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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Developmental toxicity studies conduced in rodents with lower category members, diethylene glycol and triethylene glycol, did not result in reproductive toxicity.

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:

Acceptable

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Acceptable

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the 2-generation key study, a Fertility Assessment by Continuous Breeding study (National Toxicology Program, 1984), diethylene glycol (DEG) was administered via the drinking water to 40 male and 40 female mice at concentrations of 0, 0.35, 1.75, and 3.5% (equivalent to approximately 0, 612, 3063, and 6125 mg/kg/day) for 7 days premating, a 98 day cohabitation period, and 21 days after cohabitation (study Task 2). Task 3 was performed by cross-mating the control and high dose Task 2 parental animals. In Task 4, the control and mid-dose offspring from the final Task 2 litters were mated. Exposure to DEG at levels up to 3.5% produced no significant adverse effects on fertility in Tasks 2, 3, or 4. Results from the Task 2 litter analyses show the high dose group to have a significantly decreased number of litters, with decreased litter size and adjusted pup weight. No significant differences were observed in the low or mid-dose groups. In Task 3, the only significant result observed in the litter analysis was a decrease in mean pup weight in the control male-high dose female breeding group. At necropsy, body weight in high dose females was decreased by 7% (p<0.01). No significant differences in adjusted organ weights were found for either sex. In Task 4, no significant effects were observed in fertility or litter analysis. Body weight at necropsy was significantly decreased in the mid-dose group of both sexes. Relative to controls, mid-dose males weighed 11% less and mid-dose females weighed 7% less. Mid-dose males were found to have significantly increased (by 11%) liver weights. There were no significant changes in female organ weights. No effect on any of the sperm parameters was observed in Task 3 or 4.The NOAEL for fertility and reproductive toxicity was 3063 mg/kg/day.

In 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.

Justification for selection of reproductive toxicity – oral route
The NOAEL for reproductive toxicity is based on the murine continuous breeding study for TEG, the closest ethylene glycol component in this category. Although direct reproductive toxicity data are not available for TTEG, the lack of findings with the lower ethylene glycols supports conclusion of low potential of reproductive toxicity and effect on fertility across this class of compounds.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5 630 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Very good.

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 key developmental toxicity study by Bushy Run Research Center (1991; Ballantyne and Snellings 2005b), 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).

Developmental toxicity of TEG has also been assessed in mice. 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).

In a supporting developmental toxicity study by Hellwig et al. (1995), Himalayan rabbits were exposed to nominal concentrations of 100, 400, and 1000 mg/kg bw/day diethylene glycol (DEG) by oral gavage on gestation days 7 through 19. No adverse effects attributed to DEG exposure were observed in does or fetuses. Any observed differences between dose groups were without a clear dose response relationship or were within historical control values and, therefore, determined not biologically relevant. The NOAEL for maternal toxicity, embryotoxicity and fetotoxicity were the high dose of 1000 mg/kg bw/day. This is the key study because rabbits are considered the most relevant species for hazard assessment of this chemistry.

 

Adverse developmental effects related to gestational exposure to DEG and 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 tetraethylene glycol (TTEG). No effects on the development were seen in rabbit with DEG, the most relevant species for human hazard assessment for this chemistry. Therefore, based on the category members, TTEG is not expected to produce adverse effects on development.

 

Justification for selection of developmental toxicity – oral route
Adverse reproductive effects are expected to decrease with increasing number of oxyethylene repeat units per molecule in rodents only. These effects seen in the lower ethylene glycols (DEG, TEG) were seen secondary to maternal toxicity and at doses exceeding current limit dose for guideline developmental toxicity studies. The dose descriptor for TTEG is based on data from the closest ethylene glycol category member.

Toxicity to reproduction: other studies

Additional information

Developmental toxicity studies of category members, diethylene glycol and triethylene glycol, in rodents have also been conducted. High doses that resulted in maternal toxicity did not produce developmental toxicity to fetuses.

Justification for classification or non-classification

Classification according to GHS and the Directive 67/548/EEC (DSD) regarding reproductive toxicity and developmental toxicity/teratogenicity is not warranted.