Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
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
Report date:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Details on test material:
purity: 99.6 %

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

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. 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).
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 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.
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

Examinations

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 animais after their delivery, the affected animais were, if lt was deemed necessary, examined additionatly 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.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
salivation, unsteady gait
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
chronic nephropathy in males of the high dose group
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
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
Sex:
male/female
Basis for effect level:
other: general toxicity
Remarks on result:
other: Generation: F0 and F1 (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this 2-generation reproduction toxicity study there were no indications 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. 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 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).
Executive summary:

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). 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 (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. The NOAEL for pre- and postnatal developmental toxicity (growth and development of the offspring) is 1,000 mg/kg body weight/day.