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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Good; 7 good quality studies are available to provide a sound weight of evidence approach.
A peer reviewed reliable klimisch score 1 chronic study in rats and mice showed no effect on the reproduction systems on either animal at 200mg/kg/bw/day
1 reliable kliminsch score 2 study on the read across candidate hexyl cinnamaldehyde is available and 3 peer reviewed studies on benzoic acid (derivative of the ultimate metabolite of alpha methyl cinnamaldehyde). A DEREK structural analysis, is also available (GAD, 2012) . All are klimisch score of 2
One unreliable study is available with no adverse findings.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a peer reviewed study, performed by the US national toxicity programme. There were no effects at any dosing on the genital systems or any other clinical finding of male/ female rats or mice. A NOAEL of 200mg/kg/bw/day was achieved for genital organs of male/female, rats and mice. (NTP, 2004)

In a study performed to OECD 421 protocol, the read across material hexyl cinnamaldehyde, produced no treatment-related clinical observations or gross lesions in the P generation male and female rats at any dosage level tested. In addition, none of the microscopic findings that occurred were considered related to treatment with hexyl cinnamic aldehyde to doses as high as 100 mg/kg/day (RIFM, 2010)

A DEREK analysis performed on alpha methyl cinnamaldehyde produced no structural alerts for reproduction (Gad, 2012)

3 supporting reports are available on a derivative of the ultimate metabolite product of alpha cinnamaldehyde, Benzoic acid.

In a developmental and reproductive toxicity review of Benzoic acid, NOAEL for P generation hamsters at 600mg/kg/bw/day and for F1 generation a LOAEL of 600mg/kg/bw/day were determined (Cosmetic Ingredient review Panel,2001)

In another developmental and reproductive toxicity review of Benzoic acid, NOAEL for P generation and for F1 generation rats of 500mg/kg/bw/day were determined (Cosmetic Ingredient review Panel,2001)

In a peer reviewed journal, a four generation study on the effect on development and reproduction of benzoic acid on rats, determined NOAEL to be 500 mg/kg (diet) (International Programme on Chemical Safety, 2000)


Short description of key information:
6 reliable study reports are available on the reproduction/ developmental toxicity of alpha cinnamaldehyde
In a 2year chronic study on rats and mice, there was no dose related effects of cinnamaldehyde on reproductive organs of any animal, male of female (NTP, 2004). In a OECD 421 study on the read across material hexyl cinnamic aldehyde, a NOAEL of 100mg/kg/bw/day was established (RIFM, 2010)
3 supporting reports are available on a derivative of the ultimate metabolite product of alpha cinnamaldehyde, Benzoic acid. A NOAEL of 500mg/kg/bw/day for P and F1 generation rats was established (CEP, 2001), (IPCS, 2000)
DEREK analysis confirmed a lack of reproductive structural alerts for the material alpha methyl cinnamaldehyde (GAD, 2012)
Overall alpha methyl cinnamaldehyde does not have adverse effects on fertility

Justification for selection of Effect on fertility via oral route:
Although not a reproductive study, the study was a 2 year chronic study which analysed the effect of the study of cinnamaldehyde on the rat and mice. There where no clinical finding iincluding the reproductive organs. Study is klimsch score 1 study with no adverse findings

Justification for selection of Effect on fertility via inhalation route:
No Study available

Justification for selection of Effect on fertility via dermal route:
No Study available

Effects on developmental toxicity

Description of key information
8 studies form the Weight of evidence approach for alpha methyl Cinnamaldehyde for an absence of developmental toxicity of the substance. 
Hardin at al (1987) found no effects when dosing Cinnamaldehyde to pregnant rats at 1200mg/kg/bw/day
The National Toxicty Information Service (1989) found no effects when dosing Cinnamaldehyde to pregnant rats at 1200mg/kg/bw/day
Zaitev et al, (1975) found no effects when dosing cinnamic alcohol and acid periodically to pregnant rats at 53.5 and 50mg/kg/bw/day respectively
Zaitev et al, (1973) found no effects when dosing cinnamic alcohol to pregnant rats at 50mg/kg/bw/day respectively for the whole pregnancy
CEP (2001) found no effects on multigenerations of benzoic acid (the ultimate metabolic product of cinnamaldehyde) on rats at 500mg/kg/day
In a DEREK QSAR (GAD,2012) analysis no structural alerts were found for alpha methyl cinnamaldehyde.
Mantovani et al (1989) did find effects on development at 25mg/kg/bw/day of cinnamldehyde. however the results are unconvincing and have been disregarded. Overall alpha methyl cinnamaldehyde is does not have adverse effects on developmental toxicity
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good, 7 peer reviwed endpoints form the basis of a weight of evidence argument.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

8 studies form a Weight of Evidence Approach for alpha cinnamaldehyde.

In a peer reviewed published developmental toxicity study of the treatment of cinnamaldehyde on mice, no changes were seen in: Number of dead/total; % body weight change and delivery of viable litter to the parental mice and no changes were seen in: Number of stillborn/litter; %survival; birth weight and weight gain of the offspring. Under the conditions of this study cinnamaldehyde has a NOEL for P1 and F1 mice of 1200mg/kg/bw/day (Hardin et al, 1987)

In a peer reviewed study for the US National toxicity program, cinnamaldehyde was tested for teratogenic effects. A NOAEL of 1200mg/kg/bw/day was obtained (NTIS, 1989)

In developmental studies designed to assess the effects of cinnamic alcohol and cinnamic acid on rat embryo's; NOAEL's of 53.5mg/kg (alcohol) and 50mg/kg (acid) were obtained (Zaitev, 1975)

In a developmental study designed to assess the effects of cinnamic alcohol on rat embryo's a NOAEL's of 53.5mg/kg was obtained (Zaitev,1973)

In a DEREK QSAR analysis there was no structural alerts found for alpha methyl cinnamaldehyde on reproductive and/ or developmental toxicity (GAD, 2012)

In a peer reviewed developmental study on the effects of benzoic acid on pregnant rats, the incidence of fetal malformations iof treated rats did not reach statistical significance (CEP, 2001)

In a peer reviewed study on benzoic acid on hamsters, No adverse effect in maternal survival was noted. A significant number of resorptions was noted in hamsters which received greater than or equal to; 30mg/kg/bw. The incidence of fetal malformations reached statistical significance at >600mg/kg/bw. Based on fetotoxicty:NOAEL, 60mg/kg/bw and LOAEL, 600mg/kg/bw (CEP, 2001)

Together all the above studies provide weight of evidence so that no further developmental/ teratogenicity work is planned on alpha-methylcinnamaldehyde and the substance does not require classification as such.


Justification for selection of Effect on developmental toxicity: via oral route:
Peer reviewed study used by the US National Toxicty Program to assess the safety of Cinnamaldehyde

Justification for selection of Effect on developmental toxicity: via inhalation route:
No Study available

Justification for selection of Effect on developmental toxicity: via dermal route:
Dermal route not the primary exposure No Study available

Justification for classification or non-classification

Based on the available data (14 studies providing a weight of evidence approach) alpha methyl cinnamaldehyde is not a reproductive (fertility or developmental) toxicant.

According to the classification and labelling directive of the EC commission, alpha methyl cinnamaldehyde does not need labelling for reproductive toxicity