3,6,9-trioxaundecane-1,11-diol

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: basic information given

Justification for type of information:

Please refer to category document for additional information on read across approach.

Data source

Reference

Reference Type:

publication

Title:

Reproductive Toxicity of Triethylene Glycol and Its Diacetate and Dimethyl Ether Derivatives in a Continuous Breeding Protocol in Swiss-CD-1 Mice.

Author:

Bossert, N.L., Reel, J.R., Lawton, D., George, J.D., Lamb, J.C.

Year:

1992

Bibliographic source:

Fundamental and Applied Toxicology 18, 602-608

Materials and methods

Principles of method if other than guideline:

The study was conducted under the NTP Program's RACB protocol, the details of which have been published previously.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-(ethylenedioxy)diethanol

EC Number:

203-953-2

EC Name:

2,2'-(ethylenedioxy)diethanol

Cas Number:

112-27-6

IUPAC Name:

2,2'-[ethane-1,2-diylbis(oxy)]diethanol

Details on test material:

purity: approx. 97%

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were 6 weeks of age. Two males and two females were killed and their were evaluated for antibodies against mouse viruses. All sera were negative for viral antibodies.
After a 2-week quarantine period, all study animals were individually identified, stratified by body weight, and randomly assigned to treatment groups.
Throughout these studies, all animals were housed in solid-bottom polypropylene or polycarbonate cages with Ab-Sorb-Dri bedding. Male and female mice were group-housed by sex during quarantine and for the I-week premating period. Subsequently, the animals were housed individually or as breeding pairs. Deionized/filtered water and ground rodent chow (NIH-07) were provided ad libitum. Automatically controlled photoperiods were 14 hr light/10 and temperature was maintained at 70 ± 2°F. Cages were sanitized weekly using detergent and 180°F water.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

The treatment solutions for each test compound were independently formulated by mixing the test compound (w/v) directly into different proportions of distilled water. An aliquot of each formulation of each chemical in the drinking water and the control water and bulk chemical were sent to Midwest Research Institute at 6-week intervals for confirmation of dose levels and certification of the stability of the bulk chemical.

Details on mating procedure:

Triethylene glycol was administered in drinking water to breeding pairs (20 pairs per treatment group, 40 control pairs) during a 98-day cohabitation period.

Duration of treatment / exposure:

beginning 1 week before mating of the F0-generation until end of lactation period of the F2-generation

Frequency of treatment:

continuously

Details on study schedule:

Reproductive function was assessed by the number oflitters per pair, live pups per litter, proportion of pups born alive, and pup weight.

Doses / concentrations

Remarks:

Doses / Concentrations:
0; 0.3; 1.5 and 3% (= 0, 590, 3300 and 6780 mg/kg bw/day)
Basis:
nominal in water

No. of animals per sex per dose:

20 males and 20 females per dose group , 40 control animals per sex in the control group

Control animals:

yes, concurrent no treatment

Details on study design:

This study consists of 4 tasks:
Task 1 - dose-setting study
Task 2 - continuous breeding phase
Task 3 - crossover mating trial used to determine the affected sex when a positive effect on fertility is detected in Task 2
Task 4 - assesses the reproductive performance of the offspring from Task 2 breeding pairs
On the basis of the reduced body weight gain and increased mortality (12.5%) in the 5% test group, exposure levels of 0, 0.3, 1.5 and 3% TEG were selected for this study.

Examinations

Parental animals: Observations and examinations:

Body weight, kidney weight, liver weight, mortality, food consumption, water consumption, clinical signs.

Oestrous cyclicity (parental animals):

Estrous cycle length

Sperm parameters (parental animals):

Spem concentration, motility, and morphology

Litter observations:

Pup growth to weaning, mortality

Postmortem examinations (parental animals):

Litters/pair, live pups/litter, cumulative days to litter, absolute testes/epididymis weight, sex accessory gland weight, epidid. sperm parameters.

Statistics:

Statistical analysis was performed. The level of significance for all tests was set at p<0.05.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

No treatment-related changes in physical appearance, body weight gain, fluid consumption during Task 2.
During Task 2, a total of 6 animals died - 2 females in the control, 1 male and 1 female in the 1.5% test group and 2 females in the 3% test group. The random distribution of deaths across treatment groups suggests that they were not treatment-related.
TEG during Task 2 had no effect on fertility or reproductive performance as indicated by the proportion of pairs able to produce at least 1 litter, number of litters produced per pair, number of live pups per litter or proportion of pups born alive. Continuous exposure to 1.5 or 3% significantly reduced mean live pup weight compared to the corresponding weights in the 0 and and 0.3% test group. Since TEG exerted minimal effects on reproductive performance in the Task 2 parental mice (P generation), the effect of TEG on 2 -generation fertility was assessed. The exposure was continued and the final Task 2 litters (F1), of the control and 3% TEG groups were reared to maturity (74 +/- 10 days) and then these F1 offspring were mated to non-siblings from the same treatment group. Mice from the final Task 2 litters were weighed at births and on day 21 and day 74 +/- 10, and no significant differences were observed.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

6 780 mg/kg bw/day

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Results: F1 generation

Details on results (F1)

TEG had no adverse effects on the other reproductive parameters measured, including F1 litter size, proportion of F2 pups born alive, sex of the F2 pups born alive, and adjusted F2 pup weight.
Necropsy of the F1 male offspring showed that the highest concentration had no effect on body weight, testis, epididymis, seminal vesicle, or prostate weight, epididymal sperm concentration, percentage motile sperm, or percentage morphologically abnormal sperm. Necropsy of the F1 females showed no change in body or liver weight. The weights of the brain, pituitary, ovary, oviduct, and uterus were similarly unaffected. In contrast, TEG significantly increased liver weight in males and when organ weights were adjusted for body weight, 3% TEG significantly increased female liver weight compared to controls.
Furthermore, similar to the P generation, continuous exposure of the F1 mice to 3% TEG affected neither the mating index nor the fertility index.

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

6 780 mg/kg bw/day

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Effect of TEG on fertility and reproductive performance:

	0% TEG	0.3% TEG	1.5% TEG	3.0% TEG
No. fertile/No. cohabited	37/37	19/20	18/18	18/18
Litters/pair	4.8 +/- 0.1 (37)	4.8 +/-0.2 (19)	4.8 +/- 0.2 (18)	4.6 +/- 0.3 (18)
Live pups/litter	11.7 +/- 0.4 (37)	12.2 +/- 0.5 (19)	11.7 +/- 0.6 (18)	10.9 +/- 0.7 (18)
Proportions of pups born alive	0.96 +/- 0.02 (37)	0.98 +/-0.01 (19)	0.97 +/- 0.02 (18)	0.96 +/-0.03 (18)
Live pup weight (g)	1.66 +/- 0.02 (37)	1.63 +/- 0.02 (19)	1.60 +/- 0.02 (18)*	1.59 +/- 0.02 (18)*

* Pairs of mice were cohabited and dosed with the appropoirate chemical for 14 weeks. Pairs were considered fertile if they produced one or more litters.

Effect of TEG on male body and organ weights and sperm parameters at necropsy (The 5th litter produced during Task 2 was allowed to grow until 74 +/- 10 days of age. They received either control or chemical treatment via lactation until weaning and then dosed with drinking water until necropsy at 95 +/- 10 days of age. Each value is the mean +/- SE of 20 mice. ND = parameter not determined.)

Weight or sperm parameter	0 (control)	3%
Body (g)	33.2 +/- 0.4	33.1 +/- 0.9
Liver (g)	2.02 +/- 0.03	2.13 +/- 0.05*
Kidneys/adrenals (g)	ND	ND
Right testis (mg)	120 +/- 4	115 +/- 4
Right epididymis (mg)	47 +/- 1	43 +/- 1
Prostate (mg)	34 +/- 4	32 +/- 3
Seminal vesicles (mg)	285 +/- 13	305 +/- 17
Motile sperm (%)	52 +/- 7	54 +/- 5
Abnormal sperm (%)	5.8 +/- 1.5	4.9 +/- 1.4
Sperm concentration**	700 +/- 35	719 +/-38

* significantly different (p<0.05) from the control group

** No. sperm x 10(3)/mg caudal tissue

Effect of TEG on female body and organ weights at necropsy (The 5th litter produced during Task 2 was allowed to grow until 74 +/- 10 days of age. They received either control or chemical treatment via lactation until weaning and then dosed drinking water until necropsy at 95 +/- 10 days of age. Each value is the mean +/- SE of 20 animals.)

Weight (g)	0 (control)	3%
Body	30.4 +/- 0.5	29.4 +/- 0.6
Liver	2.01 +/- 0.05	2.02 +/- 0.07

Applicant's summary and conclusion

Conclusions:

The test substance was not a reproductive toxicant in either generation of mice when administered in drinking water at concentrations of up to 3%, although developmental toxicity was noted in the first generation as reduced pup body weight.