Oxydipropanol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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

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 or test system 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 were kept for at least 21 days (weaning); dosing at 74 ± 10 days of age until mating (mother was dosed throughout).

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:
5% in water (post-cohabitation)
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
21 days post-cohabitation: 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 life 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 life 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:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): no effects on fertility index was observed in P animals.

Dose descriptor:

NOAEL

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:

not specified

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

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

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 animas 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.

Dose descriptor:

NOAEL

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

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

No reproductive toxicity studies on dipropylene glycol were available for assessment.

An assessment of reproductive parameters, sperm motility and estrous cycle, was performed in a 90-day drinking water study with rats and mice at concentration level of 80000 ppm (corresponding to actual average ingested doses in rats of 12800 mg/kg bw/day (males) and 8950 mg/kg bw/day (females) and in mice of 11000 mg/kg bw/day (males) and 14700 mg/kg bw/day (females) (National Toxicology Program, 2004). In the rat study, the left testis, cauda epididymis, and epididymis weights; motility of epididymal spermatozoa; epididymal sperm counts per cauda; and spermatid heads per gram testis of 80,000 ppm males were significantly decreased. No significant differences were noted in estrous cycle parameters between exposed and control females. In the mice study, the estrous cycle of 80,000 ppm females was significantly longer than that of the controls. There were no significant differences in sperm motility parameters between exposed and control males.

However, the toxicological relevance of the observed effects is questionable. It is obvious that the doses ingested by the study animals were excessively high, surpassing the currently by OECD and EPA established limit doses. As stated in the American Chemistry Council Expert Review, in the case of the rat study, extraordinary large dose-water concentration apparently caused palatability problems, decreased water consumption and led to severe decrements in body weight gain. Therefore, other experimental stress factors, such as major decrements in water intake and body weight, present more scientifically plausible explanations for the adverse changes in the reproductive system.

The testicular and sperm effects noted in rats at the 80,000 ppm group require analysis and discussion. The onset of puberty and sexual maturity is affected by age of the animal, body mass, growth rate and development. Nutritional deficiencies can delay the onset of puberty and sexual maturation as well as affect the growth and development of the gonads and accessory sex organs (Hamm et al. 1983; Chapin et al. 1993).Although the feed consumption values were not provided in the NTP study, feed consumption values typically mirror water consumption values in rodent species (Duffy et al. 1989). Prior to puberty, although there is continued differentiation, growth of the testes and accessory sex glands mirror somatic growth (Marty et al. 2006). With the onset of puberty, the growth of the testes and accessory sex organs are disproportionately increased when compared to somatic growth, primarily due to the growth stimulatory effects of gonadotropins and steroid sex hormones. Nutritional deficiencies (e.g. reduced feed and/or water intake) prior to puberty affect growth of the testes and sex organs as these conditions affect somatic growth. Decreases in feed and/or water consumption before puberty can also delay the onset of sexual maturation endpoints and this is why both age and body weight are collected on the day of attainment of sexual maturation endpoints (e.g. balanopreputial separation, vaginal opening and estrus cycling) in guideline regulatory studies.

However, after sexual maturity is attained, these same nutritional deficiencies (e.g. feed and/or water restriction) do not affect the growth of the testes and accessory sex organs as it does somatic growth (Holson et al. 2006). This phenomena is sometimes referred to as “testicular sparing” and describes a lack of effect of feed and/or water restriction on testes and accessory gland weights. This finding is commonly observed in repeated-exposure studies when the animals are sexually mature at the onset of the exposure period and following a period of feed and/or water restriction, the testes weights are comparable to the control group values and the relative testes weights (relative to body weight) are increased, due to the decreased overall growth of the animal. 

The 90-day rat NTP study used sexually immature F344 male rats that were 6 weeks of age at the start of the exposure. F344 male rats become sexually mature between ten and fifteen weeks of age (Blazak et al. 1985), providing normal feed consumption, body weight gains and growth patterns. However, in the NTP 90-day study, the high-dose rats consumed 40% less water during the first week of exposure when compared to controls. These decrements in water consumption (and presumably feed consumption although the data was not provided) continued throughout the exposure period to varying degrees resulting in terminal body weights in the male rats that were 53% that of the control group. Decrements in feed and water consumption (resulting in a severe decrease in rate of body weight gain) during the period of sexual maturation and growth can delay (or even prevent) the onset of puberty in male rats. This problem of feed restriction affecting sexual development is discussed in Chapin et al. (1993) and Hamm et al. (1983). Chapin et al. (1993) noted the differing response in Sprague Dawley and F344 rat strains as well as the effect of feed restriction prior to sexual maturity. The comparison suggests that 1) F344 rats (an inbred strain) are more susceptible to reproductive organ weight changes than Sprague Dawley rats (an outbred strain) and 2) that feed restriction prior to sexual maturity affected sex organ weight changes and sexual function more severely than the same extent of feed restriction that commenced after sexual maturity was attained.

With the extent of the water intake reduction and probably feed restriction noted in the 80,000 ppm group in combination with the resultant effect on male rat body weights (53% that of the control group values), it is concluded that the effects noted were the result of a primary cause from nutritional deficiencies with subsequent effects on immature testes and sex organs during the 90-day exposure period. This delay in attaining sexual maturity is therefore secondary to a nutritional and growth deficiency and does not represent an endocrine-mediated insult.

An additional consideration in the use of sexually immature F344 rats in this study is the lack of a full complement of adult metabolic enzymes required to metabolize and eliminate the administered test chemical during the first few weeks of the study. If the animals are growth-retarded from lack of adequate nutrition (with the decrements in water/feed consumption and dramatic decreases in body weight gain as evidence), then the maturation processes necessary to provide a full complement of adult metabolic enzymes (in the liver as well as other tissues) could very well be delayed. The concept of “maximally tolerated dose“ (MTD) should be dependent upon developmental life stage as the full complement of adult metabolic enzymes are not present until the animal becomes fully sexually mature. If sexual maturation is delayed from nutritional deficiencies, then the development of a full complement of adult metabolic enzymes would be expected to be delayed as a secondary consequence of the reduced nutrient intake. It is concludedfrom the dramatic decrease in body weight gain parameters observed in the 80,000 ppm dose level male rats that the MTD was clearly exceeded in these sexually immature animals.

In the 90-day mice study, the exposure concentrations were the same as in the rat study, resulting in actual ingested concentrations of 715, 1350, 2620, 4790 and 11000 mg/kg bw/day (males) and 1230, 2140, 4020, 7430 and 14700 mg/kg bw/day (females). Also these doses were significantly above the currently established limit doses by OECD and EPA. The final mean body weight and body weight gain of 10,000 ppm females were significantly greater than those of the controls. The 80,000 ppm group female mice experienced toxicity with dehydration stress (40% decrease in water intake), hypoactivity, lethality and pale feces as evidence of this exposure concentration exceeding a MTD in this group of animals. Relative liver weights of 40,000 and 80,000 ppm males and 80,000 ppm females were significantly increased. The estrous cycle of 80,000 ppm females was significantly longer than that of the controls. There were no significant differences in sperm motility parameters between exposed and control males. Similarly to the rat study, the biological relevance of the effects on fertility is considered to be questionable. This finding is also likely to reflect experimental stress rather than a toxicological response to dipropylene glycol.

 

The longer estrous cycle in the 80,000 ppm group female mice requires additional analysis and discussion. It is well accepted that caloric restrictions in female mice can cause lengthening of estrus cycles (Biology of the Laboratory Mouse 1966; Chapin et al. 1993). Although the feed consumption values were not provided in the NTP study, feed consumption values typically mirror water consumption values in rodent species (Duffy et al. 1989). In addition, the length of estrous cycles in female mice are highly variable, with a general range from 4-5 days (Cooper and Goldman, 1998). Specific to the mouse strain used in the NTP study, B6C3F1 female control mice have been reported to have estrous cycle lengths of 4.20 (±0.11), 4.40 (±0.314), 4.45 (±0.30) and 4.95 (±0.42) days in a random sample of NTP 90-day studies (NTP Technical Reports of Methylene Blue Trihydrate (CAS No. 7220-79-3),p-tert-butylcatechol (CAS No. 98-29-3), Formamide (CAS No. 75-12-7) and Bromochloroacetic Acid (CAS No. 5589-96-8)). The length of the estrous cycle in the female mice in the 80,000 ppm group was 4.56 days, well within the control group values described above. In contrast, the estrous cycle length in the control group female animals from the NTP study was 4.05 days, considerably shorter than similar NTP 90-day control results. This suggests that the difference in estrous cycle length between the control and 80,000 ppm group in the current NTP study was more likely a result of an aberrant control group value, rather than a true treatment related effect.

 

The lack of animal evidence for targetted reproductive toxicity for dipropylene glycol is supported by the chemistry of this substance. The chemical structure of dipropylene glycol is made up of twooxypropylene unitshaving aliphatic hydrocarbon (-C-C-) and aliphatic ether (-C-O-C-) backbone and two aliphatic alcohol (-C-OH) groups. Dipropylene glycol furtherlacks specific structural features that are associated with nuclear receptor binding affinity of hydrogen bond donor associated with single or multiple hydrophobic aromatic rings such as phenol or aniline (Schmieder et al. 2008). The affinity with which propylene glycol substances, including dipropylene glycol,could bind to the estrogen and androgen receptors was estiamted with the TIssue MEtabolism Simulator (OASIS TIMES software v2.27.5, LMC, Bulgaria) structure-activity relationship algorithm (Westet al., 2014). The TIMES modeling approach is based on a Common Reactivity Pattern (COREPA) which assesses the impact of three-dimensional (3-D) molecular conformation distributions and flexibility on stereo-electronic properties of the modeled substances (Mekenyanet al.2004; Mekenyan and Serafimova 2009). The modeling assessment predicted no activity against both the human estrogen and androgen nuclear receptor binding.  Thus, the modeling findings indicated thatdipropylene glycolhas no potential for endocrine disruptionviadirect receptor binding agonist or antagonist modes of action and this substance should not be considered as a potential endocrine disruptor (West et al. 2014). This conclusion agrees with the assumptions based on the chemical structure ofdipropylene glycol that lacks the necessary motifs associated with specificity for receptor-ligand interactions within the ER binding pocket.  

Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means of other than vertebrate animal tests, i. e. applying alternative methods such asin vitrotests, QSARs, grouping and read-across. A continuous breeding study with mice with the structurally related substance monopropylene glycol was available for assessment (Morrissey 1989), 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 in drinking water 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 was observed in P animals.

No effects on fertility index or mating index was 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).

References not listed in the basic data set

 

Biology of the Laboratory Mouse (1966), E.L. Green, Editor, 2nd Edition. Dover Publications, Inc., New York.

 

Blazak WF, Ernst TL and Stweart BE. (1985).Potential Indicators of Reproductive Toxicity: Testicular Sperm Production and Epididymal Sperm Number, Transit Time, and Motility in Fischer 344 Rats. Tox. Sci.5(6:1):1097-1103.

 

Chapin RE, Gulati DK, Barnes LH and Teague JL. (1993). The effects of feed restriction on reproductive function in sprague-Dawley rats.Fundam. Appl. Toxicol. 20:23-29.

 

Cooper RL and Goldman JM. (1998). Vaginal Cytology, in Daston G and Kimmel C.eds.,An Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment. ILSI Press, Developmental and Reproductive Toxicology Committee, International Life Sciences Institute, Health and Environmental Sciences Institute, Washington D.C., Chapter VI, pages 42-56.

 

Duffy PH, Feuers RJ, Leakey JEA,. Nakamura K, Turturro A and Hart RW.(1989). Effects of chronic caloric consumption on the physiologic variables related to energy metabolism in the Fischer 344 rat. Mech. Ageing Devel. 48:117-133.

 

Hamm TE Jr, Working PK and Raynor TH. (1983).The effect of restricted diet on reproduction in F-344 rats. Lab. Animal Sci. 33:505.

 

Holson JF, Nemec MD, Stump DG, Kaufman LE, Lindstrom P and Varsho BJ. (2006). Significance, Reliability and Interpretation of Developmental and Reproductive Toxicity Study Findings. Chapter 9 inDevelopmental and Reproductive Toxicology – A Practical Approach; 2nd Edition, RD Hood, Editor.

 

Marty MS, Chapin RE, Parks LG and Thorsrud BA. (2006). Development of the Male Reproductive System“ Appendix C-4 inDevelopmental and Reproductive Toxicology – A Practical Approach; 2nd Edition, RD Hood, Editor.

 

Mekenyan O and Serafimova R. (2009). Mechanism based modeling of estrogen receptor binding affinity:

a common reactivity pattern (COREPA) implementation. In: Endocrine disruption modeling. Devillers J (ed), CRC Press LLC, Boca Raton, FL, pp 259–294

 

Mekenyan OG, Dimitrov SD, Pavlov TS and Veith GD. (2004). A systematic approach to stimulating

metabolism in computational toxicology.I. The TIMES heuristic modelling framework. Curr Pharm Des.10:1273–1293

 

NTP (National Toxicology Program). (2002). NTP Technical Report on the Toxicity Studies ofp-tert-Butylcatechol (CAS No. 98-29-3) Administered in Feed in F344/N Rats and B6C3F1 Mice. Editor: JK Dunnick.

 

NTP. (2006). NTP Technical Report on the Toxicity and Carcinogenesis Studies of Methylene Blue Trihydrate (CAS No. 7220-79-3) in F344/N Rats and B6C3F1 Mice. Editor: DW Bristol.

 

NTP. (2008). NTP Technical Report on the Toxicity and Carcinogenesis Studies of Bromochloroacetic Acid (CAS No. 5589-96-8) in F344/N Rats and B6C3F1 Mice. Editor: RL Melnick.

 

NTP (2009). NTP Technical Report on the Toxicity and Carcinogenesis Studies of Formamide (CAS No. 75-12-7) in F344/N Rats and B6C3F1 Mice. Editor: RD Irwin.

 

SchmiederaP,Kolanczyk R, Aladjov H, Hornung M, Tapper M, Denny J and Sheedy,B. (2008).Expert consultation on the use of (quantitative) structure activity relationships [(Q)SAR] of estrogen binding affinity to support prioritization of heterogeneous chemicals within defined inventories for screening and testing. Organization for Economic Cooperation and Development (OECD), Paris, France. 17 Feb. 2008

 

West R, Banton M, Hu J and Klapacz J. (2014). The distribution, fate, and effects of propylene glycol substances in the environment.Reviews of Environmental Contamination and Toxicology.232:107-138.

Short description of key information:
Based on the results of the continuous breeding study with mice with a structurally related substance propylene glycol, it is concluded that dipropylene glycol does not exhibit reproductive toxicity, as no effects on fertility were observed at the highest tested dose (10100 mg/kg bw/day). A full justification for read across within the propylene glycol series is contained in a separate document attached to chapter 13 of the lead registrants IUCLID dossier.

Effects on developmental toxicity

Description of key information

Based on the results of two developmental toxicity studies with rats and rabbits, it is concluded that dipropylene glycol does not exhibit developmental toxicity, as no effects on development were observed at the highest tested dose in both species (5000 mg/kg bw/day in rats and 1200 mg/kg bw/day in rabbits).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 200 mg/kg bw/day

Quality of whole database:

Studies available in both rats and rabbits.

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

Two developmental toxicity studies, one with rats and one with rabbits, were available for assessment. Dipropylene glycol was administered by oral gavage at nominal concentrations 0, 800, 2000 and 5000 mg/kg bw/day to pregnant female rats at GD 6 -15 (NTP TER-91-013, 1992) and to pregnant female rabbits at nominal concentrations 0, 200, 400, 800 and 1200 mg/kg bw/day at GD 6 -19 (NTP TER-91-014, 1992). Clinical signs of toxicity were observed in the rat studies at dose levels 2000 and 5000 mg/kg bw/day, including ataxia, weight loss, lethargy, unstable gait, piloerection, morbidity and/or mortality. Relative liver weights were significantly increased compared to controls in maternal animals of 2000 and 5000 mg/kg bw/day groups. There were no significant differences between the exposed groups and the control in the average number of corpora lutea, implants, live fetuses, early deaths (resorptions), late deaths, or non-live implants per litter. The percent pre- and post-implantation losses per litter were not significantly different from control values. A significant decreasing linear trend from the control to high dose group was observed for mean fetal weight, however, mean male and female body weights in the DPG exposed groups were not significantly different from control. There were no other treatment-related effects.

The NOAEL for maternal toxicity was established to correspond to 800 mg/kg bw/day, the NOAEL for developmental toxicity was 5000 mg/kg bw/day (the highest dose tested).

In the rabbit study, no maternal lethality or dose-related clinical signs of toxicity were observed. Examination of the ovaries from pregnant animals revealed a significant decrease in the number of corpora lutea in the high dose group compared to control. This observation was not treatment related since exposure of the maternal animals did not begin until ca. 6 days after ovulation. The mean number of implantation sites in the dipropylene glycol exposed groups was equivalent to controls. No significant differences between the dipropylene glycol exposed groups and the control in the average number of implants, live fetuses, early deaths (resorptions), late deaths, or non-live (early deaths + late deaths) implants per litter were observed. The percent postimplantation losses per litter were not significantly different from control values. No significant effects were observed on average fetal weight or on the percent of male fetuses per litter.

Statistical examination of the prevalence of morphological abnormalities from the fetuses showed no significant effects of dipropylene glycol exposure. The only significant linear trend was associated with the number of litters with visceral malformations; however, it was within historical control ranges. No significant effects were noted in the prevalence of variations in the fetuses.

The NOAEL for both maternal and developmental toxicity was 1200 mg/kg bw/day (no effects at the highest dose tested).

Justification for classification or non-classification

Based on the absence of effects on fertility in the available continuous breeding study with mice on the structural analogue propylene glycol, and the absence of adverse effects on development in two reliable studies with rats and rabbits, classification of dipropylene glycol for reproductive and/or developmental toxicity is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.