Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No studies available.
Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study. For justification of read across see endpoint summary.
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
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. If 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).
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.
Duration of treatment / exposure:
F0: 20 weeks
F1: 19 weeks
Frequency of treatment:
once a day
Details on study schedule:
F0 generation animals and their progeny

The 100 male and 100 female animals required for the study were 35 (± 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 animals 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 animals 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 animals, 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.
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
Parental animals: Observations and examinations:
mortality; littering and lactation behavior; food consumption; body weight data
Oestrous cyclicity (parental animals):
Estrous cycle length and normality were evaluated daily for all F0 and F1 female parental rats for a minimum of 3 weeks prior to mating and were continued throughout the mating period until the female exhibited evidence of mating. Moreover, at necropsy a vaginal smear was examined to determine the stage of the estrous cycle for each F0 and FI female with scheduled sacrifice.
Sperm parameters (parental animals):
sperm motility, sperm morphology, sperm head count (cauda epididymis), sperm head count (testis)
(Sperm morphology and sperm head count (cauda epididymis and testis) were evaluated for the control and highest dose group, only)
Litter observations:
pup number and status at delivery, pup viability/mortality, sex ratio, pup clinical observations, pup body weight data, pup organ weights
Postmortem examinations (offspring):
All pups with scheduled sacrifice (i.e. pups, which were culled on day 4 p.p., and pups, which were sacrificed on day 21 after birth or subsequent days) were killed by means of CO2. These pups were examined externally and eviscerated; their organs were assessed macroscopically. All stillborn pups and all pups that died up to weaning were examined externally, eviscerated and their organs were assessed macroscopically. If there were notable findings or if abnormalities were found in the daily clinical observation of the animals after their delivery, the affected animals were, if it was deemed necessary, examined additionally using appropriate methods (e.g., skeletal staining according to a modified method of KIMMEL and TRAMMELL (Kimmel, C.A. and Trammell C., 1981)).
The stained skeletons were evaluated under a stereomicroscope or a magnifying glass. All pups without any notable findings or abnormalities were discarded after their macroscopic evaluation.
Under the conditions of this 2-generation reproduction toxicity study there were no indications from the clinical examinations, sperm evaluations and gross and histopathology, that the administration of Triethylenglykoldivinylether adversely affected reproductive performance or fertility of the F0 or F1 parental animals up to and including a dose of 1,000 mg/kg body weight/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were not affected by the test substance administration. 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).
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility and reproductive performance
Remarks on result:
other: Generation: F0 and F1 (migrated information)
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: Generation: F1 and F2 (migrated information)
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general toxicity
Remarks on result:
other: Generation: F0 and F1 (migrated information)
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.
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and Guideline study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

For reproduction toxicity (fertility) no data for the test substance 1,1'-[oxybis(ethyleneoxy)]diethylene is available. To address this endpoint, read across to the structural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. For justification of read-across, please see section on repeated dose toxicity.

The structural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) of the test item 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 (OECD 416; BASF 73R0162/03041). There were no indications from the clinical examinations, sperm evaluations and gross and histopathology, that the administration adversely affected reproductive performance or fertility of the F0 or F1 parental animals up to and including a dose of 1,000 mg/kg body weight/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were not affected by the test substance administration. 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). Thus, the NOAEL (no observed adverse effect level) for fertility and reproductive performance 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.

Short description of key information:
Read across to the stuctural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. In a 2-generation reprodution toxicity study with rats (OECD 416) a NOAEL of 1000 mg/kg bw/day was derived for effects on fertility.

Justification for selection of Effect on fertility via oral route:
The Key study was selected (GLP and Guideline study).

Effects on developmental toxicity

Description of key information
Read across to the stuctural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. In a 2-generation reprodution toxicity study with rats (OECD 416) a NOAEL of 1000 mg/kg bw/day was derived for effects on development.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study. For justification of read across see endpoint summary.
Qualifier:
according to
Guideline:
other: OECD 416 (2-generation reproduction toxicity study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
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 °C 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. lf 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
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 animals required for the study were 35 (± 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 animals 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 animals continuously received the test substance at the appropriated doses of 0; 100; 300 or 1,000 mg/kg body weight / day 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 animals, 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.
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.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and Guideline study
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
For reproduction toxicity (development) no data for the test substance 1,1'-[oxybis(ethyleneoxy)]diethylene is available. To address this endpoint, read across to the structural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. For justification of read-across, please see section on repeated dose toxicity. The structural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) of the test item 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 (OECD 416; BASF 73R0162/03041). 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.

Justification for selection of Effect on developmental toxicity: via oral route:
The Key study was selected (GLP and Guideline study).

Justification for classification or non-classification

Based on the well-conducted 2 -generation reproduction toxicity study, classification for reproductive toxicity is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008.