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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:
1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to a guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Ethoxypropanol
- Physical state: Liquid
- Analytical purity: 93%
- Impurities (identity and concentrations): 7% 2-ethoxy-1-propanol
- Lot/batch No.: GOHC Sample No. 957
- Stability under test conditions: In a companion 90-day inhalation study conducted by Huntingdon Research Centre, similar samples of ethoxypropanol analyzed throughout the 90-day study period by GC-MS and IR spectroscopy gave similar results. HRC Report No. BPC 46 / 851294
- Storage condition of test material: Ambient conditions. Drum was flushed with nitrogen when aliquots were removed for use.

Test animals

Species:
rat
Strain:
other: CrL: COBS CD (SD) BR Strain
Details on test animals and environmental conditions:
Time mated animals were ordered from the supplier. Animals were individually identified by a number tattooed on the ear.

TEST ANIMALS
- Source: Charles River UK Limited, Margate, England
- Age at study initiation: Eight to nine weeks
- Weight at study initiation: 153 – 228 g
- Housing: Five animals per cage in suspended polypropylene cages with stainless steel mesh floors and tops.
- Diet: Ad libitum access to Labsure Laboratory Diet No. 1 (LAD 1)
- Water: Ad libitum access to tap water from polypropylene bottles

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Animal holding room: 18.5 – 23 degrees C
- Humidity (%): Animal holding room: 45 – 64 % relative humidity

IN-LIFE DATES: From: To:
Between 18 September and 8 October, 1985

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The vapour was produced by metering the liquid to a stainless steel concentric jet atomizer and passing the aerosol into a glass column in which it evaporated. To facilitate vaporisation, at the high dose air to the atomizer was passed through a water bath maintained at 75 degrees C. The vapour passed through the vertical glass column into the chamber inlet duct.
The exposure chambers were constructed from stainless steel and glass and were approximately 500 liters internal volume. The chambers were of square cross section and fitted with a squat pyramidal base and top. An H-shaped extraction plenum was fitted in the base of the chambers.
Each chamber was fitted with ports for withdrawal of chamber air samples.

- Method of holding animals in test chamber: During exposures the rats were housed in individual compartments of stainless steel wire mesh cages, which were supported on two mesh shelves.
- Source and rate of air: Dry, oil-free, compressed air was passed to the annulus of the atomizer tip at a pressure of 40-50 psi. This produced a flow to the atomizer tip of approximately 10 liters per minute.
- Temperature, humidity, pressure in air chamber: Chamber air temperature and relative humidity were monitored continuously during exposure and readings were taken at hourly intervals throughout each exposure. Chamber temperature was similar for all groups during the study (range of 20.1 – 23.6 degrees C). A minimal increase in chamber relative humidity was noted in the high-dose chamber relative to the other test groups (high dose range 53 – 61.6 %; other groups range 43.3 – 55.4 %)
- Air flow rate: Diluent inlet air at 80 liters per minute entered the base of the column and mixed with the vapour entering the chamber for a total volume flow of 90 liters per minute.
- Treatment of exhaust air: The chamber atmosphere was extracted by means of individual air handling units fitted with filters. The extract flow was adjusted by means of a gate valve so as to maintain the chamber pressure approximately 5 mm of water below that of the surrounding room.

TEST ATMOSPHERE
- Brief description of analytical method used: After 6 hours of exposure, the infusion pumps were switched off. The volumes of test material remaining in each syringe were recorded and the total volume used during the exposure calculated.
In addition, the concentration of ethoxypropanol present in the exposure chambers was determined at approximately hourly intervals during each exposure. Samples of the test atmosphere were withdrawn through a gas absorption tube and the tubes connected to an oxygen-free nitrogen supply and inserted through a modified injector port into a GC fitted with a flame ionization detector.
- Samples taken from breathing zone: yes, Sampling was performed in a companion 90-day inhalation study using the same chambers to determine the spatial distribution of ethoxypropanol within the chambers. Results indicated that distribution of the test substance in the exposure chamber was adequately uniform. HRC Report No. BPC 46/851294.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See details of exposure above.
Details on mating procedure:
Animals were ordered time mated from supplier
- Proof of pregnancy: sperm in vaginal smear, day 0
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
Days 6 – 15 of gestation.
Frequency of treatment:
6 hours each day.
Duration of test:
Animals were sacrificed on day 20 of gestation.
Doses / concentrationsopen allclose all
Remarks:
0, 100, 450. 2000ppm (target concentrations)
Remarks:
0, 96, 451, 1895ppm (analytical concentrations)
No. of animals per sex per dose:
25 females per group.
Details on study design:
- Dose selection rationale:
Target concentrations were selected based on results of a companion 90-day inhalation study, which indicated that the high concentration was expected to produce an effect on the parent animals. The low and mid concentrations were set using a geometric progession.
- Rationale for animal assignment (if not random):
Animals were assigned to groups by computerized stratified randomization to give approximately equal initial mean body weights across groups.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice per day
- Cage side observations checked in table [No.?] were included. Signs of ill health or reaction to treatment, behavioural changes. Observations during exposure were limited to general responses of animals since it was not possible to see all the animals in the exposure chamber.

BODY WEIGHT: Yes
- Time schedule for examinations: Days 1, 3, 6, 10, 14, 17 and 20 of gestation.

POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day # 20
- Organs examined: Ovaries, uteri, maternal organs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Other:
Number and distribution of live young
Number and distribution of embryonic / foetal deaths
Individual foetal weights and litter weight
Foetal abnormalities

Embryonic / foetal deaths were classified as early (only placenta visible) or late (both placenta and embryonic remnants visible)

Uterine horns without visible implantations were immersed in ammonium sulphide solution to reveal evidence of embryonic death at very early stages of implantation.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
Kruskal-Wallis and Jonckheere tests, Fischer’s exact test.
Indices:
Litter size, pre-implantation loss, post-implantation loss, and sex ratio.
Historical control data:
None available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Hight dose group animals showed clinical signs including licking the inside of the mouth, piloerection, and a reduced startle response to tapping on the side of the chamber. In mid dose group, only clinical sign noted was licking the inside of the mouth during exposure.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean weight gain was reduced in top dose group. Mean weight gain was slightly lower than controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was slightly reduced in top dose group.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Details on results:
There were no effects of treatment noted in animals exposed to 100 ppm.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
100 ppm (nominal)
Basis for effect level:
clinical signs
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
No effects were seen on litter data (litter size, pre- and post-implantation loss, litter and mean foetal weights), or on embryonic or foetal development (incidences of malformation, anomalies or skeletal variants) at any exposure concentration.

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
> 2 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
NOAEC (maternal) >= 100 ppm
NOAEC (developmental) >= 2000 ppm
Substance is not developmentally toxic.
Executive summary:

In a guideline and GLP developmental toxicity study in rats, whole body inhalation exposure to ethoxypropanol vapour at concentrations up to 2000 ppm on Days 6-15 of gestation did not produce evidence of developmental effects (based on uterine and litter data, and foetal development).  Reduced weight gain and clinical signs were noted in maternal animals exposed to 450 ppm or 2000 ppm.  No effects were noted in maternal animals exposed to 100 ppm.  Based on these results the following NOAECs for developmental toxicity in the rat are established for ethoxypropanol vapour:

NOAEC (maternal) >= 100 ppm (0.425 mg/L)

NOAEC (developmental) >= 2000 ppm (8.5 mg/L)