3,6,9,12-Tetraoxatetradeca-1,13-diene

Developmental toxicity / teratogenicity

Administrative data

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; guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 416 (2-generation reproduction toxicity study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

purity: 99.6 %

Test animals

Species:

rat

Strain:

Wistar

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses mentioned were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology, BASF Aktiengesellschaft, Germany. Analytical verifications of the stability of the test substance in doubly distilled water for a period of 8 days deep frozen at -20 0C were carried out before the study was initiated.

Details on mating procedure:

In general, each of the male and female animals (F0 and F1 generation) was mated overnight at a 1 : 1 ratio for a maximum of 2 weeks. Generally, throughout the mating period, each female animal was paired with a predetermined male animal from the same dose group. Matings occurred by placing the female in the cage of the male mating partner from about 4.00 p.m. until 7.00 - 9.00 a.m. of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data.
A vaginal smear was prepared after each mating and examined for sperm. lt sperm was detected, pairing of the animals was discontinued. The day on which sperm were detected was denoted "day 0" and the following day "day 1" p.c. (post coitum).

Duration of treatment / exposure:

F0: 20 weeks
F1: 19 weeks

Frequency of treatment:

once a day

Doses / concentrations

Remarks:

Doses / Concentrations:
0; 100; 300 and 1000 mg/kg body weight/day
Basis:
nominal conc.

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

F0 generation animals and their progeny

The 100 male and 100 female animais required for the study were 35 (j± 1) days old at the
beginning of treatment, and their mean weights and weight ranges were:
-male animals: 117.0 (101.2 - 135.9) g
-female animals: 93.4 ( 79.8 - 105.7) g
The assignment of the animais to the different test groups was carried out using a randomization program, according to their weight four days before the beginning of the administration period (day -4).
After the acclimatization period, the F0 generation parental animais continuously received the test substance at the appropriated doses of 0; 100; 300 or 1,000 mg/kg body weightlday orally (by gavage) once a day always at approximately the same time of day (in the morning) until one day before they were sacrificed. The calculation of the volume administered was based on the last individual body weight. At least 75 days after the beginning of treatment, males and females from the same dose group were generally mated at a ratio of 1 : 1. The females were allowed to litter and rear their pups (F1 generation pups) until day 4 (standardization) or 21 after parturition. After weaning of F1 pups the F0 generation parental animals were sacrificed.

F1 generation parental animals and their progeny

After weaning, 25 males and 25 females of the F1 pups of test groups 00, 01, 02, and 03 (0; 100; 300 and 1,000 mg/kg bw/day) were taken per group as the basis of the F1 generation parental animals. These animals were chosen by lot during rearing; it was attempted to take each litter into account. If fewer than 25 litters in these groups were available for selection or if one sex was missing in a litter, more animals were taken from different litters from the relevant test group to give the full number. All selected animals were treated with the test substance at the same dose level as their parents from their growth into adulthood up to about one day before they were sacrificed. At least 75 days after assignment of the F1 generation parental animais, the males and females were mated at a ratio of 1 :1. The partners were randomly assigned to one another. Matings between siblings were, however, avoided. The females were allowed to litter and rear their pups (F2 generation pups) until day 4 (standardization) or 21 after parturition. The F1 generation parental animals were sacrificed after the F2 generation pups had been weaned.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: unsteady gait and/or abdominal position; transient salivation; relative kidney weights were statistically significant increased in high dose F0 and F1 males (increased incidence of chronic progressive nephropathy); increased mean liver weights

Details on maternal toxic effects:
The clinical examinations of the F0 and F1 parental rats for general signs of toxicity revealed some substance-related effects at the high dose (1,000 mg/kg bw/d). These were substantiated by unsteady gait and/or abdominal position, which occurred intermittently in several, but not all top dose rats shortly after gavage dosing and persisted only for some minutes. Moreover, all male and nearly all female F0 and F1 parental animals of the high dose group (1,000 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals only for some minutes after daily gavage dosing. Regarding pathology, kidneys and liver proved to be the target organs in both genders of the two parental generations at the top dose (1,000 mg/kg body weight/day). The absolute and relative kidney weights were statistically significant increased in high dose F0 and F1 males and showed corroborative histopathological findings (i.e. increased incidence of chronic progressive nephropathy). The mean liver weights were statistically significantly increased in high dose F0 males (relative) and in the top dose F1 males and F1 females (absolute and relative). The increased liver weights correlated with a minimal centrolobular hypertrophy of hepatocytes that was noted in seven high dose F1 males (controls: one F1 male). Although there was no histopathological correlate for the F0 males and F1 females at 1,000 mg/kg, the increased liver weights of these rats are also considered as substance related.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No test substance induced signs of developmental toxicity occurred in the progeny of the F0 or F1 parents up to and including 1,000 mg/kg body weight/day (highest dose tested).

Executive summary:

Triethylenglycoldivinylether was orally administered in a 2-generation reproduction toxicity study to groups of 25 male and 25 female Wistar rats at dosages of 0; 100; 300 and 1,000 mg/kg bw/day. The examinations of the F0 and F1 parental rats for general signs of toxicity revealed some substance-related effects at the high dose (1,000 mg/kg body weight/day). These were substantiated by unsteady gait and/or abdominal position, which occurred intermittently in several, but not all top dose rats shortly after gavage dosing and persisted only for some minutes. Moreover, absolute and relative kidney weights were statistically significantly increased in high dose F0 and F1 males and showed corroborative histopathological findings (i.e. increased incidence of chronic progressive nephropathy). No test substance induced signs of developmental toxicity occurred in the progeny of the F0 or F1 parents up to and including 1,000 mg/kg body weight/day. The test substance did not influence the number of delivered F1 and F2 pups/litter, the sex ratio, the postnatal survival, the pup body weights or the sexual maturation of the F1 progeny. Clinical and/or gross necropsy examinations of the F1 and F2 pups revealed only findings that were considered to be spontaneous in nature, due to their scattered occurrence without any relation to dose. Thus, the NOAEL for pre- and postnatal developmental toxicity (growth and development of the offspring) is 1,000 mg/kg body weight/day. The NOAEL for overall general toxicity on the parental rats could be fixed at 300 mg/kg body weight/day.