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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14. April - 17 May 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well performed and reported guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
15 pregnant animals, 1/2 of foetuses examined for soft tissue and skeletal examinations
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity > 99%

Test animals

Species:
rabbit
Strain:
other: Hoe: HIMK (SPF Wiga)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Pharma Forschung Toxikologie
- Age at study initiation: approx. 7 months
- Weight at study initiation: 2627 +/- 199 g
- Housing:single in wire cages
- Diet (e.g. ad libitum): ERKA Z 600 pellets ad libitum
- Water (e.g. ad libitum): Community tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 2 °C
- Humidity (%): 35 - 58 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 14.04.1986 To: 17.05.1986

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: Air
Details on exposure:
Exposure period: days 6 – 18 of gestation
Recovery period: 10 days
Control group: Yes, concurrent to treatment (air)
Method: OECD 412 and 414 (OECD 1981)
15 pregnant females were used per group (whole body exposure).

Ethylene glycol dimethyl ether was applied to a vaporizer and continuously evaporated at 80°C. The resulting test substance/air mixture was carried to the inhalation chambers (2.25 m3) using an air stream of 800 L/h. The Ethylene glycol dimethyl ether concentration was determined by a Miran 80 photometer every 30 min. CO, CO2 (Uras 2 T Infrared-Gasanalysator) and O2 concentration (Magnos 3 magnetic Oxygen-Analysator) as well as humidity (Transmitter HMT 12) and temperature (CMR-Meßumformer TEU 320) were determined continuously.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Please refer to "Details on exposure"
Details on mating procedure:
Females were housed with sexually mature males. The females were removed and housed individually if the daily vaginal smear was sperm positive.
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
daily
Duration of test:
Duration of exposure period: Days 6 -18 of gestation
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5 ppm (0.019 mg/L)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
16 ppm (0.06 mg/L)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
50 ppm (0.187 mg/L)
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were observed for mortality and clinical symptoms daily during treatment and the recovery period. Body weights and food consumption were determined weekly. The rabbits were sacrificed 10 days (29 days post copulationem) after the last treatment. Post mortem examination included uterine contents, uterus weight, number of resorptions and corpora lutea. Foetuses were removed by Caesarean section, weighed and examined for gross external abnormalities. After incubation at 32°C for 24 hours, the viability of the foetuses was determined. Foetuses were sacrificed and sexed. One half of all foetuses and all foetuses that were found dead in the uterus were fixed and stained with Alizerinred S for skeletal examination. The remaining foetuses were fixed in Bouin´s fixative and examined by a combination of serial sections of the body. The dams were subjected to a macroscopical examination. Heart, spleen, liver and kidneys were weighed.

Examinations

Maternal examinations:
Mortality, clinical signs, body weight, food consumption, macroscopical examination, weight of heart, spleen, liver and kidneys
For details please refer to "Further details on study design"
Ovaries and uterine content:
Examination of uterine contents, uterus weight, number of resorptions and corpora lutea
Fetal examinations:
viability, sex determination, skeletal examination and examination of the soft tissue
For details please refer to "Further details on study design"
Statistics:
included
Indices:
no data
Historical control data:
included

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality/Viability:
All animals survived. With the exception of one abortion in the 16 ppm dose group no serious clinical signs were noted at any dose level. The urine of one rabbit at the 16 ppm level was stained red on day 9 of gestation.

Body weight (dams):
Body weight gain of all animals in the 0, 5 and 16 ppm dose group was not affected. During the first week of treatment the body weight of the animals of the 50 ppm dose group was decreased. Within the second week of treatment this effect disappeared.

Food consumption (dams):
There were no effects upon the mean daily food consumption observed at the 5 ppm dose level. The food consumption of the animals of the 50 ppm and 16 ppm dose level was slightly decreased during the exposure period. The effect diminished after the last treatment.

Organ weights (dams):
The organ weights were within the control range.

Macroscopic/microscopic findings (dams):
No changes occurred at any dose level with the exception of one abortion in the 16 ppm dose group. Grey areas on the kidney surface were found in one control animal, 4 animals of the 5 ppm dose group, 2 animals of 16 ppm dose group and 1 animal of the high dose group.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEC
Effect level:
0.019 mg/L air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
0.06 mg/L air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEC
Effect level:
0.06 mg/L air
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Examination of litters:
There was no effect on foetal development and body weight observed at any dose level. Sex ratio was regular. The vitality of the litters within the first 24 hours after Caesarean section at 50 ppm exposure was considerably decreased.

Skeletal examination (foetuses):
One foetus of the control group had an abnormal orientation of the fore-paws and an umbilical hernia. In the 5 ppm dose group 3 foetuses with skull malformations were found. One foetus of the 16 ppm dose level showed a retarded skeletal development and multiple malformations of skull, spine and extremity (left fore-paw almost completely missing). In the 50 ppm dose group 10 foetuses had an abnormal orientation of one or both fore-paws. Two foetuses showed skull malformations. Irregularity of the skull ossification was observed in 2 foetuses of the control group, 1 foetus of the 5 ppm dose group, 3 foetuses of the 16 ppm group and 8 foetuses of the high dose group. There was an increased incidence of rib anomalies combined with an increased dosage (statistically significant). The skeletal development of viable foetuses was not affected by treatment compared to the control group.

Soft tissue examination (foetuses):
Cases of lung anomalies and blood within the chest were present in all groups. Enlarged stomachs were observed in the 16 ppm and 50 ppm dose groups as well as in the control group. 2 foetuses of the high dose group had red-bordered spots on the skin (mandible, neck and below the eyes).

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the slightly decreased food consumption of female rabbits exposed to 16 ppm and the decreased viability of foetuses within the first 24 hours after caesarean section and and anomalies, the NOEC (maternal) is considered to be 5 ppm (0.019 mg/L) and the NOEC (developmental) was set at 16 ppm (0.06 mg/L). The maternal NOAEC is considered to be 16 ppm (0.06 mg/L).
Executive summary:

A develpomental inhalation toxicity study was performed in pregnant rabbits. The animals were exposed to an Ethylene glycol dimethal ether atmosphere of 0, 5 (0.019 mg/L), 16 (0.06 mg/L) and 50 ppm (0.187 mg/L) on gestations days 6 to 18.

Maternal observations:

All animals survived. With the exception of one abortion in the 16 ppm dose group no serious clinical signs were noted at any dose level. The urine of one rabbit at the 16 ppm level was stained red on day 9 of gestation. Body weight gain of all animals in the 0, 5 and 16 ppm dose group was not affected. During the first week of treatment the body weight of the animals of the 50 ppm dose group was decreased. Within the second week of treatment this effect disappeared. There were no effects upon the mean daily food consumption observed at the 5 ppm dose level. The food consumption of the animals of the 50 ppm and 16 ppm dose level was slightly decreased during the exposure period. The effect diminished after the last treatment. The organ weights were within the control range. No changes occurred at any dose level with the exception of one abortion in the 16 ppm dose group. Grey areas on the kidney surface were found in one control animal, 4 animals of the 5 ppm dose group, 2 animals of 16 ppm dose group and 1 animal of the high dose group.

Litter examinations:

There was no effect on foetal development and body weight observed at any dose level. Sex ratio was regular. The vitality of the litters within the first 24 hours after Caesarean section at 50 ppm exposure was considerably decreased. One foetus of the control group had an abnormal orientation of the fore-paws and an umbilical hernia. In the 5 ppm dose group 3 foetuses with skull malformations were found. One foetus of the 16 ppm dose level showed a retarded skeletal development and multiple malformations of skull, spine and extremity (left fore-paw almost completely missing). In the 50 ppm dose group 10 foetuses had an abnormal orientation of one or both fore-paws. Two foetuses showed skull malformations. Irregularity of the skull ossification was observed in 2 foetuses of the control group, 1 foetus of the 5 ppm dose group, 3 foetuses of the 16 ppm group and 8 foetuses of the high dose group. There was an increased incidence of rib anomalies combined with an increased dosage (statistically significant). The skeletal development of viable foetuses was not affected by treatment compared to the control group. Cases of lung anomalies and blood within the chest were present in all groups. Enlarged stomachs were observed in the 16 ppm and 50 ppm dose groups as well as in the control group. 2 foetuses of the high dose group had red-bordered spots on the skin (mandible, neck and below the eyes).