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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Based on the grouping approach including their toxicological profile (see § 7.1), studies on Cinnamaldehyde, its tautomer alcohol (Cinnamic alcohol) and their corresponding acid (cinnamic acid) were considered reliable to assess the developmental toxicity of HCA and justify the read-across approach. Study published in german langage and only english summary is available. This is a published study following a stablished screening protocol that makes it adequate as a preliminary developmental toxicity study. It contains sufficient details to regard it as reliable for use in hazard assessment in a weight of evidence approach.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1987

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
It follows a short-term in vivo screening test based on proposal by Chernoff and Kavlock: Chernoff and Kavlock. An in vivo teratology screen utilizing pregnant mice as desccribed in J. Toxicol Environ Health 10: 541-550, 1982. Pregnant mice were dosed from day 6 to day 13 on gestation and were then allowed to deliver litters. Then litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recoreded as indices of potential developmental toxicity.
This is also address in: Hardin et al. Workshop on the Chernoff/Kavlock preliminary developmental toxicity test. Teratog Carcinog Mutagen 7, 119-27, 1987.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):Cinnamaldehyde
- Analytical purity: no data

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Charles River Breeding Laboratories
- Age at study initiation: 6-8weeks at receipt
- Weight at study initiation:no data
- Fasting period before study:no data
- Housing: singly housed in solid-bottom boxes
- Diet (e.g. ad libitum):ad libitum (BP Nutrition rat mouse breeder diet no. 3, Purina certified rodent chow)
- Water (e.g. ad libitum):ad libitum
- Acclimation period:3-5 days. Mice were received from vendor on gestation day 1-3, and on day 6 those judge unsuitable for the study were discarded

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%):no data
- Air changes (per hr):no data
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: To:no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Standard dosing volume was 10ml/kg. Volume was determined on the basis of body weights on day 6 of gestation.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
Time-mated mice were received from the vendor on days 0-2 of gestation.
Duration of treatment / exposure:
From day 6-13 of gestation
Frequency of treatment:
daily
Duration of test:
Total approximately 20 days:
Mice were allowed to deliver their pups. This was expected on day 18 of gestation. On postnatal day 3 dams and litter were discarded. On day 22 those that didn't deliver were killed.
Doses / concentrations
Remarks:
Doses / Concentrations:
1200 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
49 time-mated females to ensure at least 20 surviving pregnant mice at term. This was in consideration to the fact that it was expected that 10% of them would not survive and a pregnancy sucess of 50%.
Control animals:
other: corn oil
Details on study design:
- Dose selection rationale: A dose range finding study was conducted with 5 doses using ten virgin female mice per group. The LD10 predicted on the basis of this study was the single dose used.
- Rationale for animal assignment (if not random): random
- Other:

Examinations

Maternal examinations:
Body weights
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily during treatment and once daily on gestation days 14-17

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation day 6, 17 and postnatal day 3

FOOD CONSUMPTION : No

WATER CONSUMPTION : No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice only of those females that failed to deliver a litter by the presumed gestation day 22.
- Organs examined: uteri

Ovaries and uterine content:
uteri of females that failed to deliver litter by presumed gestation day 22
Fetal examinations:
litter weight on post natal day 1 and 3
number of live and dead pups on postnatal day 1 and 3
Statistics:
2-tail ANOVA for body weights on day 6 of gestation.
1-tail Fisher's exact test for proportion of pregnant animals delivering a viable litter (at least one liveborn pup) compared to control group.
2-tail Mann-Whitney U-test for mice that delivered viable litter: maternal body weight change from gestation day 6 to postnatal day 3, number of livborn pups per litter, percent neonatal survival to postnatal day 3, average pup weight at birth, average pup weight gain by postnatal day 3.
Indices:
Liveborn per litter, percentage survival of litter.
Historical control data:
none

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No mortality was observed. There was no difference in body weight gain or number of viable litters compared to control group.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEL
Effect level:
>= 1 200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
>= 1 200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Liveborn per litter, percentage survival of litter, pup birth weight and pup weight gain were comparable in the cinnamaldehyde treated group and control group.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOEL for maternal toxicity and the NOEL for developmental toxicity are 1200 mg/kg bw/day or higher cynnamaldehyde since no adverse effects were observed in mice.
Executive summary:

This study is used in a read-across approach to extrapolate the toxicity to development for alpha-hexylcinnamaldehyde. In a preliminary developmental study testing 60 chemicals, a dose of 1200 mg/kg bw/day of cinnamaldehyde was administered once daily by gavage to mice from days 6 -13 of gestation. The selected dose represented the predicted maternal LD10. Dams were allowed to deliver their litter around day 18 of gestation. Maternal body weights were recorded on gestation days 6, 17 and day 3 postpartum. Number of live pups and weight of pups was recorded on postnatal days 1 and 3. Reproductive endpoints were maternal weight change, litter size, birth weight and neonatal growth and survival to postnatal day 3.

Cinnamaldehyde induced no effect on maternal survival, maternal bodyweight gain and viable litters. Neonatal response showed no difference on liveborn / litter and percentage survival. Birth weight and weight gain was were normal for all pups. Following the classification used by Chernoff and Kavlock, cynnamaldehyde was recorded in the group of those that had no effect. Results in this assay and conventional mouse teratology tests were concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three non teratogen) of which 11 (nine teratogens, one fetotoxin and one non teratogen) produced evidence of developmental toxicity. Therefore, cynnamaldehyde was considered as low priority candidates for conventional testing on the basis of results.

Under the test conditions, no maternal toxicity and no development effect was observed at the highest dose tested. The No Observed Effect Level was higher than 1200 mg/kg bw/d for maternal toxicity and development toxicity in mice.

This study is considered as acceptable for the developmental toxicity.