(3-chloroprop-1-enyl)benzene

Endpoint summary

Description of key information

Cinnamyl chloride (CAS 2687-12-9; T000749) is a light yellow, light brown liquid with a moderate molecular weight (152.63 g/mol), a moderate partition coefficient (log Kow of 3.3 at pH 7; log Kow ranging from 1.5 to 2.8 at pH 7 for the main degradation products) and a low volatility (vapour pressure of 2.0 Pa at 20°C and 3.6 Pa at 25°C).

The backbone of the substance is a benzene group, with a 3-chloropropene group attached. The substance does not contain acidic or basic groups and therefore considered a neutral liquid. Sincecinnamyl chloridereacts with water to cinnamyl alcohol and hydrochloric acid, the substance is considered hydrolytically unstable at neutral pH (with a measured half-life of < 1h). Therefore, the water solubility of the parent compound cannot be tested. It is expected that the hydrolysis rate increases at higher and lower pH values due to alkaline or acid catalyzed hydrolysis reactions respectively.

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is set to 50%, the default for the oral route of exposure.

The respiratory absorption factor is estimated to be 100% in a conservative approach, and the dermal absorption factor is determined to be 50%.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Cinnamyl chloride (CAS 2687-12-9; T000749) is a light yellow, light brown liquid with a moderate molecular weight (152.63 g/mol), a moderate partition coefficient (log Kow of 3.3 at pH 7; log Kow ranging from 1.5 to 2.8 at pH 7 for the main degradation products) and a low volatility (vapour pressure of 2.0 Pa at 20°C and 3.6 Pa at 25°C).

The backbone of the substance is a benzene group, with a 3-chloropropene group attached. The substance does not contain acidic or basic groups and therefore considered a neutral liquid. Sincecinnamyl chloridereacts with water to cinnamyl alcohol and hydrochloric acid, the substance is considered hydrolytically unstable at neutral pH (with a measured half-life of < 1h). Therefore, the water solubility of the parent compound cannot be tested. It is expected that the hydrolysis rate increases at higher and lower pH values due to alkaline or acid catalyzed hydrolysis reactions respectively.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour.

Absorption

Oral/GI absorption:

Due to its instability in water leading to hydrolysis of the substance into the gastrointestinal fluids, cinnamyl chloride is expected to undergo degradation into two main metabolites by elimination: cinnamyl alcohol and 1-phenyl-2-propen-1-ol (Červený et al., 1982). The parent compound is expected to be present in the GI tract for a limited period of time, and cinnamyl alcohol is likely to be formed as the main degradation product.

In a combined 28-day repeated dose toxicity with the reproductive/developmental toxicity screening test (OECD 422; Pels Rijcken, 2017), the test substance was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 11, 33 and 100 mg eq/kg bw/day. Results showed that at 100 mg eq/kg/d, significant general toxicity was observed in both sexes, most severely in females. Clinical signs of toxicity appeared after a few days of treatment and included hunched posture, piloerection, lean appearance, lethargy and rales. Additionally, salivation (up to moderate degree) occurred after dosing. One female was found dead in the morning of Day 7. The other animals showed significant weight loss (on average 10 and 15% of the initial weight in males and females, respectively). These findings led to the early sacrifice of the 100 mg eq/kg animals (on Day 7 prior to dosing) and adaptation of the dose volume (from 1 to 5 ml/kg bw) for the Group 1-3 animals from Day 7 onwards. The 100 mg eq/kg animals had macroscopic and microscopic changes in the esophagus and stomach indicative of local toxicity resulting from the irritant properties of the test item. At 33 mg eq/kg/d, the effects observed were not considered to be adverse (local irritation in the forestomach, percentage of neutrophils slightly below the normal range). No reproduction was observed at 11 and 33 mg eq/kg/d, and no data were available for reproductive performance assessment at 100 mg eq/kg/d.The higher number of females with an increased prenatal mortality and concurrent relatively low post implantation survival index observed at 33 mg eq/kg might indicate a relation to treatment.

An acute oral toxicity study was performed according to the OECD guideline 423 (Latour, 2016) in which cinnamyl chloride was administered on a single occasion by oral gavage to 2 subsequent groups of 3 female Wistar rats at 2000 mg/kg body weight. At 2000 mg/kg, one animal was found dead on Day 2 in the first test group. No deaths occurred in the second test group. Lethargy, flat posture, hunched posture, piloerection, ptosis, uncoordinated movements, decreased locomotor activity, abnormal gait, slow breathing, flat gait, hypotonia and/or lean appearance were noted for all animals between Days 1 and 3 following test item administration. The LD50 was established as greater than 2000 mg/kg. No acute oral toxicity is expected.

 

Based on the physicochemical properties and the results of the toxicity studies, the oral absorption factor is set to 50%, the default for the oral route of exposure.

Respiratory absorption:

Because the substance has a low volatility, the availability of the liquid for inhalation as a vapour is limited.

The moderate log Kow value indicates favourable absorption directly across the respiratory tract epithelium by passive diffusion. However, the instability of cinnamyl chloride in water will most likely cause the substance to degrade into cinnamyl alcohol in contact with the water or moisture contained in the mucus and then be transported out of the respiratory tract.

Therefore, the respiratory absorption factor is estimated to be 100%.

 

Dermal absorption:

Since cinnamyl chloride is a liquid, the product can readily be taken up by the skin in a greater extent compared to solid products.

An acute dermal toxicity study (OECD guideline 402; Latour, 2016) where 2000 mg/kg of the substance was applied on a single occasion to 5 male and 5 female Wistar rats, demonstrated only local effects and no indications of systemic toxicity after dermal application, confirming the expectations described above. However, the substance is demonstrated to be irritating to skin based on an in vivo acute dermal irritation study (equivalent to OECD guideline 404; van Ravestyn C, 1985).

Cinnamyl chloride was assessed for its skin sensitising potential using the Local Lymph Node Assay in the CBA/Ca strain of mouse (method similar to OECD Guideline 429; Sanders, 2004). With an EC3 value of 36.3% calculated based on the simulation indexes, cinnamyl chloride was considered sensitizing to the skin.

As a result, the dermal absorption factor is determined to be 50%.

 

Metabolism

Cinnamyl alcohol, the main degradation product of cinnamyl chloride in presence of water, undergoes extensive metabolism (Bickers et al., 2005). The alcohol is rapidly converted to the aldehyde via alcohol dehydrogenase to generate firstly cinnamaldehyde, then cinnamic acid as the predominant metabolic intermediate. The major urinary metabolites for cinnamyl alcohol are glycine or glucuronic acid conjugates of benzoic acid, which forms as a result of b-oxidation of cinnamic acid. Glycine and glucuronic acid conjugates of cinnamic acid are formed in small amounts. Other minor metabolites have also been identified.

Fifty-two percent (52%) of an oral dose of cinnamyl alcohol (335 mg/kg) was recovered in 24h in the urine as the glycine conjugate of benzoic acid (hippuric acid). Ten minor metabolites cumulatively accounted for about 10% of the dose. 

The following metabolites were identified as a percent of the dose of cinnamyl alcohol in 24 hours (Nutley et al., 1990): hippuric acid (52.1%), benzoyl glucuronide (1.1%), 3-hydroxy-3-phenylpropionic acid (1.9%), benzoic acid (2.8%), acetophenone (0.3%), cinnamyl alcohol (0.4%), cinnamaldehyde (0.5%) and cinnamic acid (0.4%). Three unidentified metabolites were also excreted.

The production of numerous metabolites indicates that cinnamyl alcohol is bio-available and is rapidly metabolized within the living system.   

Distribution

No target organs have been identified after repeated oral administration of cinnamyl chloride to rats. Limited distribution data are available on cinnamyl alcohol; however, the chemical is expected to have a similar distribution pattern to the metabolite, cinnamaldehyde, which is primarily found in the gastrointestinal tract, kidneys and liver.

Excretion

Although no data is available on the parent compound cinnamyl chloride, excretion data from the main degradation product provides indication of the fate of the compounds after absorption.

Following an oral dose of 2.5mmol/kg bodyweight cinnamyl alcohol given to rats, 71% of radioactivity [14C] was excreted in the urine, and 6% in the feces within 24h; at 72h, 82% and 9% were excreted in the urine and feces, respectively.

Accumulation

Based on the study on cinnamyl alcohol (Bickers et al., 2005), it can be concluded that the chemical is expected to have low bio-accumulation potential. Similar behaviour is expected for the parent compound cinnamyl chloride.

 

References

Bickers et al. (2005) A toxicologic and dermatologic assessment of cinnamyl alcohol, cinnamaldehyde and cinnamic acid when used as fragrance ingredients. Food and Chemical Toxicology 43. 799–836

Červený L,Křivská M, Marhoul A, Růžička V.Basic hydrolysis of cinnamyl chloride. Collect. Czech. Chem. Commun. (1982) 47, 290-295

Nutley BP (1990) Investigations into the Metabolism of Cinnamic Acid, Cinnamyl Alcohol, and Cinnamaldehyde in Relation to their Safety Evaluation. PhD Thesis, University of London, Department of Pharmacology.