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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-12-12 to 2011-10-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientifically well performed study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
3 animals per dose group; no histopathology
Principles of method if other than guideline:
The study was performed for the purpose of read-across justification. 3 males and 3 females were used per group.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bis(2-(2-methoxyethoxy)ethyl) ether
EC Number:
205-594-7
EC Name:
Bis(2-(2-methoxyethoxy)ethyl) ether
Cas Number:
143-24-8
Molecular formula:
C10H22O5
IUPAC Name:
2,5,8,11,14-pentaoxapentadecane

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
54 days for females; 28 days for males
Frequency of treatment:
daily
Details on study schedule:
- Age at mating of the mated animals in the study: 11-12 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
actual ingested
0; 250 (LD); 500 (MD); 1000 (HD) mg/kg bw
No. of animals per sex per dose:
3
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice a day except during weekend and holidays where observations were made only once
- Pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity, including mortality were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: males were weighed weekly during the entire study period and at termination. Females were weighed weekly during pre
mating period, on gestation day 0, 7, 14, 20 and on PND 0 (within 24 hours of parturition) and 4 along with pups.

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food consumption was measured on corresponding day of body weight after beginning of the dose administration. Food consumption was not measured during mating period.
Litter observations:
The duration of gestation was recorded and is calculated from day 0 of pregnancy.
Each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities.
Live pups were counted and sexed and litters weighed within 24 hours of parturition (day 0 post-partum) and on day 4 post-partum. Live pups were identified by writing actual numbers on the back with the help of permanent marker In addition to the observations on parent animals, any abnormal behaviour of the spring was recorded.
Postmortem examinations (parental animals):
SACRIFICE
- Males from control, low and mid dose were sacrificed after the completion of mating period (minimum total dosing of 28 days) and females were sacrificed on
respective post natal day 4 along with pups by using high dose of sodium pentobarbital
- Surviving male and female animals from high dose group were sacrificed on treatment day 19 after 9 day recovery period

GROSS NECROPSY
- adult animals were examined macroscopically for any abnormalities or pathological changes. Special attention was paid to the organs of the reproductive system.

- The number of implantation sites and corpora lutea was recorded in all pregnant females.

HISTOPATHOLOGY / ORGAN WEIGHTS
- The testes, epididymides, prostate, seminal vesicles with coagulating gland of all male adult animals and ovaries, uterus with cervix of all female adult animals were weighed.
- Paired organs were weighed separately. Organs of found dead animals were not weighed.
Postmortem examinations (offspring):
- Dead pups and pups killed at day 4 post-partum were carefully examined for grossabnormalities.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
no significant toxicity
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
at 1000 mg/kg bw for females during the pregnancy
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
at 1000 mg/kg bw for females during the pregnancy
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: gavage application

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
gestation period prolonged for animals of 500 and 1000 mg/kg bw

Details on results (P0)


Parental toxicity in males: Upon clinical observation no significant toxic effect was found. The body weight was comparable for treated and control animals. No clear alteration could be identified upon hematology and clinical biochemistry investigations. All males of 1000 mg/kg bw exhibited reduced organ weight for testes (mean value reduced to 60% of controls) and epididymides (mean value reduced to 70% of controls).

Parental toxicity in females: Upon clinical observation no significant toxic effect was found. No body weight effect was found for the premating period. The body weight gain was reduced to 30% of the control value for animals of 1000 mg/kg bw during the gestation period. No obvious effect was found for animals of 500 mg/kg bw and 250 mg/kg bw. The body weight gain in the lactation phase was reduced dose dependently for all treated animals. No clear alteration could be identified for hematology and clinical biochemistry. No clear effect was found for ovary and uterus weights.


Effect levels (P0)

open allclose all
Dose descriptor:
dose level:
Effect level:
1 000
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Male exhibited reduced testes and epididymides
Dose descriptor:
dose level:
Effect level:
>= 500 - <= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: females exhibited prolonged gestation period

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
no live pubs at 1000 mg/kg bw; reduced number of live pubs at 500 mg/kg bw
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Effect levels (F1)

Dose descriptor:
dose level:
Generation:
F1
Effect level:
>= 500 - < 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no live pubts at 1000 mg/kg bw and reduced number of live pubs at 500 mg/kg bw

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Pre and postnatal data: At 1000 mg/kg bw no live pubs were delivered. At 500 mg/kg bw the number of live pubs per litter were reduced compared to the controls (8 vs 11). No effect was found for the dose level of 250 mg/kg bw. The body weight development of live born pubs was comparable for treated and control animals.

Conclusion: The test substance at dose levels 500 mg/kg bw and above induced clear toxic effects on the reproduction performance. At dose level of 1000 mg/kg bw no live pubs were born. At dose levels of 500 the number of live born pubs was reduced.

Applicant's summary and conclusion

Conclusions:
The reproduction toxicity of tetraglyme was investigated according to OECD 421 with deviations of using limited number of animals. Tetraglyme induced reproduction toxicity in dose levels not associated with apparent parental toxicity and should be classified as reprotoxic category 3, R62.
Executive summary:

3 males and 3 females per dose groups were treated according to Guideline 421, the dose levels being 250, 500 and 1000 mg/kg bw.

At 1000 mg/kg bw no live pubs and at 500 mg/kg bw reduced number of live pubs were found. In males testes and epididymides were remarkably reduced. The reported study demonstrate clearly that tetraglyme induces toxicity on male reproduction system and reproduction performance.

The reported study is to be used as bridging study to justify the read-across approach for the hazard assessment of tetraglyme. Since the proposed source substances were found to be reprotoxicants, similar toxicity was expected for tetraglyme. The obtained study result confirms tetraglyme as a reprotoxicant, thereby supporting the proposed read-across approach.

Further, the study itself qualifies to be used as key study for regulatory purposes (classification and labelling). In the reported study, it could be clearly demonstrated that tetraglyme induced toxicity on male reproduction organs and reproduction performance. The reduced number of animals used in this study or the non-GLP status is of less relevance, because the same results can be expected for a regular OECD 421 study. The obtained study result is sufficient to classify tetraglyme as reprotoxicant: reprotoxic category 3, R62.