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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
471-480-0
EC Name:
-
Cas Number:
1645-83-6
Molecular formula:
Hill formula: C3H2F4 CAS formula: C3H2F4
IUPAC Name:
(1E)-1,3,3,3-tetrafluoroprop-1-ene

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10 - 11 weeks old
- Housing: macrolon cages
- Diet: ad libitum except during exposure
- Water: ad libitum except during exposure
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS°C
- Humidity (%): 40 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
nose only
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose only exposure units, cylindrical PVC column with volume of ~ 70 litres, surrounded by a transparent hood
- Source and rate of air:humidified compressed air
- System of generating particulates/aerosols: not applicable
- Temperature, humidity in air chamber: 21.9 - 23.1 °C; 34 - 45 % humidity;
- Method of particle size determination: not applicable
- Treatment of exhaust air: not described

TEST ATMOSPHERE
- Brief description of analytical method used: total carbon analysis
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
total carbon analysis with flame ionization detector
Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1/2
- Length of cohabitation:
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: not necessary
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [ sperm in vaginal smear] referred to as [day 0] of pregnancy
Duration of treatment / exposure:
gestation day 6 - 19
Frequency of treatment:
6 hours/day
Doses / concentrationsopen allclose all
Dose / conc.:
5 000 ppm (nominal)
Remarks:
Group 2: Low dose
Dose / conc.:
15 000 ppm (nominal)
Remarks:
Group 3: Mid dose
Dose / conc.:
50 000 ppm (nominal)
Remarks:
Group 4: High dose.
No. of animals per sex per dose:
25
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses used were similar to those used for other inhalation repeated dose studies conducted on this test material. As noted in paragraph 13 of OECD guideline 414, the dose levels should be selected taking into account any existing toxicity. The highest dose tested in the this study (15000 ppm) was based on the cardiac effects observed in the 2 week, 4 week, and 13 week toxicity studies conducted in rats. As noted in the table attached in the background info section. In the 2 wk, 4 week, and 90 day inhalation toxicity studies, cardiac effects including mononuclear cell infiltrates were observed at of 15000 – 20000 ppm and higher. In these studies, there were also no clinical signs of toxicity. The rat prenatal toxicity study did not include evaluation of the cardiac tissue as this is not a standard endpoint for these studies and data were available on this endpoint from the repeated dose studies. Honeywell considers the existing rat prenatal toxicity study to be compliant with the REACH regulation.

Table 1- Summary of effects seen in the heart of rats exposed to HFO-1234ze1
Study / effects Males Females
2-Week exposure levels in 1000 ppm 0 5 20 50 0 5 20 50
Myocardial vacuolation
Slight 0 0 1 3 0 0 0 1
Moderate 0 0 0 2 0 0 0 4
Total 0 0 1 5** 0 0 0 5**
Pyknosis
Very slight 0 0 1 5 0 0 0 4
Slight 0 0 0 0 0 0 0 1
Total 0 0 1 5** 0 0 0 5**
Mononuclear cell infiltrate
Very slight 1 0 0 4 0 3 0 2
Slight 0 0 1 0 0 0 0 2
Moderate/multifocal 0 0 4 0 0 0 5 0
Total 1 0 5* 4 0 3 5** 4*

4-Week exposure levels in 1000 ppm 0 1 5 10 15 0 1 5 10 15
Myocardial vacuolation 0 0 0 0 2 0 0 0 0 0
Myocardial vacuolation,
not associated with inflammation 0 0 0 0 0 0 0 1 0 0
Mononuclear cell infiltrate
Very slight 0 1 1 1 3 0 0 2 1 2
Slight 0 0 0 0 1 0 1 0 0 0
Moderate/multifocal 0 0 0 0 1 0 0 0 0 0
Total 0 1 1 1 5** 0 1 2 1 2

13-Week exposure levels in 1000 ppm 0 1.5 5 15 0 1.5 5 15
Very slight to slight focal
mononuclear cell infiltrate 4 6 6
1 3 5 6 4
Multifocal mononuclear cell infiltrate
Very slight 0 0 0 1 0 0 0 1
Slight 0 0 0 7 0 0 0 4
Moderate 0 0 0 1 0 0 0 0
Totals 0 0 0 9*** 0 0 0 5*

*p < 0.05; **p < 0.01; ***p < 0.001
1 N= 5 animals/sex/group in the 2-week and 4-week exposure studies; N=10 animals/sex/group in the 13-week exposure study

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS for clinical signs and mortality: Yes, daily

BODY WEIGHT: Yes (GD 0, 3, 6, 9, 12, 15, 19 and 21)

FOOD CONSUMPTION: Yes (GD 0 - 3, 3 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 19, and 19 -2 1)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- Soft tissue examinations: Yes: half per litter
Skeletal examinations: Yes: half per litter
Statistics:
Fisher's exact probability test, one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison tests or Kruskal-Wallis
nonparametric analysis of variance followed by the Mann-Whitney U-test as appropriate. Statistical evaluations on variables associated with the fetuses were considered on a litter basis in accordance to standard procedures.
Indices:
Female fecundity index, Gestation index

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No remarkable clinical signs were observed compared to controls
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No effect observed on mean maternal body weight during pregnancy (however, body weight loss was noted in all groups including controls were noted during GD 6-9 and 19-21). The mean body weight change during the total exposure was comparable in all groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects were observed in food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
No differences were noted in female fecundity index and corpora lutea.
Weights of gavid uterus, carcass, empty uterus, and ovaries were not different from controls.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOEC
Effect level:
> 15 000 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
> 15 000 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in litter size and weights:
not specified
Anogenital distance of all rodent fetuses:
not specified
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences in the incidence of external observations were observed among the groups.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal examinations did not show a statistically significant difference in incidence of skeletal malformations, anomalies, or variation were observed among the groups. There was no difference in total foetal skeletal retardations based on fetal or litter incidence. The effects observed are not considered to be adverse.
Visceral malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in the incidence of visceral malformations, anomolies, or variations.
Details on embryotoxic / teratogenic effects:
Enlarged placenta was seen in all live foetusus in one high dose dam but no abnormalities were observed when these placentas were evaluated micropscopically. Placental weights were not different.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
> 15 000 ppm
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In conclusion, under the conditions of this study, HFO-1234ze given by inhalation to pregnant female rats from gestation day (GD) 6 - 20 for 6 hours per day up to 15000 ppm did not induce maternal or prenatal developmental toxicity. Therefore this level represents the NOAEC for developmental effects in this study.