mice (BRRC project 91-22-23801)
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for morbidity and mortality. Prior to the treatment period, animals were observed for clinical signs once daily. During treatment, animals were observed for clinical signs immediately before and during dosing, and approximately 1 hour following each daily dosing period. Subsequent to the treatmnet period, animals were observed for clinical signs once daily (a.m.)

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, 18


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION: Yes
- Time schedule for examinations: gestation days 0, 3, 6, 9, 12, 15

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 18
- Organs examined: uterus, ovaries (including corpora lutea), cervix, vagina, peritoneal and thoracic cavities were examined grossly; maternal liver and kidneys were weighed and kidneys preserved for possible subsequent microscopic evaluation.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test for equality of variances, analysis of variance (ANOVA) and t-tests. The latter were used when the F value from the ANOVA was significant. When Levene's test indicated equal variances, and the ANOVA was significant, a pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by a separate variance t-test for pairwise comparisons. Nonparametric data were statistically evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney U test when appropriate. Incidence data were compared using the Fisher's Exact test.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption was increased in the 10.0 ml/kg bw/day groups during gestation days 6 to 9, 9 to 12, 12 to 15, for the combined treatment interval, gestation day 6 to 15, and subsequent to treatment from gestation days 15 to 18. In the 5.0 ml/kg bw/day group, water consumption was increased during treatment from 12 to 15 and sebsequent to treatment from gestation days 15 to 18. In addition, though not statistically significant, water consumption values were increased in the middle dose group from gestation days 9 to 12 of treatment and for the combined treatment interval (gestation days 6 to 15) by 6-7% of control values.
Organ weight findings including organ / body weight ratios:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Details on maternal toxic effects:
There were no treatment-related necropsy findings of the dams at the scheduled sacrifice on gestation day 18. There were no effects of treatment on terminal body weight, gravid uterine weight, corrected body weight, corrected weight change, or relative and absolute liver and kidney weight. There were no effects of treatment on the number of ovarian corpora lutea, on the number of implantations/litter.
Dose descriptor:
NOAEL
Effect level:
520 mg/kg bw/day (actual dose received)
Basis for effect level:
water consumption and compound intake
Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no effects on fetal body weights/litter which were attributed to treatment.
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no treatment related increases in the incidences of individual fetal external or visceral variations.
Details on embryotoxic / teratogenic effects:
Statistically significant increases in the incidences of fetal atelectasis and poorly ossified supraoccipital bone and an decrease in the incidence of extra ossification site in the nasal fontanel in the 0.5 ml/kg/day group were not considered to be treatment-related due to the lack of a dose-response relationship.
Dose descriptor:
NOAEC
Effect level:
1 040 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
no effects observed
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 400 mg/kg bw/day
Species:
mouse
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the developmental toxicity study with mice (Bushy Run Research Center, 1993), monopropylene glycol was administered to pregnant mice at dose levels of 0, 0.5, 5.0 and 10.0 ml/kg bw/day (0, 52, 520 and 10400 mg/kg bw/day) on gestation days 6 through 15. Mice were sacrificed on gestation day 18 and evaluation of fetuses, uterine weight, number of corpora lutea and implantation sites was performed. Increased water consumption was observed in the 10.0 ml/kg bw/day group and, although not statistically significant, in the middle dose group.No further treatment-related clinical signs, effects on maternal body weights and body weight gains, food consumption were observed at any dose level and no treatment-related necropsy findings of the dams at the scheduled sacrifice on gestation day 18 were found.Therefore, the increase in water consumption is likely to be a normal physiological reaction to the administration of a high quantity of substance by gavage, which may cause a surge in the osmolarity of body fluids. Consequently, this effect is not considered to be of toxicological significance. There were no effects of treatment on gravid uterine weight, the number of ovarian corpora lutea, the number of total, viable or nonviable implantations/litter or on sex ratio. Also no effects on fetal body weights/litter were observed which were attributed to treatment. There were no treatment related increases in the incidences of individual fetal external or visceral variations. Based on the results of the study, the NOAEL for developmental toxicity was established to correspond to 10400 mg/kg bw/day.

Additional studies on developmental toxicity in rats, mice, hamsters and rabbits, conducted under the contract for the FDA (FDRL. Teratologic evaluation of FDA 71-56 (propylene glycol) are available in mice, rats, hamsters and rabbits. (Food and Drug Research Laboratories, Inc., 1973):), These studies showed no signs of maternal, fetal toxicity or teratogenicity at the maximum tested doses (1600 mg/kg bw/day for rats, and mice, 1550 mg/kg bw/day for hamsters and 1230 mg/kg bw/day for rabbits). The study reports had some shortcomings in that no detailed information on study design and no statistical information was reported. Propylene glycol was also tested in a mouse screening assay (Kavlock et al., Teratog. Carcinog. Mutagen. 1987, 7, 7-16); however, the endpoints evaluated (number of dams pregnant, mortality, the number of dams with resorptions, the number of live pups and their weights on postnatal days 1 and 3) and the dosing period (gestation days 8-12) were not adequate for a comprehensive developmental toxicity study. Nevertheless, against the criteria for such a screening study, the outcome was negative. Available data on developmental toxicity of monopropylene glycol were evaluated and assessed by the expert panel of the CERHR In summary, the Panel concluded that the available data are sufficient to evaluate the developmental toxicity of monopropylene glycol. The panel concluded that data from the Bushy Run Research Center (1993) indicated that monopropylene glycol is not a developmental toxicant in mice. The maternal NOEL was 5000 mg/kg bw/day based on increases in water consumption observed at 5000 and 10000 mg/kg bw/day. The panel concluded that it was reasonable to speculate that this effect was a physiological response to the high doses of propylene glycol administered. Data in other species, although inadequately presented, are consistent with the findings in mice. Despite the limitations of each study, no adverse developmental or maternal effects were noted in any species at the highest tested dose (10000 mg/kg bw/day in mice in the screening study; 1600 mg/kg bw/day in rats, 1550 mg/kg bw/day in hamsters and 1230 mg/kg bw/day in rabbits). The overall data were judged to be adequate for human risk assessment. Based on these findings, the Panel concluded that current estimated exposures to monopropylene glycol are of negligible concern for developmental toxicity in humans. From a REACH perspective, the Bushy Run study provides unequivocal and reliable evidence that this substance does not cause developmental toxicity in mice. There are other supporting studies that confirm this. There is no single study that is considered sufficiently reliable on its own to meet the requirement for a developmental toxicity study in a second species. However, the FDA studies in three further species (rat, hamster and rabbit) do provide what is regarded as sufficient weight of evidence that the result in mice is not anomalous and that propylene glycol does not cause developmental effects

Justification for classification or non-classification

Based on the absence of adverse effects on reproduction and development in available continuous breeding study and developmental toxicity study with mice (NOAEL > 10000 mg/kg bw/day), monopropylene glycol does not have to be classified for reproductive and developmental toxicity in accordance with EU Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.