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REACH

Reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-d

EC number: 907-132-6 | CAS number: -

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Fertility data are available for components of reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-diol, triethylene glycol (TEG) and tetraethylene glycol (TTEG).

Link to relevant study records

Reference

Endpoint:: two-generation reproductive toxicity
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:: Read across is based on the category approach. Please refer to attached category document.
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
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.
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.
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.
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.
Dose descriptor:: NOAEL
Effect level:: 6 780 mg/kg bw/day
Sex:: male/female
Basis for effect level:: other: overall effects
Dose descriptor:: NOAEL
Effect level:: 6 780 mg/kg bw/day
Sex:: male/female
Basis for effect level:: other: overall effects
Remarks on result:: other: Generation: fertility
Dose descriptor:: NOAEL
Generation:: F1
Effect level:: 3 300 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: body weight and weight gain
Reproductive effects observed:: not specified
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.

Effect on fertility: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 6 780 mg/kg bw/day
Study duration:: chronic
Species:: mouse
Quality of whole database:: A RACB study is available for TEG, a component of the reaction mass. Supporting data are available for TTEG, another component of the reaction mass.

Additional information

In the key study, a Reproductive Assessment by Continuous Breeding study with TEG (Bossert et al., 1992), groups of Swiss CD-1 mice were exposed to 0, 0.3, 1.5, and 3% (equivalent to 0, 590, 3300, and 6780 mg/kg bw/day) TEG in the drinking water during a 98-day cohabitation period. No reproductive toxicity in either generation was observed at concentrations up to 3%. Reduced pup body weight was observed at the mid and high dose levels in F1 offspring only. No effect on pup body weight was seen in F2 offspring. No effect of treatment on the proportion of pairs with a litter, the number of litters per pair, the number of live pups per litter or the proportion of live born pups in the study. Therefore, the NOAEL for parental toxicity and for fertility was 6780 mg/kg bw/day.

In a 28 day drinking water study, 2000 mg/kg/day TTEG produced no evidence of reproductive effects in Wistar rats based on testicular and ovarian weights and gross and histopathological examination of reproductive organs (Schladt et al., 1998).

Additionally, TTEG was negative in the reproductive rodent dominant lethal assay performed by Bushy Run Research Center (UCC, 1993). In the study, male rats were treated for five days with 5000, 25000 or 50000 ppm TTEG in the drinking water and subsequently mated to naïve females over ten weeks, with the females replaced weekly. Treatment produced evidence of toxicity in males at the high dose and urinary findings consistent with an osmotic diuresis at 25000 and 50000 ppm; however, no indications of subsequent reproductive or gestational effects were observed, including no significant pre-implantation loss over the ten week period. The NOEL for general toxicity was 25000 ppm.

Based on these component data, the reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-d is not expected to produce adverse effects on fertility and reproduction.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Study period:

23 January - 10 February 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable, well-documented publication which meets basic scientific principles

Justification for type of information:

Read across is based on the category approach. Please refer to attached category document.

Principles of method if other than guideline:

performed according to EPA TSCA Testing Guidelines (1985; 1987)

GLP compliance:

yes (incl. QA statement)

Remarks:

testing lab.

Limit test:

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

170 virgin male and 176 virgin female albino rats were used. All animals were quarantined for two weeks, during which time representative animals were subjected to fecal sampling, histologic examination of selected organs and to serum viral antibody examination. Rats were housed in stainless steel wire-mesh cages with food and water available ad libitum. Females and males were housed two per cage per sex during quarantine. All animals were assigned a unique number and received a stainless steel ear tag.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Timed-pregnant dams were dosed daily with undiluted test substance or vehicle alone gestation day 6 - 15. The dose volume was based on the dose group and the dam's most recent body weight. The doses employed were 0.0, 1.0, 5.0 or 10.0 ml/kg/day based on results from a dose range-finding study. Vehicle control animals were dosed with water at the top dose volume of 10.0 ml/kg.
All females on study were weight on gestation day 0, 6, 9, 12, 15 (during the dosing period) and day 18 and 21. Food and water consumption were measured at 3-day intervals throughout gestation. All females were examined daily for clinical signs of toxicity.

Analytical verification of doses or concentrations:

Details on analytical verification of doses or concentrations:

Test material was administered undiluted.

Details on mating procedure:

Rats were mated 1:1 (1 male/1 female) in stainless steel cages and the paperboard beneath the cages was checked for dropped copulation plugs. Each male was used only once in the study. Plug-positive females were housed only for the duration of the study. The day a copulation plug was found was designated gestational day 0.
25 plug-positive females were assigned to each experimental group by a randomization procedure stratified by body weight such that all groups were equivalent in both mean body weight and body weight range on gestation day 0.

Duration of treatment / exposure:

gestation days 6 - 15

Frequency of treatment:

daily

Duration of test:

21 days

No. of animals per sex per dose:

Total: 170 males, 176 females

Control animals:

yes, concurrent vehicle

Details on study design:

The doses employed were 0.0, 1.0, 5.0 or 10.0 ml/kg/day based on results from a dose range-finding study also performed on timed-pregnant rats.

Maternal examinations:

All live fetuses were weighed and sexed. All fetuses were examined for external malformations including cleft palate, and variations. All live fetuses in each litter were examined for thoraric and abdominal visceral abnormalities. One-half of the live fetuses (even-numbered fetuses from litters with an even number of live fetuses, odd-numbered fetuses from litters with an odd number of live fetuses) in each litter were decapitated and their heads were fixed in Bouin's solution for examination of craniofacial structures by sectioning methods modified from Wilson. All fetuses (50% intact, 50% decapitated) in each litter were eviscerated, fixed in ethanol, processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.
Kidneys from high dose and control dams were examined by light microscopy.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes

Fetal examinations:

All live fetuses were weighed and sexed. All fetuses were examined for external malformations including cleft palate, and variations. All live fetuses in each litter were exarnined for thorarcic and abdominal visceral abnormalities by modification of methods described by Staples (1974).
One-half of the live fetuses (even-numbered fetuses from litters with an even number of live fetuses, odd-numbered fetuses from litters with an odd number of live fetuses in each litter were decapitated and their heads were fixed in Bouin's solution for examination of craniofacial structures by sectioning methods modified from Wilson (1965; 1973). All fetuses (50% intact, 50% decapitated) in each litter were eviscerated, fixed In ethanol, processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations.

Statistics:

The unit of comparison was the pregnant female or the litter. Results of the quantitative continuous variables were intercompared for the three TEG-exposed groups and the vehicle control group by use of Levene's test for equal variances and t-tests with Bonferroni probabilities for pairwise comparisons. When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by the separate variance t-test.
Non-parametric data obtained following laparohysterectomy were statistically treated using the Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate. Incidence data were compared using Fisher's Exact Test. For all statistical tests, the probability value of p <0.05 (two tailed) was used as the critical level of significance.

Indices:

No additional information available.

Historical control data:

No additional information available.

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: Decreased maternal body weights, decreased food consumption and increased water consumption

Details on maternal toxic effects:
One female at 5.0 ml/kg/day died prior to scheduled sacrifice on g.d. 11. The cause of her death could not be determined. No females aborted. One control female delivered early (on g.d. 20) and was euthanized, and removed from study. Her data were eliminated from subsequent summarized results.

Pregnancy rate was equivalent for all dose groups, ranging from 80.0-96.0%. All litters had one or more live fetuses at scheduled sacrifice. A total of 19 to 24 litters were examined in each group.

Periodic maternal body weights were significantly reduced at 10.0 ml/kg/day on gestational days 9, 12, 15 (during treatment) and 18 (post-treatment). At 5.0 ml/kg/day maternal body weight was significantly reduced following the treatment period on g.d. 18. Body weight gains were significantly reduced at 10.0 ml/kg/day for gestational days 6-9, 6-15 (the treatment period) and 0-21 (the gestational period). Body weight gains at 1.0 and 5.0 ml/kg/day were equivalent to control values.

Clinical observations of the dams were recorded daily. There were no statistically significant treatment-related clinical signs of toxicity. However, treatment-associated clinical signs were observed in a few dams only at 10.0 ml/kg/day; these included urine stains, audible respiration, periocular encrustation and perioral wetness.

Food consumption during gestation expressed in g/dam/d was significantly reduced at 10.0 ml/kg/d for g.d. 6 -9, 9 -12 and 12 -15 and for g.d. 6-15; at 5.0 ml/kg/day, food consumption was significantly reduced for days 6-9 of the treatment period.

Increased water consumption was observed at 5.0 and 10.0 ml/kg/day for days 6-9, 9-12, 12-15 and 6-15. In addition, following treatment on days 15-18, water consumption was significantly increased at 10.0 ml/kg/day.

There were no statistically significant treatment-related necropsy findings in the dams at sacrifice on g.d. 21.

There were no treatment-related differences in maternal terminal body weight or in gravid uterine weight. However, corrected terminal body weight (body weight at sacrifice minus gravid uterine weight) and corrected body weight change (gestational weight gain minus gravid uterine weight) were significantly reduced in dams at 10.0 ml/kg/day. Liver weight (absolute and relative to corrected body weight) and absolute kidney weight were unaffected by treatment. Relative kidney weight, however, was significantly increased at 10.0 ml/kg/day. Subsequent evaluation by light microscopy of maternal kidneys from the control and 10.0 ml/kg/day dose groups revealed no treatment-related lesions.

Dose descriptor:

NOEL

Effect level:

1 other: ml/kg/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: decreased fetal weight

Details on embryotoxic / teratogenic effects:
There was no effect of treatment in the number of ovarian corpora lutea, total, viable or non-viable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (percent males). Percent preimplantation and postimplantation loss were equivalent across groups.

Fetal body weights (all fetuses, male or female) per litter were significantly reduced at 10.0 ml/kg/day (Table 1).

There were no statistical differences in the incidences of any individual malformations. However, the incidence of unilateral rudimentary rib #13 (on thoracic arch #13) at 10.0 ml/kg/day was 4.6 times that observed in control fetuses (Table 2). There were no significant differences in malformations by category (external, visceral including craniofacial or skeletal) or of total malformations among all groups. However, the total number of fetuses with skeletal malformations appeared slightly increased in the highest dose.

There were no significant differences among groups in the incidences of individual fetal external or visceral variations. A total of 95 different types of fetal skeletal variations were observed. Of these, only one bilobed thoracic centrum #10, exhibited a significantly increased incidence at 10.0 ml/kg/day when compared to the control group. There was also one statistically significant reduction in the incidence of unossified sternebra #5 at 1.0 ml/kg/day. While not statistically significant, there were apparent increases in the incidences of several other individual skeletal variations involving reduced ossification in bones of the thoracic region at 10 ml/kg/day. These included increased incidences of poorly ossified thoracic centra #10, #11, #12 and #13, bilobed thoracic centra #1 and #13, short rib #13 and callused ribs. In addition, although observed only in one fetus at 10 ml/kg/day, poorly ossified thoracic arches (#13) is an uncommon finding.

There were no treatment-related increases in the incidence of variations by category or of total variations.

Dose descriptor:

NOEL

Effect level:

5 other: ml/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

skeletal malformations

other: skeletal variations

Abnormalities:

not specified

Developmental effects observed:

not specified

Table 1

DEVELOPMENTAL TOXICITY STUDY OF TRIETHYLENE GLYCOL ADMINISTERED

BY GAVAGE TO CD (SPRAGUE-DAWLEY) RATS

SUMMARY OF GESTATIONAL PARAMETERS

	Females
group: ml/kg/day	0.0	1.0	5.0	10.0
Fetal body weights/litter (g)
All FetusesMean (S.D.)	5.280 (0.3731)	5.333 (0.2340)	5.304 (0.3977)	4.990 (0.3273)*
Male Fetuses Mean (S.D.)	5.426 (0.3681)	5.465 (0.2286)	5.433 (0.4320)	5.115 (0.3225)**
Female FetusesMean (S.D.)	5.126 (0.3864)	5.204 (0.2596)	5.173 (0.4000)	4.846 (0.3317)*

* Significantly different from control group (p <0.05)

** Significantly different from control group ( p < 0.01)

TABLE 2

DEVELOPMENTAL TOXICITV STUDY OF TRIETHVLENE GLYCOL ADMINISTERED

BY GAVAGE TO CD (SPRAGUE-DAWLEY) RATS

Summary of malformations in fetuses and litters^a

Dose Group	Fetuses				Litters
(ml/kg/day)	0	1	5	10	0	1	5	10
Number examined externally^b	325	356	281	362	22	24	19	23
Short tail	0	0	1	0	0	0	1	0

Number examined viscerallyc	325	356	281	362	22	24	19	23
lateral ventricle dilated - tissue depressed	2	0	3	1	2	0	3	1
hydronephrosis - unilateral	2	3	2	5	2	3	2	4
hydronephrosis - bilateral	4	2	1	1	3	2	1	1
hydronephrosis - unilateral	2	6	2	9	2	3	2	5
hydronephrosis - bilateral	8	8	6	18	5	5	4	3
missing testicle	0	0	1	0	0	0	1	0
situs inversus viscerum	0	0	0	1	0	0	0	1

number examined skeletally^d	325	356	281	362	22	24	19	23
lumbar arch(es) #6 - missing	3	3	2	3	2	2	2	1
lumbar arch(es) #6 - missing	3	3	2	3	2	2	2	1
rudimentary rib #13 - on thoracic arch #13 - unilateral	3	4	5	14	3	4	2	9
rudimentary rib #13 - on thoracic arch #13 - bilateral	1	2	2	4	1	1	2	3
bone island - on thoracic arch #13 - unilateral	0	0	0	2	0	0	0	2
bone island - on thoracic arch #13 - bilateral	0	0	0	1	0	0	0	1

total malformations
number with external malformations	0	0	1	0	0	0	1	0
percent with external malformations	0.0	0.0	0.4	0.0	0.0	0.0	5.3	0.0

number with soft tissue malformations	16	17	13	31	7	7	7	7
percent with soft tissue malformations	4.9	4.8	4.6	8.6	31.8	29.2	36.8	30.4

number with skeletal malformations	6	6	8	19	3	5	4	9
percent with skeletal malformations	1.8	1.7	2.8	5.2	13.6	20.8	21.1	39.1

total number with malformations	22	22	22	49	8	10	10	14
total percent with malformations	6.8	6.2	7.8	13.5	36.4	41.7	52.6	60.9

None significantly different from control (0.0 ML/KG/OAV )

a For all findings, the number (of fetuses affected or litters with one or more affected fetuses) is presented.

A single fetus may be represented more than once in listing individual defects. Only live fetuses were examined.

^bAl1 fetuses were examined external1y.

^c All fetuses were examined viscerally (Staples. 1974), and approximately 50% of each litter were examined for soft tissue craniofacial defects (Wilson, 1965; van Julsingha and Bennett, 1977).

^d All fetuses were examined for skeletal defects after staining with Alizarin Red S.

Conclusions:

Administration of triethylene glycol by gavage to timed-pregnant rats during organogenesis at 0.0, 1.0, 5.0 or 10.0 ml/kg/day resulted in maternal toxicity at 5.0 and 10.0 ml/kg/day and fetotoxicity at 10.0 ml/kg/day. There was a slight treatment-related increase in the incidence of two minor skeletal malformations at 10.0 ml/kg/day. The no observable effect level (NOEL) for maternal toxicity was 1.0 ml/kg/day, and the NOEL for developmental toxicity was 5.0 ml/kg/day.

Executive summary:

Timed-pregnant CD® (Sprague-Dawley) rats were exposed to triethylene glycol (CAS No. 112-27-6) by gavage on gestational days (gd) 6 through 15 at doses of 0.0, 1.0, 5.0 or 10.0 ml/kg/day. Twenty-five (25) plug-positive females were assigned to each group. As the test chemical was dosed "neat" (undiluted), the dose volume employed was based on the dose selected for each group and the individual animal's most recent body weight. Vehicle control animals were dosed with deionized water at a volume equivalent to the top dose volume (10.0 ml/kg/day). Clinical observations were taken daily and maternal body weights were measured on gd 0, 6, 9, 12, 15, 18 and 21. Food and water consumption were measured at three day intervals throughout gestation (gd 0-21). At scheduled sacrifice on gd 21, the dams were evaluated for body weight, liver weight, kidney (2) weight, gravid uterine weight and status of implantation sites (i.e. resorptions, dead fetuses, live fetuses). Maternal kidneys from all dose groups were retained in fixative and maternal kidneys from control and high dose dams were subsequently examined by light microscopy. Live fetuses were dissected from the uterus, counted, weighed, sexed and examined for external abnormalities. All live fetuses in each litter were examined for visceral malformations and variations. Approximately one-half of the live fetuses in each litter were then decapitated and the heads fixed in Bouin's solution; serial free hand sections of the heads were examined for soft tissue craniofacial malformations and variations. All fetuses (50% intact, 50% decapitated) in each litter were eviscerated, fixed in alcohol, stained with alizarin red S and examined for skeletal malformations and variations.

There were no treatment-related maternal deaths, No dams aborted. One control female delivered early, and was removed from study. A total of 19-24 litters were examined in each dose group. Maternal gestational body weights were significantly reduced at 10.0 ml/kg/day for days 9 through 15 of treatment and subsequent to treatment on day 18. At 5.0 ml/kg/day, body weights exhibited a significant reduction on day 18. Gestational weight gain was significantly reduced at 10.0 ml/kg/day for days 6-9, throughout the treatment period (days 6-15), and during gestation (days 0-21). Weight gains were unaffected at 1.0 and 5.0 ml/kg/day. Food consumption was significantly reduced at 10.0 ml/kg/day for days 6 through 15, and at 5.0 ml/kg/day for days 6 to 9 of the treatment period. Water consumption was significantly increased at 10.0 ml/kg/day during treatment (days 6-9, 9-12, 12-15 and 6-15) and immediately following treatment on days 15-18. Water consumption was increased at 5.0 ml/kg/day for days 6-9, 9-12, 12-15 and 6-15 (the entire treatment period). Treatment-related clinical signs were observed only at 10.0 ml/kg/day and included audible respiration, urine stains, periocular encrustation and perioral wetness. At the gd 21 sacrifice, maternal body weight (corrected for gravid uterine weight) and gestational weight gain (corrected) were reduced at 10.0 ml/kg/day. Relative (but not absolute) kidney weights were significantly increased at 10.0 ml/kg/day. Gestational parameters, including number of ovarian corpora lutea, total, viable and nonviable implantations per litter, and sex ratio were unaffected by treatment. Fetal body weights per litter (all fetuses, males and females) were significantly reduced at 10.0 ml/kg/day.

While there were no significant increases in the incidences of individual or pooled external, visceral or skeletal malformations, or of total malformations in any treatment group, two (2) skeletal malformations, rudimentary rib #13 and bone island (rather than rib) on thoracic arch #13 were slightly increased at 10.0 ml/kg/day. There were no treatment-related differences among groups for individual external or visceral variations or for pooled or total variations. However, the incidence of one skeletal variation, bilobed thoracic centrum #13, was statistically increased at 10.0 ml/kg/day. In addition, there were nine (9) skeletal variations which involved ossification of bones in the thoracic region which were slightly (but not significantly) increased and were suggestive of minimal fetotoxicity at 10.0 ml/kg/day.

In conclusion, exposure of pregnant CD® (Sprague-Dawley) rats to triethylene glycol by gavage at 1.0, 5.0 and 10.0 ml/kg/day during organogenesis resulted in significant maternal effects at 5.0 and 10.0 ml/kg/day and consistent evidence of fetotoxicity at 10.0 ml/kg/day. No biologically significant embryotoxicity or teratogenicity was observed at any dosage employed, including those which produced maternal effects. The "no observable effect level" (NOEL) for maternal toxicity was 1.0 ml/kg/day, and the NOEL for developmental toxicity was 5.0 ml/kg/day.

Effect on developmental toxicity: via oral route

Dose descriptor:: NOAEL
: 5 630 mg/kg bw/day
Study duration:: subacute
Species:: rat
Quality of whole database:: Developmental toxicity studies are available for TEG, a component of the reaction mass.

Additional information

In the key study by Bushy Run Research Center (UCC, 1991; Ballantyne and Snellings 2005b), developmental toxicity was assessed rats exposed to TEG. Sprague-Dawley rats received doses of 1, 5, and 10 ml/kg TEG by oral gavage (equivalent to 1126, 5630, and 11260 mg/kg bw/day) on gestation days 6 through 15. Maternal toxicity was characterized by body weight reductions at 5 and 10 ml/kg/day, decreased body weight gain at 10 ml/kg/day, treatment associated clinical signs at 10 ml/kg/day, reduced food consumption at 5 and 10 ml/kg/day, increased water consumption at 5 and 10 ml/kg/day, and increased relative kidney weight with no correlated histopathologic changes at 10 ml/kg/day. Fetal body weights were reduced at 10 ml/kg/day and treatment-related reduced ossification of the thoracic region was observed at this dose level. The NOEL for maternal toxicity was 1 ml/kg/day (1100 mg/kg/day) and the NOEL for developmental toxicity was 5 ml/kg/day (5630 mg/kg/day).

In a supporting study, CD-1 mice received doses of 0.5, 5, and 10 ml/kg/day by oral gavage (equivalent to 563, 5630, and 11260 mg/kg bw/day) on days 6 through 15 of gestation (Bushy Run Research Center, 1990; Ballantyne and Snellings 2005b; Dow 2015). Clinical signs observed at 10 ml/kg/day included hypoactivity and audible and rapid respiration. A treatment related decrease in body weight gain was observed at the 10 ml/kg/day dose level and a treatment related decrease in body weight gain corrected for gravid uterine weight was observed at 5 and 10 ml/kg/day dose levels (Dow, 2015). Water consumption was increased at the mid and high dose (Dow, 2015). Relative kidney weight was significantly increased at 10.0 ml/kg/day, but no histopathologic changes were observed (BRRC, 1990). Decreased fetal weight and delayed bone ossification observed at 5 and 10 ml/kg/day represent a fetal developmental delay secondary to maternal toxicity (BRRC, 1990). The NOEL for both maternal toxicity and developmental toxicity was 0.5 ml/kg/day (563 mg/kg/day) (Dow, 2015).

Adverse developmental effects related to gestational exposure to TEG predominantly consisted of decreased fetal weight and related delays in skeletal ossification in rodents. These effects were found secondary to maternal toxicity and in all cases were observed at doses exceeding the current guideline limit dose for developmental toxicity studies. Delayed ossification is not considered adverse as these variations would be fully expected to ossify postnatally and would have no impact on the viability or function of the offspring (Carney and Kimmel, 2007; Marr et al., 1992). Pup weights would also be expected to reach the control levels postnatally (Marr et al., 1992). Because adverse reproductive effects are expected to decrease with increasing number of oxyethylene repeat units, similarly low potential for developmental toxicity is expected for TTEG and pentaethylene glycol. Based on these data, the reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-diol is not expected to produce adverse effects on development.

Justification for classification or non-classification

Reproductive Toxicity

The NOAEL for reproductive toxicity is based on the murine continuous breeding study for TEG, the shortest component of this reaction mass. The lack of findings for TEG, as well as absence of changes in reproductive organs in repeated dose studies with TTEG, supports conclusion of low potential of reproductive toxicity and effect on fertility across this class of compounds.

Developmental Toxicity

Adverse reproductive effects are expected to decrease with increasing number of oxyethylene repeat units per molecule in rodents only. These effects seen with TEG were secondary to maternal toxicity and at doses exceeding current limit dose for guideline developmental toxicity studies. Therefore, the NOAEL for developmental toxicity of reaction mass of 2,2'-(ethylenedioxy)diethanol and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol and 3,6,9,12-tetraoxatetradecane-1,14-diol is based on the rat NOAEL for triethylene glycol.

Additional information

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	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)*

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

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