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Description of key information

NOAEL 720d oral = 110mg/ kg/ bw/ day
NOAEL 720d dermal = 110mg/ kg/ bw/ day
The dermal NOAEL is an extrapolated value from the 720d trans-cinnamaldehyde study (NTP, 2004). The subchronic study on HCA had a maximum dose of 25mg/ kg/ bw/ day. However this study is not suitable for the basis from which to calculate a dermal DNEL. The reason for this is that the achieved NOAEL was highest dose received in the study (25 mg/kg/bw/day) (RIFM 1981). However, a sub-chronic oral study (90d) on alpha methylcinnamaldehyde produced much higher NOAEL of 220mg/kg/bw/day. In addition a chronic 720d study on cinnamaldehyde achieved an NOAEL of 100mg/kg/bw/day, NTP, 2004. Given that oral exposure is appears more harmful derived from the acute studies on alpha methylcinnamaldehyde where an oral LD50 of 2050mg/kg/bw/day was established (Russell, 1973) and where a dermal LD50 of >5000mg/kg was established (Russell, 1973), the use of another study other than the dermal study is appropriate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
110.6 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Very good; 7 reliable studies available. All are klimisch code 1or2.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
110.6 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The achieved NOAEL was highest dose received in the study (25 mg/kg/bw/day) (RIFM 1981). A subchronic oral study (90d) on AMC produced much higher NOAEL of 220mg/kg/bw/day. In addition a chronic 720d study on cinnamaldehyde achieved an NOAEL of 100mg/kg/bw/day, NTP, 2004. Given that oral exposure is appears more harmful from acute studies on alpha methylcinnamaldehyde where an oral LD50 of 2050mg/kg/bw/day was established (Russell, 1973) and where a dermal LD50 of >5000mg/kg was established (Russell, 1973), the actual NOAEL for dermal exposure is expected to be several factors more. Therefore, for the CSA an extrapolated value taken from the Chronic 720d study will be used

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

8 reliable repeated dose;oral studies are available. 1 is a reliable 2 year chronic study, 5 are reliable peer reviewed subchronic studies.

In a peer reviewed published 2 year repeated dose oral study on the chronic effects of trans-cinnamaldehyde on male or female rats, a NOAEL of 100mg/kg/bw/day was obtained (NTP, 2004).

Trubeck Labs (1958) found alpha-methylcinnamaldehyde to have a NOAEL (90d, oral) of 220mg/kg/bw/day.

In a published peer reviewed subchronic (12 week, oral) study of cinnamaldehyde on rats, no adverse effects were observed on appearance, behavior, growth, food consumption, efficiency of food utilization, presence of sugar or albumin in the urine, blood hemoglobin, liver and kidney weights, or gross pathology. Cinnamaldehyde has a NOAEL of 227mg/kg/bw/day (JECFA, 1981)

In a peer reviewed subchronic oral study of cinnamaldehyde on rats.. No statistically significantly differences were observed between treated and control groups on growth, food intake, efficiency of food utilization or other physiological criteria. Cinnamaldehyde has a NOAEL of 200mg/kg/bw/day (Trubeck Labs, 1958b)

In a peer reviewed subacute (2 weeks) oral toxicity study, rats were administered cinnamaldehyde by oral gavage. The test substance at dose 470 mglkglday and above produces forestomach hyperplasia and was lethal at dose of 1880mg/kg and above. Cinnamaldehyde has a NOAEL of 235mg/kg/bw/day (Herbert 1994)

Carpanini et al (1973) found the read across material amylcinnamaldehyde to have a 90d oral NOAEL of 29.9 mg/kg/bw/day (males) and 32mg/kg/bw/day (females).

Oser et al (1965), found no effect of amylcinnamaldehyde at a maximum dose of 6.1 mg/kg/bw/day (males) [2% in food] in a 90d oral study.

A good quality 14d range finding oral study on the read across material Hexyl cinnamic aldehyde gave a NOAEL 500 mg/kg/bw/day.

All the studies are reliable and produce similar NOAEL for the substances concerned.

In a reliable (Klimisch code 2) peer reviewed, 90d dermal toxicity study performed by RIFM (1981) on hexyl cinnamic aldehyde a NOAEL of 25 mg/ kg/ bw/ day was determined. This was the maximum dose received in the study and represents a conservative NOAEL..

Dermal Repeated Dose Toxicity

In a key read across repeated dose dermal toxicity study (T & O Toxicology Inc., 1981), the test material (Hexyl Cinnamic Aldehyde in phenyl ethyl alcohol) at a dose of 25 mg/Kg was applied topically to the clipped backs of Sprague Dawley Albino rats daily for 90 days. There were five male and five female rats/group. A control group of five male and five female rats received Phenyl Ethyl Alcohol, 1 mL/Kg.

 

All rats were observed daily and skin reactions were recorded. Body weights were recorded weekly. At termination, selected haematology, clinical chemistry and urinalysis parameters were evaluated. All animals were examined grossly and liver and kidneys were weighed. Microscopic examination of the skin, liver, kidney and spinal cord was conducted.

 

One male rat treated with Hexyl Cinnamic Aldehyde died on Day 14. At necropsy, there was evidence of a lung infection. The death was not considered to be related to treatment. Of the other parameters evaluated, there was no evidence of toxicity induced by treatment with the test article. The NOEL was therefore determined to be 25 mg/Kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
8 reliable repeated dose;oral studies are available.
In a peer reviewed published 2 year repeated dose oral study on the chronic effects of trans-cinnamaldehyde on male or female rats, a NOEL of 50mg/kg/bw/day was obtained (NTP, 2004). Trubeck Labs (1958) found alpha-methylcinnamaldehyde to have a NOAEL (90d, oral) of 220mg/kg/bw/day. In a published peer reviewed subchronic (12 week, oral) study of cinnamaldehyde on rats, no adverse effects were observed on appearance, behavior, growth, food consumption, efficiency of food utilization, presence of sugar or albumin in the urine, blood hemoglobin, liver and kidney weights, or gross pathology. Cinnamaldehyde has a NOAEL of 227mg/kg/bw/day (JECFA, 1981). In a peer reviewed subchronic oral study of cinnamaldehyde on rats.. No statistically significantly differences were observed between treated and control groups on growth, food intake, efficiency of food utilization or other physiological criteria. Cinnamaldehyde has a NOAEL of 200mg/kg/bw/day (Trubeck Labs, 1958b). In a peer reviewed subacute (2 weeks) oral toxicity study, rats were administered cinnamaldehyde by oral gavage. The test substance at dose 470 mglkglday and above produces forestomach hyperplasia and was lethal at dose of 1880mg/kg and above. Cinnamaldehyde has a NOAEL of 235mg/kg/bw/day (Herbert 1994). Carpanini et al (1973) found the read across material amylcinnamaldehyde to have a 90d oral NOAEL of 29.9 mg/kg/bw/day (males) and 32mg/kg/bw/day (females). Oser et al (1965), found no effect of amylcinnamaldehyde at a maximum dose of 6.1 mg/kg/bw/day (males) [2% in food] in a 90d oral study. A good quality 14d range finding oral study on the read across material Hexyl cinnamic aldehyde gave a NOAEL 500 mg/kg/bw/day. All the studies are reliable and produce similar NOAEL for the substances concerned.
Therefore alpha-methylcinnamaldehyde has a NOEL (720d oral) of 55mg/kg/bw/day (extrapolated), and a NOAEL (720D) of 110mg/kg/bw/day (extrapolated)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Studies on the primary routes of exposure are available

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Studies on the primary routes of exposure are available

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
In 1 peer reviewed 90d dermal study performed by RIFM (1981) on hexyl cinnamic aldehyde a NOAEL of 25 mg/ kg/ bw/ day was determined. This was the maximum dose received in the study. The NOAEL is the highest dose received and is conservative for the endpoint
The achieved NOAEL was highest dose received in the study (25 mg/kg/bw/day) (RIFM 1981). A subchronic oral study (90d) on AMC produced much higher NOAEL of 220mg/kg/bw/day. In addition a chronic 720d study on cinnamaldehyde achieved an NOAEL of 100mg/kg/bw/day, NTP, 2004. Given that oral exposure is appears more harmful from acute studies on alpha methylcinnamaldehyde where an oral LD50 of 2050mg/kg/bw/day was established (Russell, 1973) and where a dermal LD50 of >5000mg/kg was established (Russell, 1973), the actual NOAEL for dermal exposure is expected to be several factors more

Justification for classification or non-classification

8 reliable repeated dose oral studies are available.

Alpha methyl cinnamaldehyde has a NOAEL (720d) oral and dermal exposure of 110mg/kg/bw/day and is therefore not classified for repeated dose toxicity (extrapolated from cinnamaldehyde NOAEL (720d), 100mg/kg/bw/day), and therefore should not be classified for repeated dose toxicity