1-Propene, 1,3,3,3-tetrafluoro-

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No adverse effects on fertility were observed in the inhalation 2-Generation reproductive toxicity study up to exposure levels of 93200 mg/m3 (20000 ppm). Additionally, no adverse effects on reproduction or development were observed in rat or rabbit developmental toxicity studies or following histological examination of reproductive organs following 90-days of repeated inhalation exposure in any of the exposure groups.  

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

September 2011 - November 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3800 (Reproduction and Fertility Effects)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Agricultural Production Bureau

Version / remarks:

November 20, 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: (P) 40 - 46 days; (F1) 21 days
- Weight at study initiation: (P) Males: 180 - 262 g; Females: 123 - 193 g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study: none
- Housing: barriered facility, plycarbonate cages w/bedding or stainless steel grid floor cages during mating. Animals were housed up to 4 per cage (by sex) during acclimation and pre-mating, one male and one female/cage during the mating period, and one female/cage during gestation and lactation (one dam with litter/cage)
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 18 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 29 to 70
- Air changes (per hr): none, supplied with filtered fresh air, passed to atmosphere with no re-circulation
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 2011-09-15 to 2012-06-13

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Whole body exposure chamber: 0.75 m3 chamber of stainless–steel and glass construction
- Method of holding animals in test chamber: Individual stainless steel mesh compartments
- Source and rate of air: From in-house compressed air system – breathing quality 147 to 149 L/minute
- System of generating particulates/aerosols: In-line flowmeters monitored continuously for generation feeds and diluent airflows. Chamber pressure differential monitored by Magnahelic set between 1 to 5 mm/H2O to ensure a slight negative pressure within the chamber to equate to 150 L/minute.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: up to 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually in polycarbonate cages with wood bedding
- Any other deviations from standard protocol: No

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromotography

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

The F0 generation received HFO-1234ze 6 hr/day, 7 days/week for ten weeks before pairing, throughout pairing, gestation, lactation and until termination. The F1 generation received HFO-1234ze from weaning for a minimum of 10 weeks before pairing, throughout pairing, gestation and lactation and until termination. Exposure of pregnant females was not performed from gestation Day 20 to lactation Day 4.

Details on study schedule:

- F1 parental animals not mated until 10 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.

Dose / conc.:

2 000 ppm (nominal)

Remarks:

Group 2: Low dose

Dose / conc.:

5 000 ppm (analytical)

Remarks:

Group 3: Mid dose

Dose / conc.:

20 000 ppm (analytical)

Remarks:

Group 4: High dose.

No. of animals per sex per dose:

P0 generation: 28
F1 generation: 24

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Based on the 90 day study in rat where the high dose (15000 ppm) was considered a LOAEL for cardiac effects. A high dose of 20000 ppm was selected to better evaluate these and any other toxic effects. For details on cardiac effects reference is made to the section on details of materials and methods.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during the first week of treatment, twice weekly during Weeks 2 to 4 (middle and end of each week) and weekly thereafter, detailed observations were recorded at the following times in relation to dose administration: Pre-exposure observation, During dosing, Post exposure, up to 1.5 hours after dosing

BODY WEIGHT: Yes
- Time schedule for examinations: One week before treatment started, on the day treatement started, weekly during treatment, and on the day of necropsy. Females were also weighed on gestation Days 0, 7, 1, and 20 and on lactation Days 1, 4, 7, 14, 21 and 25.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/rat/week: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OTHER:

Oestrous cyclicity (parental animals):

Vaginal smears taken daily for 22 days before pairing (including the day of pairing)

Sperm parameters (parental animals):

Parameters examined in p and F1 male parental generations: testis weight, epididymis weight, sperm count in testes, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals when the majority of litters had been weaned.
- Maternal animals: All surviving animals after their respective litter was weaned.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed*, respectively.
Adrenals*
Brain*
Epididymis (right)*
Heart*
Ovaries*
Pituitary*
Prostate*
Sciatic nerves (females only)
Seminal vesicles
Spinal cord
Spleen
Testis (right)*
Uterus with cervix and oviducts*
Vagina
Other organs and tissues showing any abnormalities

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 30 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated below were prepared for microscopic examination (but not evaluated) and weighed*, respectively.
Brain*
Epididymides
Ovaries
Prostate
Seminal vesicles
Spleen*
Testes
Thymus*
Uterus with cervix and oviducts
Vagina
Other tissues or organs with macroscopic abnormalities

Reproductive indices:

Pre-cital inerval: time elapsing between initial pairing and mating
Percentage mating = Number animals mating/ Animals paired x 100
Conception rate (%) = Number animals achieveing pregnancy/Animals mated x 100
Fertility index (%) = Number of aniamls achieveing pregnancy/Animals pairing x 100
Gestation length: number of gestation days up to and including the day on which the first offspring are observed
Gestation index (%) = Number of live litters born/Number pregnant x 100
Post implanatation survival index (%) = Total number of offspring born/Total number of uterine implantation sites X 100
Live birth index (%) = Number of live offspring on Day 1 after littering/Total number of offspring born X 100
Viability index (%) = Number of live offspring on Day 4 before culling/Number live offspring on Day 1 after littering x100
Lactation index (%) = Number of live offspring on Day 21 after littering/Number of live offspring on Day 4 (after culling)
Percentage males = Number of males in litter/Total number of offspring in litter x 100

Offspring viability indices:

Offspring viability indices
- number of pups delivered (live- and stillborn)
- number of live pups (daily)
- number of pups lost measured as above (daily)
- number of litters lost entirely
- number of male pups at day 1,4, 21
- number of implantation sites
- number of lost implantations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

mortality in the highest dose group

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality in the F0 generation:
There were 9 female decedents in the F0 generation, 1 at 2000 ppm and 8 at 20000 ppm.
The decedent at 2000 ppm (no 151) was sacrificed following prolonged parturition. In isolation and in the absence of any effects on parturition at higher concentrations of HFO-1234ze, this is considered unrelated to the test article.
At 20000 ppm one female (no 208) was sacrificed on Day 19 of gestation due to poor condition and apparent blood in the vagina. Marked centrilobular hepatocyte necrosis was seen in the liver histologically and this was identified as a factor contributing to death. No other findings were noted in other animals in this group at late gestation so in isolation this death is considered to be unrelated to the test article.
The remaining 7 decedents at 20000 ppm are considered to be due to the test article and all occurred in late lactation (between Days 11 and 21 post partum). Four animals at 20000 ppm were found dead (no.s 212, 213, 215 and 216); a factor contributory to death was undetermined histologically for these 4 females. Three animals at 20000 ppm were sacrificed due to limited use of hindlimbs (no.s 201, 202 and 218). In female 201, marked neuronal necrosis, moderate swelling of astrocytes with vacuolation of the neuropil, slight haemorrhage and moderate gliosis were seen in the cerebellum with moderate gliosis, moderate vacuolation of the neuropil and moderate neuronal loss of the lumbar spinal cord, along with moderate murine progressive cardiomyopathy with an atrial thrombus in the heart; the factor contributing to death was brain lesions. Minimal or slight murine progressive cardiomyopathy was seen in the hearts of females 218 and 202, with minimal neuronal necrosis and neuronal loss seen in the brain of female 202, but the factor contributing to death was undetermined in these females. Clinically loss/limited use of hindlimbs accompanied by abnormal gait and underactive behaviour was seen in some or all these animals.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Treatment related findings were observed in the heart, brain and spinal cord of females at 20000 ppm

Histopathological findings: neoplastic:

not specified

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

> 20 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on any reproductive parameter

Key result

Dose descriptor:

NOEL

Effect level:

5 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic toxicity / mortality

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

mortality in the highest dose group

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Mortality in the F1 generation:
There were 3 female decedents in the F1 generation at 20000 ppm, all occurring in the lactation phase. Two females (no.s 471 on Day 14 post partum and 470 on Day 15 post partum) were found dead in the cage at the initial animal check. No clinical signs had been noted previously. No factors contributing to death were established in these females. A third female (no 475) was sacrificed on Day 24 post partum due to poor condition. This death occurred 12 days after treatment had been terminated; no factor contributing to death was determined and due to the timing of the death of this female not replicating those seen in the F0 generation, this is considered unrelated to HFO-1234ze.
Following the deaths of females 470 and 471, administration of HFO-1234ze to the remaining females at 20000 ppm was terminated, as the effects seemed to replicate those in the F0 generation females during lactation.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Bodyweight gain of the F1 generation up to weaning at 20000 ppm from Day 7 for males and Day 4 for females was slightly lower than the Controls. Slightly lower bodyweights persisted throughout the F1 generation.

Bodyweight of males and females F1 generation offspring derived from parents exposed at 20000 ppm was slightly reduced from Day 7 for male offspring and Day 4 post cull for female offspring (up to 0.90 X Control for males and 0.88X Control for females).
There were considered to be no effects on bodyweight at the lower exposure concentrations; whilst group mean bodyweight was lower than the controls at 2000 ppm, there was no difference at 5000 ppm and as such the lower weights at 2000 ppm are considered unrelated to HFO-1234ze.

Food consumption and compound intake (if feeding study):

not examined

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

Urinalysis findings:

not examined

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

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

> 20 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on any reproductive parameter

Key result

Reproductive effects observed:

not specified

Conclusions:

In this study, groups of 28 CD rats/sex/group were exposed to the test substance by inhalation to 0 (sham control), 2000 ppm, 5000 ppm and 20000 ppm for two generations. There were no effects on reproductive indexes, food consumption, clinical observations, organ weights or histopathological observations in the parental animals. There were no effects on development, sexual maturation, litter size, litter survival, litter sex ratio, clinical observations, organ weights or macroscopic findings in the pups from either generation. At 20000 ppm, there were 7 F0 generation female decedents during late lactation (between Day 11 to 21), and 2 F1 generation female decedents during late lactation (Day 14 and 15). Three of the F0 generation decedents were sacrificed following hindlimb paralysis. Brain lesions were established as the cause of death in one F0 generation female. The cause of death for the remaining females was not determined. Due to the fact that mortality was only observed in the high exposure level group, this was considered to be related to the exposure to the test article. The NOEL for paternal (systemic) toxicity was therefore considered to be 5000 ppm. The NOEL for fertility and development was 20000 ppm, because no adverse effects on fertility parameters or offspring were observed.

Executive summary:

In this study, groups of 28 CD rats/sex/group were exposed to the test substance by inhalation to 0 (sham control), 2000 ppm, 5000 ppm and 20000 ppm for two generations. There were no effects on reproductive indexes, food consumption, clinical observations, organ weights or histopathological observations in the parental animals. There were no effects on development, sexual maturation, litter size, litter survival, litter sex ratio, clinical observations, organ weights or macroscopic findings in the pups from either generation. At 20000 ppm, there were 7 F0 generation female decedents during late lactation (between Day 11 to 21), and 2 F1 generation female decedents during late lactation (Day 14 and 15). Three of the F0 generation decedents were sacrificed following hindlimb paralysis. Brain lesions were established as the cause of death in one F0 generation female. The cause of death for the remaining females was not determined. Due to the fact that mortality was only observed in the high exposure level group, this was considered to be related to the exposure to the test article. The NOEL for paternal (systemic) toxicity was therefore considered to be 5000 ppm. The NOEL for fertility and development was 20000 ppm because no adverse effects on fertility parameters or offspring were observed.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

93 200 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

The study is considered to be of good quality (K1) as it is performed according to the GLP Regulation and most recent OECD 416 Guidance.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the 2 -Generation reproductive toxicity study groups of 28 CD rats/sex/group were exposed by inhalation to 0 (sham control), 2000, 5000 and 20000 ppm (respectively 9320, 23300 and 93200 mg/m3) for two generations. There were no effects on reproductive indexes, food consumption, clinical observations, organ weights or histopathological observations in parental animals. Additionally, there were no effects on development, sexual maturation, litter size, litter survival, litter sex ratio, clinical observations, organ weights or macroscopic findings in the pups from either generation. At 20000 ppm there were some decedents, but as mortality was only observed in the high exposure level groups this was considered to be related to exposure to the test article. Therefore, the NOEL for parental toxicity (systemic) was considered to be 5000 ppm, while the NOEC for fertility and development was 20000 as no adverse effects on fertility parameters or offspring were observed.

 

Short description of key information:

No adverse effects on fertility were observed in the inhalation 2-Generation reproductive toxicity study up to exposure levels of 93200 mg/m3 (20000 ppm). Additionally, no adverse effects on reproduction or development were observed in rat or rabbit developmental toxicity studies or following histological examination of reproductive organs following 90-days of repeated inhalation exposure in any of the exposure groups.  

Effects on developmental toxicity

Description of key information

In the developmental toxicity studies no maternal or fetal toxicity was observed in rats or rabbits exposed by inhalation to concentrations up to 15000 ppm (69900 mg/m3) during gestation.  Furthermore, in the 2-generation study with rats, no developmental effects were observed up to concentrations of 20000 ppm (93200 mg/m3).

Link to relevant study records

Reference

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

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

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

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

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

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

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

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.

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

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.

Key result

Dose descriptor:

NOAEC

Effect level:

> 15 000 ppm

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

not specified

Key result

Developmental effects observed:

not specified

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

69 900 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

There are developmental toxicity studies available both on rat and rabbit, a 2-generation study on rats and a 90-day repeated dose exposure study also on rats. All studies are of very good quality (K1).

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In the rat and rabbit teratology studies, no maternal or developmental toxicity was observed after exposure up to 15000 ppm (69900 mg/m3) HFO-1234ze. Furthermore, no adverse effects were observed following histological examination of the gonads in male and female rats following 90-days of exposure to 15000 ppm (69900 mg/m3) HFO-1234ze. This was confirmed in the 2-generation reproductive toxicity study as no developmental effects were observed after exposure up to 20000 ppm (93200 mg/m3) (including histology).

Justification for classification or non-classification

Based on the available information, classification is not required for the test substance in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.