1-Propene, 2-bromo-3,3,3-trifluoro-

Endpoint summary

Description of key information

Toxicokinetic Assessment

No specific study has been performed on the absorption/distribution/metabolism/excretion (ADME) of 2‑bromo‑3,3,3‑trifluoropropene (BTP).However, data are currently available from anin vitrovial equilibration method used to determine partition coefficients for blood and tissues andin vivotoxicology studies performed with this substance.

2‑bromo‑3,3,3‑trifluoropropene is a fire extinguisher agent, aclear liquid with a slight yellow tint,with a small molecular weight 174.95 and a Log P value of 2.7. It is very soluble (1000 mg/L).These physicochemical properties suggest that 2‑bromo‑3,3,3‑trifluoropropene will be readily absorbed across biological membranes via all routes. It is expected to have a high bioavailability but lack bioaccumulation properties.2‑Bromo‑3,3,3‑trifluoropropene is highly volatile and boils just below body temperature (recorded boiling point = 34.4°C) therefore it is expected that the inhalation route rather than the dermal route will be a major route of exposure. The skin irritation study was performed using occlusive (airtight) bandage and the skin sensitisation study was waived on the basis of its high volatility and low boiling point.

 

Absorption

 

Oral route

No data is available on absorption via the oral route.

 

Dermal route

It is generally accepted that compounds with a partition coefficient in the range of 1 to 4 (optimally between 1 and 2) and a molecular weight of less than 500 may be absorbed, at least in part, via the dermal route. The partition coefficient of 2‑Bromo‑3,3,3‑trifluoropropene is 2.7 and the molecular weight is 174.95; accordingly, it is considered likely that this material will cross the skin barrier. However, the low boiling point (below body temperature) indicates that the material will not be in contact with the body for a long period of time. Therefore, steps (airtight administration) were taken to maximise exposure timein thein vivoskin irritation study.No dermal reaction in thisin vivoskin irritation study was observed in any animal throughout the duration of the study. There was no sign of toxicity or ill health in any rabbit during the observation period.

 

 Inhalation route

The values of the blood: air partition coefficients calculated for human and rat predicts that BTP is absorbed via the lungs. The comparison of the human and rat values indicates that BTP is taken up more by rats than by humans. The human blood:air partition coefficient (0.21) is smaller than the rat blood:air partition coefficient (0.52).

In the acute studies, treatment related clinical signs and histopathological findings were mainly indicative of the substance irritant properties to the respiratory tract however decreased activity were also noted after the higher exposure level. BTP was considered moderately toxic with an LC50of ~11,726 ppm.

During the range finding and 90 day repeated dose toxicity studies, treatment-related, but transient, clinical signs, related to inhalation of an irritant material (shallow breathing, piloerection, grinding teeth and hunched posture) and possible CNS effects (unresponsiveness to external stimuli, underactivity, and partially closed eyelids), were evident during and after exposure at all exposure levels. In the 90 day repeated dose toxicity study, reductions in grip strength and motor activity were apparent for animals exposed to 505 or 2876 ppm.Histopathological changes related to systemic effects from the treatment were seen in the liver (centrilobular hepatocyte hypertrophy), and spleen (capsular inflammation and/or thickening and adhesion), with animals at 505 and 2876 ppm.

Exposure of 2‑bromo‑3,3,3‑trifluoropropene to rats in both reproductive toxicity screenings was associated with adverse effects on male and female toxicity (similar to the repeated dose toxicity), and reproductive performance and development at 175, 505 and 2900 ppm. Exposure at 505 and 2900 ppm produced effects on oestrous cycles, fertility (2900 ppm only), extended duration of gestation, sperm counts and motility, implantation counts, reduced in utero and post-partum survival, in the presence of signs of adult toxicity. In addition, at 2900 ppm, reduced size of corpora lutea in the ovaries was noted.

Increase in mean water consumption for females during gestation, longer mean pre-coital interval, longer mean gestation length, and the reduced postnatal survival were noted in the 175 ppm group.

In animals treated with BTP at 10,000 ppm, transient test substance-related clinical findings were noted at 15 minutes following exposure to males and females and included hypoactivity, decreased respiration, completely shut eyelids, lacrimation,salivation and red and/or clear material around the mouth and/or nose.

In a specific study, positive evidence of cardiac sensitisation were observed as the presence of multiple multifocal ectopic beats or ventricular fibrillation following adrenaline administration during a 10 minute inhalation exposure of the test substance in dogs at 0.49%, 1.00% and 1.50% v/v in air (Huntingdon Life Sciences, AAS 001/01/014630).

In a separate study but following the same administration schedule as the cardiac sensitisation study, arterial blood levels of 2‑bromo‑3,3,3‑trifluoropropene were measured during and after inhalation administration of the test substance in dogs at 1% v/v in air (WAG0016).Concentrations increased during exposure reaching a maximum between 7 and 10 minutes (37.3 mg/L at 10 min after start of exposure) into the exposure. Clinical signs seen during exposure were minor in nature and consisted of hunched posture, restlessness, deep breathing, body tremors and pawing at the face mask.

Altogether, this data indicates that 2‑Bromo‑3,3,3‑Trifluoropropene is absorbed readily and quickly through the lungs.

 

Distribution

Tissue to air partition coefficients, the measured blood levels of BTP and the findings of the acute, short term and reproduction inhalation studies including CNS effects, histopathological changes in the liver and spleen, cardiac sensitisation in dogs and effects on the reproductive system of males and females ratsprovide evidence that the test substance is distributed systemically when absorbed via the lungs. The values of the blood: air and tissue: air partition coefficients calculated for human and rat confirm the distribution of BTP throughout the body and its uptake by different tissues (BatelleProject No. 64197, 2013). Although the blood to air partition coefficient in rat is 0.52 ± 1.79, test substance was found to be present in the blood of dogs during exposure to BTP by the inhalation route. The fat: air partition coefficient was 15.74 ± 1.07 which indicates that BTP is particularly taken up by the rat fat tissue as found in the brain. Transient CNS effects in the acute and repeated dose studies confirm that the brain is a target organ. The liver: air partition coefficient of 3.43 ± 1.15 indicates that the liver is also a target organ. There was evidence of distribution to the liver and spleen of rats in the 90 day repeated dose inhalation study. Minimal centrilobular hepatocyte hypertrophy is considered to be an adaptive change as a result of exposure to the test material.Capsular inflammation and/or thickening and adhesion of the spleen seen in animals exposed to 2876 ppm and, to a lesser extent, animals exposed to 505 ppm is likely to be a direct toxic effect of the test substance. The test substance reached the heart too, as demonstrated by a positive sensitisation effect following adrenaline administration during inhalation of the test substance in dogs at 10,000 ppm (Huntingdon Life Sciences, AAS 001/01/014630).Distribution to the heart was predicted by the muscle to air partition coefficient (1.80± 2.60). BTP seems to be delivered also to reproductive organs as evidenced by effects on oestrous cycles, fertility, reduced size of corpora lutea in the ovaries, extended duration of gestation, sperm counts and motility, implantation counts, reduced in utero and post-partum survival, in the presence of signs of adult toxicity.

Metabolism

No data are available on metabolism in the existing toxicity studies.Metabolic activity would appear to be supported by microscopic changes seen in the 90-day toxicity study where centrilobular hepatocyte hypertrophy were noted in both male and female rats at the two highest dose levels.

 

Excretion

No data are available on excretion in the existing toxicity studies. However arterial blood levels of 2‑bromo‑3,3,3‑trifluoropropene were measured during and after inhalation administration of the test substance in dogs at 1% v/v in air (WAG0016). Blood levels of the substance increase quickly to a maximum (37.3 mg/L) between 7 and 10 minutes after start of exposure and then very quickly decreased after completion of exposure to less than half of the concentrationsmeasured at the end of exposure one minute post-exposure. The test article was present in small amounts (approximately 1.3% of the end of exposure concentrations) at the 60 minutes post-exposure timepoint.All clinical signs resolved quickly following cessation of exposure to the test material.

An acute inhalation study was performed in rats with 2‑Bromo‑3,3,3‑Trifluoropropene in which groups of 10 rats were exposed nose-only for 30 minutes to inhalation concentrations of 5%. During and after exposure, all rats were lethargic and exhibited clinical signs of anaesthesia. All clinical signs of toxicity had resolved by 10 minutes following exposure.

This recovery following exposure to the substance was also seen in the 90 day toxicity study. Following the 4 week recovery period, there was complete recovery of test material related histopathological changes seen in the liver, pancreas, heart, thymus, larynx and teeth and partial recovery for the findings see in the spleen (capsular inflammation and/or thickening) and nasal turbinates (atrophy/disorganisation/vacuolation of the olfactory epithelium and nasolacrimal duct inflammation).

This suggests that the substance is rapidly excreted and does not seem to be accumulating.

  

Conclusion

As suggested by physicochemical properties and confirmed by toxicitystudies performed with BTP is readily absorbed via the lungs. Exposure via the skin will be limited by the compounds volatility and boiling point close to body temperature. There is evidence of systemic distribution to the brain, the liver, the spleen, the heart and reproductive organs in rats or dogs. Histological changes in the liver would suggest some metabolic activity. Post-exposure quick blood concentration decrease and rapid recovery of some of the toxic effects suggest rapid excretion and a lack of bioaccumulation which is supported by its partition coefficient.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

0

Absorption rate - dermal (%):

0

Absorption rate - inhalation (%):

100

Additional information

Refer to the attached document in section 13 of this dossier for a full discussion of a Toxicokinetic Assessment of the available in-vivo test results.

Conclusion to the Toxicokinetic Assessment:

As suggested by physicochemical properties and confirmed by toxicity studies performed with 2-Bromo-3,3,3-Trifluoropropene is readily absorbed via the lungs. Exposure via the skin will be limited by the compounds volatility and boiling point close to body temperature. There is evidence of systemic distribution to the liver, the spleen, the heart and reproductive organs in rats or dogs. Histological changes in the liver would suggest some metabolic activity. Post-exposure quick blood concentration decrease and rapid recovery of some of the toxic effects suggest rapid excretion and a lack of bioaccumulation which is supported by its partition coefficient.