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REACH

Cinnamyl alcohol

EC number: 203-212-3 | CAS number: 104-54-1

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Toxic effect type:: dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity study

OECD 421 study: NOAEL for reproductive and developmental toxicity was determined to be 350 mg/kg bw/day (highest dose tested) in rats following oral gavage exposure. The study was performed according to OECD 421 and GLP and was given a Klimisch 1 score.

Link to relevant study records

Reference

Endpoint:: screening for reproductive / developmental toxicity
Type of information:: experimental study
Adequacy of study:: key study
Study period:: March 2020 to June 2020
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:: 2016
Deviations:: no
GLP compliance:: yes (incl. QA statement)
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Details on species / strain selection:: In-house bred.
Sex:: male/female
Details on test animals or test system and environmental conditions:: The rats were 9 weeks of age at receipt. Females were nulliparous and non-pregnant.
Body weight at receipt :
Males: 250.25 to 297.51 g
Females: 200.85 to 249.90 g
Animals were housed under standard laboratory conditions in an environmentally monitored, air-conditioned room with adequate fresh air supply (12 to 15 air changes per hour), room temperature 19.6 to 23.2oC and relative humidity 46 to 65%, with 12 hours fluorescent light and 12 hours dark cycle. The temperature and relative humidity were recorded once daily
Animals were housed in a standard polypropylene cage (size: L 430 x B 285 x H 150 mm) with stainless steel mesh top grill having facilities for holding pelleted food and drinking water in water bottle fitted with stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
- During acclimatization, two animals of same sex were housed.
- Pre-mating – In each cage, two animals of the same sex and group were housed.
- Cohabitation Period (mating) – In each cage, two animals (one male and one female) of the same group were housed.
- Post-mating - After confirming presence of sperm in the vaginal smear and/or vaginal plugs (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually. Sterilized paper shreds were provided as a nesting material for mated females from gestation day 20 onwards.

Altromin maintenance diet for rats and mice (manufactured by Altromin Spezialfutter GmbH & Co.KG) was available ad libitum to the animals throughout the experimental period. The contaminant analysis test report of the feed is included as Annexure 2. A sample of feed from the batch used in the study was retained until the finalization of study report and was discarded on the day of finalization of study report.

Water was available ad libitum throughout the acclimatization and experimental period. Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
Route of administration:: oral: gavage
Vehicle:: corn oil
Details on exposure:: The test item/vehicle was administered by oral (gavage) route using stainless steel intubation cannula attached to a disposable syringe. All the doses were administered in an equivolume of 5 mL/kg with the concentration of 17.5, 35 and 70 mg/mL for low, mid and high dose groups, respectively. Vehicle was administered to the control group at an equivolume of 5 mL/kg body weight. The actual dose volume for each animal was calculated based on the most recent body weight. The test item formulations were administered as soon as possible after preparation
Details on mating procedure:: The males and females were placed in 1:1 ratio. Every morning, the vaginal smear of each female was examined for presence of sperm in the vaginal smear. Each femalerat was housed with its respective male rat until pregnancy occured by evidence of sperm in the vaginal smear or until two weeks. Day ‘0’ pregnancy was confirmed by the presence of sperm in the vaginal smear. Four females one each from groups G1, G2 and two from group G4 were not mated during the 14 days cohabitation period. These females were paired with a proven male on the day 14 of cohabitation till day 17 for animals from groups G1, G2 and till day 15 for the animal from group G4. The females confirmed with mating but not littered were sacrificed on day 25 after gestation day ‘0’.
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Homogeneity and dose formulation analysis was done by Analytical Chemistry department of Bioneeds India Private Limited. The analysis was done as per methods detailed in the Study Plan No. BIO-ANM 1588 and the results are presented in the report. Sampling and analysis of the formulations were performed during week 1 and week 5 of the treatment. The samples were collected in duplicates from top, middle and bottom layers from low, mid and high dose concentrations and in duplicates from single layer from vehicle control. The exact volumes of test item formulation samples are included in the study report. The prepared test item formulations were stirred using magnetic stirrer during sampling.The collected samples were transferred to Analytical Chemistry Department of Bioneeds India Private Limited for dose formulation analysis. One set of aliquots of each formulation were analyzed. The second aliquot was stored for backup purpose at established stability conditions. The second set of samples were discarded as the analysis results of first set of samples were within the limits. Formulations were considered acceptable, since the mean results were within the range of 85 to 115% of the nominal concentration and the relative standard deviation (% RSD) is ≤10%.
Duration of treatment / exposure:: The males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 35 days of treatment). Thefemales were treated for two weeks pre-mating period, during mating and pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on PND 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed).
Frequency of treatment:: Once daily.
Dose / conc.:: 350 mg/kg bw/day (nominal)
Remarks:: G4
Dose / conc.:: 175 mg/kg bw/day (nominal)
Remarks:: G3
Dose / conc.:: 87.5 mg/kg bw/day (nominal)
Remarks:: G2
Dose / conc.:: 0 mg/kg bw/day (nominal)
Remarks:: Vehicle control (G1)
No. of animals per sex per dose:: 12
Control animals:: yes, concurrent vehicle
Details on study design:: - Dose levels were selected based largely on the results of an OECD 414 with cinnamaldehyde (CAS 104-55-2) (Sustainability Support Services Europe AB, Study No 19_49_143). In this OECD 414 study, unexpected mortality was observed at 500 mg/kg bw/day (1 dam on GD 9) and at 1000 mg/kg bw/day (multiple dams from GD 6 and onwards). Dose levels in the study after inclusion of an additional dose group were 0, 125, 250, 500 and 1000 mg/kg bw/day. NOAEL for general maternal toxicity was established at 250 mg/kg bw/day due to significant/severe toxicity at 500 mg/kg bw/day, which included: one death, clinical signs of toxicity (at least one of the following symptoms were observed in all animals treated at 500 mg/kg bw/day: hypothermia, lethargy, prostration, and excessive salivation), biologically significant changes in body weight on GD 20, and gross and microscopic lesions in stomach and lung. Based on these data and considering the longer exposure duration in an OCD 421 study compared with an OECD 414 study, a top dose of 350 mg/kg bw/day was selected in present study. This dose level was expected to produce clinical signs of toxicity, biologically/statistically significant decreases in body weight, and pathological lesions, but no mortality or suffering. Both cinnamyl alcohol (CAS 104-54-1) and cinnamaldehyde (CAS 104-55-2) are aromatic monocyclic compounds. The basic structure of these two substances is the monocyclic benzene moiety with a three-carbon unsaturated (i.e., at the 2,3- position) chain. Cinnamyl alcohol has a hydroxy group at the end of the chain, while cinnamaldehyde has an aldehyde group at the same position. The metabolic pathway of cinnamyl alcohol and cinnamaldehyde is also well-described (Bicker, et al., Food and Chemical Toxicology, 43 (2005) 799–836 and JECFA, 2000. WHO Food Additives Series: 46). Cinnamyl alcohol and cinnamaldehyde are both rapidly absorbed from the gut, metabolized and excreted primarily in the urine and to a minor extent, in faeces. Cinnamyl alcohol is rapidly converted to aldehyde via alcohol dehydrogenase to cinnamaldehyde, which would be converted to cinnamic acid in turn. Thus, cinnamic acid is the major intermediate metabolite for both chemicals. On this basis, the toxicological data on cinnamaldehyde in the mentioned OECD 414 study was considered appropriate and sufficient for dose level selection in the presented OECD 421 study with cinnamyl alcohol.

- The animals were weighed and arranged in ascending order of their body weights. These body weight stratified animals were distributed to all the groups using Microsoft Excel Spreadsheet, such that body weight variation of animals selected for the study did not exceed ±20% (Males: -12.73 to 14.55%; Females: -14.11 to 8.69%) of the mean body weight of each sex. The grouping was done one day prior to the initiation of treatment by randomization based on the body weights. Body weight of the animals were analyzed statistically for mean body weight to rule out statistically significant differences between groups within each sex prior to dosing.
Positive control:: Not included.
Parental animals: Observations and examinations:: Mortality, clinical signs of toxicity, body weight, food intake, gestation length, and pre-coital interval.
Oestrous cyclicity (parental animals):: Oestrus cyclicity was monitored for two weeks after the five days of acclimatization to evaluate the normal oestrus cycle (4 to 5 days). Only females with normal oestrus cyclicity were selected for the treatment. Vaginal smears were monitored daily from the beginning of the treatment period until evidence of mating. When obtaining vaginal/cervical cells, care was taken to avoid disturbance of mucosa, which may induce pseudopregnancy. The status of oestrus cyclicity of females was determined on termination day (lactation day 14).
Litter observations:: Number of pups per litter, sex ratio, live birth index, pup survival, pup weight, anogenital distance, male pup nipple/areolae retention.
Postmortem examinations (parental animals):: Uteri observations, hormone levels, organ weight, gross pathology and histopathology as per OECD 421 (2016).
Postmortem examinations (offspring):: Gross pathology
Statistics:: STATISTICAL ANALYSIS
The raw data was subjected to computer statistical processing. The computer printout of the data (in the form of appendix) was verified with the raw data. After verification, the data was subjected to various statistical analyses using SPSS software version 22. All analysis and comparisons were evaluated at the 95% level of confidence (P<0.05), indicated by the aforementioned tests were designated by the superscripts throughout the report as stated below:
* Statistically significant (P<0.05) change than the vehicle control group.

Note: Data of non-pregnant females were presented in the individual animal data but excluded for mean calculations and statistical analysis. The data of females mated but not littered and lactation data of females with total litter loss were presented in individual animal data and considered for mean calculations and statistical analysis where applicable.
The statistical analysis was followed but not limited to the parameters as mentioned below table.
Reproductive indices:: Male mating index, male fertility index, female mating index, female fertility index, gestation index, and parturition index.
Offspring viability indices:: Live birth index and pup survival indexes on PND 4, 7, and 13.
Clinical signs:: no effects observed
Description (incidence and severity):: There were no clinical signs of toxicity in the study.
Mortality:: no mortality observed
Description (incidence):: All animals survived to scheduled sacrifice.
Body weight and weight changes:: no effects observed
Description (incidence and severity):: There were no significant changes in body weight or in body weight gain with respect to day 1 of treatment.
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: No significant changes were observed except for statistically significant decreases in food intake between GD 7-14 (mean 20.52 g/rat/day) and between 14 to 20 (mean, 23.25 g/rat/day) in G4 dams compared to G1 dams (mean, 23.07 g/rat/day between GD 7-14 and mean, 26.34 g/rat/day between GD 14-20). These effects were considered to be non-adverse since no significant changes in body weight or body weight gain were observed during gestation or lactation.
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: not examined
Haematological findings:: not examined
Clinical biochemistry findings:: no effects observed
Description (incidence and severity):: No significant changes in serum thyroxine (T4) hormone levels were observed (examined in G1, G2, G3 and G4 male rats).
Endocrine findings:: no effects observed
Description (incidence and severity):: No significant changes in serum thyroxine (T4) hormone levels were observed (examined in G1, G2, G3 and G4 male rats).
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Histopathological findings: non-neoplastic:: no effects observed
Description (incidence and severity):: Microscopic findings were restricted to minimal degeneration of seminiferous tubules in testes observed in two males treated at 350 mg/kg. This finding was considered incidental as the changes were of minimal severity, distributed in focal areas, and unilateral in nature, and as such changes are commonly observed in laboratory rats.
Histopathological findings: neoplastic:: no effects observed
Reproductive function: oestrous cycle:: no effects observed
Description (incidence and severity):: There were no irregularities observed in the oestrus cyclicity of females in any of the tested dose groups during pre-mating and mating treatment periods. The mean length of oestrus cycle per female during pre-mating and mating treatment period was unaffected by the test item administration in any of the tested dose groups when compared with vehicle control group.
Reproductive function: sperm measures:: not examined
Reproductive performance:: no effects observed
Description (incidence and severity):: Male Mating Index (%): A total of 11 (out of 12), 11 (out of 12), 12 (out of 12) and
10 (out of 12) males were confirmed with mating with a mating index of 91.7%,
91.7%, 100.0% and 83.3% from group G1, G2, G3 and G4, respectively. There were
no statistically significant differences noted in male fertiltiy index at any of the tested dose groups when compared with vehicle control group.

Male Fertility Index (%): A total of 11 (out of 12), 11 (out of 12), 12 (out of 12) and
10 (out of 12) males were confirmed with impregnating a female with a fertiltiy index of 91.7%, 91.7%, 100.0% and 83.3% from group G1, G2, G3 and G4, respectively. There were no statistically significant differences noted in male fertiltiy index at any of the tested dose groups when compared with vehicle control group.

Female Mating Index (%): All the 12 females from each tested dose group (G2, G3 and G4) and vehicle control group (G1) were confirmed with mating with a mating index of 100% for each group.

Female Fertility Index (%): A total of 12 (out of 12), 11 (out of 12), 11 (out of 12) and 11 (out of 12) females were confirmed with pregnancy (presence of implantations / presence of live or dead fetuses / evidence of parturition) with a fertility index of 100.0%, 91.7%, 91.7% and 91.7% from group G1, G2, G3 and G4, respectively. There were no statistically significant effects on female fertility indices of dosed groups when compared with vehicle control group.

Pre-coital Interval (Days): A total of 12 pairs were left for cohabitation initially from each tested dose group and vehicle control group. The mean pre-coital interval was 6.75, 8.08, 7.83 and 8.92 days for groups G1, G2, G3 and G4, respectively. There was no statistically significant difference in this parameter in dosed groups when compared with the vehicle control group.

Gestation Length (Days): The mean gestation length [confirmation of mating to
parturition] was 22.58, 22.55, 22.55 and 22.73 days for groups G1, G2, G3 and G4,
respectively. There was no statistically significant difference in this parameter in any of the dosed groups when compared with the vehicle control group.

Gestation Index / Parturition Index (%): A total of 12 (out of 12), 11 (out of 11), 11
(out of 11), and 11 (out of 11) females were confirmed with live born pups with a
gestation / parturition index of 100%, 100%, 100% and 100% from group G1, G2, G3 and G4 respectively.

Pregnancy Index (%): A total of 12 (out of 12), 11 (out of 12), 11 (out of 12), and 11 (out of 12) females were confirmed with live born pups with a pregnancy index of 100.0%, 91.7%, 91.7% and 91.7% from group G1, G2, G3 and G4, respectively. There was no statistically significant difference in this parameter in any of the dosed groups when compared with the vehicle control group.

Mean number of Implantations (No.): The mean number of implantations per litter was 11.75, 11.18, 10.91 and 11.55 from group G1, G2, G3 and G4, respectively. There was no statistically significant difference in this parameter in any of the dosed groups when compared with the vehicle control group.

Post implantation loss per litter (No.) and (%): The post implantation losses per litter was 0.50, 0.55, 0.09 and 0.45 with a percentage of 4.01, 4.33, 5.31 and 4.66 from group G1, G2, G3 and G4, respectively. There was no statistically significant
difference in this parameter in any of the dosed groups when compared with the
vehicle control group.

Postnatal losses on Lactation Day 13 (No.) and (%): There was no postnatal loss
noted in any of the litters from all the dosed and vehicle control groups.

Percentage of male/female offspring per litter (%): The percentage of male and female offspring per litter was 48.83 and 51.17 for G1, 55.51 and 44.49 for G2, 47.13 and 52.87 for G3 and 56.90 and 43.10 for G4 respectively. There was no statistically significant difference in this parameter in any of the tested dose groups when compared with the vehicle control group.

The data of 12 (out of 12 mated females), 11 (out of 12 mated females),
11 (out of 12 mated females) and 11 (out of 12 mated females) females confirmed with parturition from group G1, G2, G3 and G4, respectively, were considered for mean calculations and subjected to statistical analysis to analyse the maternal endpoints.
: Key result
Dose descriptor:: NOAEL
Effect level:: >= 350 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: clinical signs; mortality; body weight and weight gain; food consumption and compound intake; clinical biochemistry; organ weights and organ / body weight ratios; gross pathology; histopathology: non-neoplastic; histopathology: neoplastic; reproductive function (oestrous cycle); reproductive performance
: Key result
Critical effects observed:: no
Clinical signs:: no effects observed
Description (incidence and severity):: No abnormal behaviour was observed in any of the pups.
Mortality / viability:: mortality observed, non-treatment-related
Description (incidence and severity):: Live birth indexes were 99.40, 98.48, 100, and 100% in G1, G2, G3, and G4, respectively. Pup survival index was 100% in all groups on PND 4, 7, and 13.
Body weight and weight changes:: no effects observed
Food consumption and compound intake (if feeding study):: not examined
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: not examined
Haematological findings:: not examined
Clinical biochemistry findings:: no effects observed
Description (incidence and severity):: No significant changes in serum thyroxine (T4) hormone levels were observed (examined in pups on PND 13).
Urinalysis findings:: not examined
Sexual maturation:: not examined
Anogenital distance (AGD):: no effects observed
Description (incidence and severity):: No significant changes in AGD or AGD ratio (cube root body weight) were observed.
Nipple retention in male pups:: no effects observed
Description (incidence and severity):: There were no occurrences of nipples in male pups examined on PND 13.
Organ weight findings including organ / body weight ratios:: not examined
Gross pathological findings:: no effects observed
Description (incidence and severity):: No gross pathological changes were observed in any of the adult animals or pups.
Histopathological findings:: not examined
: Key result
Dose descriptor:: NOAEL
Generation:: F1
Effect level:: >= 350 mg/kg bw/day (nominal)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: viability; sexual maturation; clinical signs; mortality; body weight and weight gain; clinical biochemistry; gross pathology
: Key result
Critical effects observed:: no
: Key result
Reproductive effects observed:: no
Conclusions:: The study-derived NOAEL for general, reproductive, and developmental toxicity was 350 mg/kg bw/day.
Executive summary:: A reproduction/developmental toxicity screening test as per the GLP compliance and in accordance with OECD TG 421 was performed using male and female Sprague Dawley rats for assessing the potential of the test chemical to cause adverse effect on the reproductive potential and effects on the developing fetuses. In this study 12 animals per sex per group were included which were grouped into 4 groups i.e. 0 mg/kg bw (Vehicle Control Group), 87.5 mg/kg bw (Low Dose Group), 175 mg/kg bw (Mid Dose Group) and 350 mg/kg bw (High Dose Group), respectively. Males were dosed for a period of 35 days (two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period, while females were dosed for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13 (day 49 to day 67 ). The vehicle and test chemical formulations were administered orally by gavage at the dose volume of 5 mL/kg body weight. All the animals were observed once daily for clinical signs, twice daily for mortality and morbidity. The weekly body weight and weekly feed consumption was recorded once weekly (except during cohabitation) for all the animals. The serum thyroxine hormone (T4) levels were estimated for all males by ELISA method. The gross pathology and organ weighing were performed on the day of termination for all animals. Detailed histopathological examination was conducted on ovaries, testes and epididymis from the groups G1 and G4 animals with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure. All the males were evaluated for reproductive performance such as, mating and fertility index. All the dams were evaluated for reproductive performance such as, mating index, fertility index, gestation index, parturition index, pre-coital interval and gestation length. All the females were evaluated for oestrus cyclicity during premating, mating treatment periods and at termination. The body weight and feed consumption was recorded for all the females during gestation day 0, 7, 14 and 20 and on lactation days 1, 4, 7 and 13. The terminal body weight for all the animals was measured on the day of the termination (LD 14). At birth/litter observation parameters such as, number of live/dead pups born, litter size, sex ratio, live birth index per litter and pup survival index were observed / calculated for all the litters. The total number of implantations per litter was recorded during necropsy and the post-implantation and post-natal losses were calculated. The pups were observed once daily for external examinations and twice daily for mortalities till termination [post-natal day (PND) 13], weighed individually on PND 1, 4, 7 and 13, measured for ano-genital distance (AGD) to calculate AGD ratio on PND 4, observed for retention of any nipples/areolae in male pups on PND 13. All the pups were observed for gross pathological observations at termination and analyzed the serum collected from PND 13 pups for thyroxine hormone (T4) levels by using ELISA method. There were no clinical signs of toxicity and no mortality/morbidity noted at all in any of the tested dose groups of either sex animals. There were no changes noted in mean body weight, percent change in mean body weight gain and mean feed consumption at all thein any of the tested dose groups of both the either sex. There were no changes noted in mean serum thyroxine hormone (T4) levels at all in any of the tested dose group of males. The absolute and relative organ weights did not reveal any changes at all thein any of the tested dose groups. No macroscopic changes noted during conduct of necropsy in at all the vehicle control and tested dosed groups of both either the sex. Histopathological examination conducted for group G4 animals of both sexes did not reveal any test chemical related microscopic changes. For reproduction toxicity end points, there were no effects noted in male mating and fertility indexes of all tested dose groups. No effects were noted in female mating index, fertility index, gestation index, parturition index, pre-coital interval and gestation length in at all tested all dosed groups. For maternal toxicity end points, there were no irregularities noted in oestrus cyclicity and no changes in mean cycle length, no changes in mean body weight, percent change in mean body weight gain and mean feed consumption were observed all dosed groups during gestation and lactation periods at all the tested dose groups. There were no changes observed in birth parameters and litter observations during lactation period. The number of implantations, post-implantation and post-natal losses were unaffected by the test chemical at all the tested in all treated dose groups. For developmental toxicity end points, there were no external anomalies noted and no test chemical-related mortalities among pups noted were observed in pups during post-natal period at doses tested. at all the tested dose group litters. There were no test chemical-related changes noted in mean pup weight and mean pup ano-genital distance ratio per litter in either sex at all the tested dose groups at doses tested. There were no occurrences of nipples in male pups of vehicle control and treated groups on PND 13 examined on PND 13 from all the tested dose and vehicle control group litters. There were no gross pathological changes noted in any of the pups during scheduled sacrifice from all the tested and control group litters at any doses tested. There were no changes noted in serum thyroxine (T4) hormone levels estimated for PND 13 (from all litters) pups at all the tested dose groups up litters. Thus, based on all the available data, it was concluded that the test chemical did not induce any systemic or reproductive toxicity in all animals in the tested dose groups and therefore the NOAEL for the test chemical was considered to be 350 mg/kg bw/day viz. the highest dose tested for the study.

Effect on fertility: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 350 mg/kg bw/day
Study duration:: subacute
Species:: rat
Quality of whole database:: Klimisch 1

Effect on fertility: via inhalation route

Endpoint conclusion:: no study available

Effect on fertility: via dermal route

Endpoint conclusion:: no study available

Additional information

Toxicity to reproduction:

Study 1:

A reproduction/developmental toxicity screening test as per the GLP compliance and in accordance with OECD TG 421 was performed using male and female Sprague Dawley rats for assessing the potential of the test chemical to cause adverse effect on the reproductive potential and effects on the developing fetuses. In this study 12 animals per sex per group were included which were grouped into 4 groups i.e. 0 mg/kg bw (Vehicle Control Group), 87.5 mg/kg bw (Low Dose Group), 175 mg/kg bw (Mid Dose Group) and 350 mg/kg bw (High Dose Group), respectively. Males were dosed for a period of 35 days (two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period, while females were dosed for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13 (day 49 to day 67 ). The vehicle and test chemical formulations were administered orally by gavage at the dose volume of 5 mL/kg body weight. All the animals were observed once daily for clinical signs, twice daily for mortality and morbidity. The weekly body weight and weekly feed consumption was recorded once weekly (except during cohabitation) for all the animals. The serum thyroxine hormone (T4) levels were estimated for all males by ELISA method. The gross pathology and organ weighing were performed on the day of termination for all animals. Detailed histopathological examination was conducted on ovaries, testes and epididymis from the groups G1 and G4 animals with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure. All the males were evaluated for reproductive performance such as, mating and fertility index. All the dams were evaluated for reproductive performance such as, mating index, fertility index, gestation index, parturition index, pre-coital interval and gestation length. All the females were evaluated for oestrus cyclicity during premating, mating treatment periods and at termination. The body weight and feed consumption was recorded for all the females during gestation day 0, 7, 14 and 20 and on lactation days 1, 4, 7 and 13. The terminal body weight for all the animals was measured on the day of the termination (LD 14). At birth/litter observation parameters such as, number of live/dead pups born, litter size, sex ratio, live birth index per litter and pup survival index were observed / calculated for all the litters. The total number of implantations per litter was recorded during necropsy and the post-implantation and post-natal losses were calculated. The pups were observed once daily for external examinations and twice daily for mortalities till termination [post-natal day (PND) 13], weighed individually on PND 1, 4, 7 and 13, measured for ano-genital distance (AGD) to calculate AGD ratio on PND 4, observed for retention of any nipples/areolae in male pups on PND 13. All the pups were observed for gross pathological observations at termination and analyzed the serum collected from PND 13 pups for thyroxine hormone (T4) levels by using ELISA method. There were no clinical signs of toxicity and no mortality/morbidity noted at all in any of the tested dose groups of either sex animals. There were no changes noted in mean body weight, percent change in mean body weight gain and mean feed consumption at all thein any of the tested dose groups of both the either sex. There were no changes noted in mean serum thyroxine hormone (T4) levels at all in any of the tested dose group of males. The absolute and relative organ weights did not reveal any changes at all thein any of the tested dose groups. No macroscopic changes noted during conduct of necropsy in at all the vehicle control and tested dosed groups of both either the sex. Histopathological examination conducted for group G4 animals of both sexes did not reveal any test chemical related microscopic changes. For reproduction toxicity end points, there were no effects noted in male mating and fertility indexes of all tested dose groups. No effects were noted in female mating index, fertility index, gestation index, parturition index, pre-coital interval and gestation length in at all tested all dosed groups. For maternal toxicity end points, there were no irregularities noted in oestrus cyclicity and no changes in mean cycle length, no changes in mean body weight, percent change in mean body weight gain and mean feed consumption were observed all dosed groups during gestation and lactation periods at all the tested dose groups. There were no changes observed in birth parameters and litter observations during lactation period. The number of implantations, post-implantation and post-natal losses were unaffected by the test chemical at all the tested in all treated dose groups. For developmental toxicity end points, there were no external anomalies noted and no test chemical-related mortalities among pups noted were observed in pups during post-natal period at doses tested. at all the tested dose group litters. There were no test chemical-related changes noted in mean pup weight and mean pup ano-genital distance ratio per litter in either sex at all the tested dose groups at doses tested. There were no occurrences of nipples in male pups of vehicle control and treated groups on PND 13 examined on PND 13 from all the tested dose and vehicle control group litters. There were no gross pathological changes noted in any of the pups during scheduled sacrifice from all the tested and control group litters at any doses tested. There were no changes noted in serum thyroxine (T4) hormone levels estimated for PND 13 (from all litters) pups at all the tested dose groups up litters. Thus, based on all the available data, it was concluded that the test chemical did not induce any systemic or reproductive toxicity in all animals in the tested dose groups and therefore the NOAEL for the test chemical was considered to be 350 mg/kg bw/day viz. the highest dose tested for the study.

Effects on developmental toxicity

Description of key information

Read-across on developmental toxicity

The structural comparability between cinnamyl alcohol (CAS number: 104-54-1) and cinnamaldehyde (CAS number: 104-55-2) and the similarities in their metabolism products presented above support this read-across hypothesis that the target and source substances have similar toxicological properties because they bio-transform into common products. Cinnamic acid is the common intermediate metabolite, and the major urinary metabolites for both substances are glycine or glucuronic acid conjugates of benzoic acid, which are formed as a result of the β-oxidation of cinnamic acid.

The key aspects of the present read-across justification are as follows:

1) The similar chemical structure and physicochemical characteristics of the target and source substances result in similar bioavailability, metabolism, and reactivity, resulting in similar biological and functional effects.

2) The toxicologically relevant metabolite of the target and source substances is identical (cinnamic acid as the common intermediate metabolite).

3) The target and source substances are absorbed almost exclusively through the gastrointestinal tract and metabolised in the same way.

4) The suspected rate and extent of absorption and metabolism of the target and source substances are similar, based on the available toxicokinetic studies of humans and physicochemical properties. This results in similar exposures to the common metabolite cinnamic acid.

5) Available toxicological study data suggest similar local and systemic toxicity profiles for the target and source substances.

6) In-silico toxicological profile of the target and source substances is remarkably similar.

Therefore, based on the considerations above, it can be concluded that the outcome of a prenatal developmental toxicity study in the rat with the source substance is likely to predict the same properties of the target substance and is considered adequate to fulfil the information requirement of Annex IX, 8.7.2. The dose descriptors obtained from the existing prenatal developmental toxicity study performed with cinnamaldehyde (CAS number: 104-55-2) are considered an appropriate starting point for deriving a DNEL. Using the worst-case scenario, the following dose descriptors are predicted for prenatal developmental toxicity of cinnamyl alcohol (CAS number: 104-54-1): NOAEL_{maternal systemic}= 250 mg/kg bw/day, NOAEL_{developmental}=250 mg/kg bw/day.

OECD 414 with cinnamaldehyde (CAS 104-55-2):

The substance (CAS 104 -55 -2) was given by oral gavage to 25 pregnant Wistar rats at 0 (vehicle), 125, 250 and 500 mg/kg bw/day from GD 5 to 19. The study was performed according to OECD 414 (adopted in 2018) and GLP. NOAEL for maternal systemic toxicity was considered at 250 mg/kg bw/day. This effect level was based on mortality, clinical signs of toxicity, statistically/biologically significant decreases in body weight on GD 17 and 20, significant decreases in food intake on GD 8 and 11, and several gross/histopathology findings at 500 mg/kg bw/day. NOAEL for developmental toxicity was considered at 250 mg/kg bw/day. This effect level was based on lower foetal body weights at 500 mg/kg bw/day.

Link to relevant study records

Referenceopen all close all

Reference 1

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In this read-across, we intend to predict the outcomes of the prenatal developmental toxicity of cinnamyl alcohol (CAS number: 104-54-1, EC: 203-212-3). This prediction is based on the hypothesis that the target and source substances have similar toxicological properties because they bio-transform into common products. This hypothesis corresponds to scenario 1 under Read-Across Assessment Framework (RAAF).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attached justifiation file

3. ANALOGUE APPROACH JUSTIFICATION
The structural comparability between cinnamyl alcohol (CAS number: 104-54-1) and cinnamaldehyde (CAS number: 104-55-2) and the similarities in their metabolism products presented above support this read-across hypothesis that the target and source substances have similar toxicological properties because they bio-transform into common products. Cinnamic acid is the common intermediate metabolite, and the major urinary metabolites for both substances are glycine or glucuronic acid conjugates of benzoic acid, which are formed as a result of the β-oxidation of cinnamic acid.
The key aspects of the present read-across justification are as follows:
1) The similar chemical structure and physicochemical characteristics of the target and source substances result in similar bioavailability, metabolism, and reactivity, resulting in similar biological and functional effects.
2) The toxicologically relevant metabolite of the target and source substances is identical (cinnamic acid as the common intermediate metabolite).
3) The target and source substances are absorbed almost exclusively through the gastrointestinal tract and metabolised in the same way.
4) The suspected rate and extent of absorption and metabolism of the target and source substances are similar, based on the available toxicokinetic studies of humans and physicochemical properties. This results in similar exposures to the common metabolite cinnamic acid.
5) Available toxicological study data suggest similar local and systemic toxicity profiles for the target and source substances.
6) In-silico toxicological profile of the target and source substances is remarkably similar.

4. DATA MATRIX
See attached justification file

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

Systematic toxicity

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: not specified

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: not specified

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Conclusions:

it can be concluded that the outcome of a prenatal developmental toxicity study in the rat with the source substance is likely to predict the same properties of the target substance and is considered adequate to fulfil the information requirement of Annex IX, 8.7.2. The dose descriptors obtained from the existing prenatal developmental toxicity study performed with cinnamaldehyde (CAS number: 104-55-2) are considered an appropriate starting point for deriving a DNEL. Using the worst-case scenario, the following dose descriptors are predicted for prenatal developmental toxicity of cinnamyl alcohol (CAS number: 104-54-1): NOAELmaternal systemic= 250 mg/kg bw/day, NOAELdevelopmental =250 mg/kg bw/day.

Executive summary:

The key aspects of the present read-across justification are as follows:

2) The toxicologically relevant metabolite of the target and source substances is identical (cinnamic acid as the common intermediate metabolite).

3) The target and source substances are absorbed almost exclusively through the gastrointestinal tract and metabolised in the same way.

5) Available toxicological study data suggest similar local and systemic toxicity profiles for the target and source substances.

6) In-silico toxicological profile of the target and source substances is remarkably similar.

Reference 2

Endpoint:: developmental toxicity
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Justification for type of information:: Data is from a study report.
Qualifier:: according to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:: 25 June 2018
Principles of method if other than guideline:: According to OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: Wistar
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Animals were procured from CPCSEA approved vendor
- Age at study initiation: 10-12 weeks at the time of receipt
- Weight at study initiation: 213.94 g to 215.56 g
- Fasting period before study: No Data Available
- Housing: One to three rats were housed in each polycarbonate cage (length 37 cm X breadth 21 cm X height 20 cm). During mating, one male and two female rats were housed in a single cage. Pregnant females were housed individually. Sterilized corn-cob produced from pure corn, dried and free from dust, procured from approved supplier, was used as bedding material. It was renewed as often as necessary to keep the animals dry and clean.
- Diet (e.g. ad libitum): A conventional laboratory pellet diet from approved supplier (Nutrivet Life Sciences, Pune) was offered ad libitum.
- Water (e.g. ad libitum): Aquaguard™ filtered drinking water was offered ad libitum in regularly cleaned bottles.
- Acclimation period: 2-3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.20 and 23.90 °C
- Humidity (%): 46.20 and 66.50 %.
- Air changes (per hr): at least 12 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark
Route of administration:: oral: gavage
Vehicle:: corn oil
Details on exposure:: PREPARATION OF DOSING SOLUTIONS:The test chemical was weighed and dissolved in corn oil to achieve desired concentration of test item, at each dose level. Formulations were prepared one day prior or every day and stored at room temperature until usage due to the proved stability of up to 24 hours. At the time of dosing, dose formulations were kept on a magnetic stirrer for maintaining homogeneity of test formulation.

DIET PREPARATION
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was dissolved in corn oil. Corn oil was selected as a vehicle, since it is widely used as vehicle in oral toxicity study and it is well tolerated at the selected dose volume.
- Concentration in vehicle: 0 mg/ml (control), 31.25 mg/ml (Low Dose), 62.5 mg/ml (Mid Dose) and 125 mg/ml (High Dose)
- Amount of vehicle (if gavage): 4 ml/kg bw
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The dose formulation samples [of doses viz; 0 mg/kg (Control), 125 mg/kg (Low dose), 250 mg/kg (Mid dose), and 500 mg/kg (High dose)] were analyzed. Two replicates of approximately 2 mL samples from each upper, middle and lower layer were analyzed for homogeneity and active ingredient analysis. The concentration were calculated and reported. The dose formulation analysis was carried out in the first week of treatment and in the last week of treatment, using a validated analytical method.
Details on mating procedure:: - Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: two females were kept with a single male (2:1 pairing)
- Length of cohabitation: Until evidence of copulation was observed.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: No Data Available
- Further matings after two unsuccessful attempts: No Data Available
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: N/A
Duration of treatment / exposure:: Pregnant females were exposed to test chemical from gestation day 5 to gestation day 19.
Frequency of treatment:: Once Daily from gestation day 5 to gestation day 19.
Duration of test:: Up to GD 20
Dose / conc.:: 0 mg/kg bw/day (actual dose received)
Remarks:: Control Group
Dose / conc.:: 125 mg/kg bw/day (actual dose received)
Remarks:: Low Dose Group
Dose / conc.:: 250 mg/kg bw/day (actual dose received)
Remarks:: Mid Dose Group
Dose / conc.:: 500 mg/kg bw/day (actual dose received)
Remarks:: High Dose Group
No. of animals per sex per dose:: 25 animals per sex per dose
Control animals:: yes, concurrent vehicle
Details on study design:: Experimental design: Pregnant females were exposed from GD 5 to 19. On gestation day 20 females were sacrificed, the uterine content was examined, and the foetuses were evaluated for gross, visceral, and skeletal malformations and variations/anomalies.
Dose selection rationale: dose levels were selected based on published data.
The rationale for animal assignment (if not random): Randomization was done based on the body weight of the pregnant females on GD 0. The animals were assigned in an unbiased manner to the control and treatment groups. Females inseminated with the same male were evenly distributed across the groups. Individual body weights were within ± 20% of the respective groups mean after randomiz
Maternal examinations:: MORTALITY/MORBIDITY: Yes
All animals were observed twice daily (once before and once after the day’s activities) for morbidity and/or mortality.
DETAILED CLINICAL OBSERVATIONS: Yes
All animals were observed daily for clinical signs and symptoms after approximately 1 hour after dose administration.
BODY WEIGHT: Yes
Animals were weighed at the time of receipt, on gestation day 0, on the first day of dosing (GD 5), and on gestation days 8, 11, 14, 17 and 20.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes,
The weight of feed provided, and that leftover was recorded on gestation day 0, on the first day of dosing (GD 5), and on gestation days 8, 11, 14, 17 and 20. The mean feed consumption was calculated on gestation day 5, 8, 11, 14, 17 and 20.
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not data.
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not examined.
POST-MORTEM EXAMINATIONS: Yes
Sacrifice on gestation day (GD) 20. All animals including those found dead or sacrificed in moribund condition were subjected to complete gross necropsy.
BLOOD COLLECTION & HORMONE ANALYSIS: Yes
Blood was collected at termination (on GD 20) from all females; serum was separated and stored. Blood samples were assessed for serum levels of thyroid hormones (T3 and T4) and thyroid stimulating hormone (TSH).
HISTOPATHOLOGY: Yes
Histopathological analysis was performed on females from the control and high-dose (500 mg/kg bw/day) groups. The thyroid and parathyroid glands were collected from all females, but the histopathological evaluation was conduced on samples from the control and high-dose (500 mg/kg bw/day) groups. All gross lesions found during the necropsy examination were collected and subjected to microscopic examination.
Ovaries and uterine content:: EXAMINATION OF UTERINE CONTENT: Yes
After the termination (GD 20), uteri were removed, and the pregnancy status of the animals was evaluated. Uteri that appear non-gravid were further examined using ammonium sulphide staining to confirm non-pregnant status. The total weight of the gravid or non-gravid uteri including cervix were recorded for all animals except for the animals found dead during the study. The ovarian and placental weight, the number of corpora lutea, number of implantation sites, number of live/viable foetuses, number of dead foetuses and number of resorptions were recorded.
Fetal examinations:: All foetuses were weighed, sexed and examined for external abnormalities, crown to rump length, anogenital distances (AGD) and skeletal and soft tissue abnormalities with special emphasis to reproductive organs. Male foetuses were evaluated for incomplete testicular descent/cryptorchidism.
External examinations: Yes: [all per litter]
- Soft tissue examinations (visceral alterations & head razor sectioning: Yes: [half per litter]
- Skeletal examination including (growth retardation, delayed ossification, etc): Yes: [half per litter]
Statistics:: The mean and standard deviation were calculated using the software and all data were summarized in tabular form. All continuous data (body weight, feed consumption, hormone estimation, absolute and relative organ weights, maternal and pup parameters etc.) were checked for normality using Shapiro Wilk test. All homogenous data was analysed using ANOVA and data showing significance in their variances was subjected to Dunnett’s t-test. All heterogeneous data was analysed using Student’s t-test, Dunn’s Test, Kruskal-Wallis, ANOVA on ranks. P values of ≤ 0.05 were deemed to be statistically significant.
Indices:: Pregnancy rate (%), Live foetuses (%)
Pre-implantation loss (%): [(no. of corpora lutea − no. of implantations)/ no. of corpora lutea] x 100;
Post-implantation loss (%): [(no. of implantations - no. of live foetuses)/ no. of total implantations] x 100
Historical control data:: In-house historical control data was used.
Clinical signs:: effects observed, treatment-related
Description (incidence and severity):: Treatment-related clinical signs were observed in all females dosed with 500 mg/kg bw/day. These clinical signs included hypothermia, lethargy, prostration and excessive salivation, they were observed from the first day of dosing and continued till termination. No clinical signs or symptoms were observed in animals dosed up to 250 mg/kg body weight/day.
Dermal irritation (if dermal study):: not examined
Mortality:: mortality observed, treatment-related
Description (incidence):: No morbidities or mortality were recorded in animals up to the dose level of 250 mg/kg bw/day throughout of the experiment.
At 500 mg/kg, one animal was found dead on GD 9.
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: No significant changes in body weight or body weight gain were observed at 125 or 250 mg/kg. At 500 mg/kg, a significant decrease in maternal body weight (by 6.4%) was found on GD 17 as compared to the control group. On GD 20, a trend of lower maternal body weight (by 6.9%) was found at 500 mg/kg as compared to the control group.
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: Significant decreases in maternal food intake were observed at 500 mg/kg on GD 8 (by 31.2%) and on GD 11 (by 13.9%) as compared to the control group.
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: not examined
Haematological findings:: not examined
Clinical biochemistry findings:: no effects observed
Description (incidence and severity):: No significant changes in T3, T4 or TSH levels were observed.
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Description (incidence and severity):: No significant changes were observed in the absolute and relative weights of ovary, uterus and thyroid-parathyroid gland.
Gross pathological findings:: effects observed, treatment-related
Description (incidence and severity):: No gross findings were observed at 0 or 125 mg/kg. At 250 mg/kg, two non-pregnant animals showed pathological alterations in stomach which included white spots of muscular portion, increased size/swelling of muscular portions, and swelling of glandular portion. At 500 mg/kg, a total of 15 pregnant/non-pregnant animals showed pathological alterations in stomach which included white spots of muscular tissue, increased size of muscular portion, and increased size/swelling of glandular portion and red discolouration of the lung.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: Microscopic findings at 250 mg/kg included focal hyperkeratosis in stomach in one animal (minimal in severity). At 500 mg/kg, microscopic findings included focal/multifocal hyperkeratosis in stomach; focal, erosion and oedema of muscular tissue in stomach, leukocyte infiltration in muscular tissue in stomach, diffuse degeneration of glandular tissue in stomach and focal alveolar haemorrhage in lung in 7 animals.
Histopathological findings: neoplastic:: no effects observed
Other effects:: no effects observed
Number of abortions:: no effects observed
Description (incidence and severity):: No signs of abortion was observed in any dose group.
Pre- and post-implantation loss:: no effects observed
Description (incidence and severity):: The number of implantation sites and the pre-and post-implantation loss (%) remained unchanged in treatment groups when compared to control.
Total litter losses by resorption:: no effects observed
Description (incidence and severity):: No significant changes in the number of resorptions were observed in any dose groups.
Early or late resorptions:: no effects observed
Description (incidence and severity):: The early and late resorptions were found to be comparable among all the treatment groups and control group.
Dead fetuses:: no effects observed
Description (incidence and severity):: No dead foetuses were observed in any dose groups.
Changes in pregnancy duration:: not examined
Changes in number of pregnant:: effects observed, non-treatment-related
Description (incidence and severity):: At termination 18/25, 24/25, 17/25 and 13/25 females were found to be pregnant from the control 125 mg/kg bw, 250 mg/kg bw, and 500 mg/kg bw dose groups, respectively. Pregnancy rates were calculated as 72%, 96%, 68% and 52% for the control, 125 mg/kg bw, 250 mg/kg bw/day, and 500 mg/kg dose groups, respectively. The reduction in pregnancy rate at 500 mg/kg bw/day was considered a non-treatment related effect as no other maternal developmental toxicity parameters examined i.e. number of corpora lutea, implantation sites, pre-and post-implantation loss, resorption demonstrated significant changes when compared to the control. As per historical control data from the test facility, pregnancy rate in previosly conducted OECD 414 studies range from 72 to 100%.
Other effects:: not specified
Dose descriptor:: NOAEL
Remarks:: systemic toxicity
Effect level:: 250 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: body weight and weight gain; clinical biochemistry; clinical signs; food consumption and compound intake; gross pathology; histopathology: neoplastic; histopathology: non-neoplastic; maternal abnormalities; mortality; necropsy findings; organ weights and organ / body weight ratios
Dose descriptor:: LOAEL
Remarks:: Systemic toxicity
Effect level:: 500 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: body weight and weight gain; clinical signs; food consumption and compound intake; gross pathology; histopathology: neoplastic; histopathology: non-neoplastic; mortality; organ weights and organ / body weight ratios
Dose descriptor:: NOAEL
Remarks:: Developmental toxicity
Effect level:: 500 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: changes in number of pregnant; dead fetuses; early or late resorptions; maternal abnormalities; necropsy findings; number of abortions; pre and post implantation loss; total litter losses by resorption
Abnormalities:: no effects observed
Fetal body weight changes:: effects observed, treatment-related
Description (incidence and severity):: At 500 mg/kg, a significant decrease in female foetal weight (by 8.2%) and a significant decrease in sex-combined foetal weight (by 6.4%) were observed as compared to the control group. No other significant changes in foetal weight were observed.
Reduction in number of live offspring:: no effects observed
Description (incidence and severity):: No reduction in number of live offspring was observed in any dose group when compared to control.
Changes in sex ratio:: no effects observed
Description (incidence and severity):: The sex ratios were comparable in all groups.
Changes in litter size and weights:: no effects observed
Description (incidence and severity):: No significant differences in litter size were observed in any groups.
Changes in postnatal survival:: not examined
External malformations:: effects observed, non-treatment-related
Description (incidence and severity):: Gross external observation of foetuses revealed that 2.09, 3.79, 5.00 and 6.60 percentage of foetuses from G1 (control), G5 (125 mg/kg), G2 (250 mg/kg) and G3 (500 mg/kg) respectively showed malformations/variations. The variation included haemorrhage:1.57 (G1), 2.07 (G5), 3.89 (G2), 4.72 (G3) percent of foetuses and the malformations include: retarded growth (Runt): 0.52 (G1), 1.38 (G5), 0.56 (G2) and 1.89 (G3) percent of foetuses; dome-shaped head: 1.03 (G5) and 0.94 (G3) percent of foetuses; Anury (absence of tail): 0.56 (G2) percent of foetuses.
Skeletal malformations:: effects observed, non-treatment-related
Description (incidence and severity):: A number of skeletal variations/malformations were observed, however none of them were attributed to the test chemical since they lacked dose dependency and (or) were considered common to developing foetuses.
The following skeletal malformations/variations were observed in the skull: incomplete ossification of Frontal and Parietal observed in 1 /57 foetus at 500 mg/kg, dome-shaped Frontal and Parietal found in 1/150 foetus at 125 mg/kg, 1/57 at 500 mg/kg, flattened Parietal observed in 1/150 at 125 mg/kg and 1/57 at 500 mg/kg, fused Nasal, Premaxilla and Maxilla found in 1/150 at 250 mg/kg, elongated and bipartite Interparietal in 1/94 foetus at 250 mg/kg, small triangular-shaped Interparietal observed in 1/150 at 125 mg/kg, absence of Zygomatic in 2/94 at 250 mg/kg, absence of Hyoid in 2/100 foetuses at 0 mg/kg. Fused ribs were observed in 1/94 foetuses at 250 mg/kg, branched ribs in 1/57 foetuses at 500 mg/kg, misaligned ribs at 1/94 at 250 mg/kg and 2/57 foetuses at 500 mg/kg. Misaligned ribs were seen in 2/57 foetuses at 500 mg/kg, absent Thoracic, Lumbar, Sacral and caudal Vertebrae in 1/94 foetuses at 250 mg/kg.
Visceral malformations:: no effects observed
Description (incidence and severity):: No variations/malformations were observed during visceral and head razor examinations in any of the groups.
Other effects:: no effects observed
Description (incidence and severity):: No significant differences in crown to rump length or anogenital distance were observed in any of the groups.
Dose descriptor:: NOAEL
Effect level:: 250 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: reduction in number of live offspring; changes in sex ratio; fetal/pup body weight changes; changes in litter size and weights; external malformations; skeletal malformations; visceral malformations; other: crown to rump length, AGD
Dose descriptor:: LOAEL
Effect level:: 500 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: fetal/pup body weight changes
Abnormalities:: no effects observed
Developmental effects observed:: yes
Lowest effective dose / conc.:: 500 mg/kg bw/day (actual dose received)
Treatment related:: yes
Relation to maternal toxicity:: developmental effects as a secondary non-specific consequence of maternal toxicity effects
Conclusions:: NOAEL for maternal systemic toxicity was considered at 250 mg/kg bw/day. This effect level was based on mortality, clinical signs of toxicity, statistically/biologically significant decreases in body weight on GD 17 and 20, significant decreases in food intake on GD 8 and 11, and several gross/histopathology findings. NOAEL for developmental toxicity was considered at 250 mg/kg bw/day. This effect level was based on lower foetal body weights at 500 mg/kg bw/day.
Executive summary:: The substance was given by oral gavage to 25 pregnant Wistar rats at 0 (vehicle), 250, 500 and 1000 mg/kg bw/day from GD 5 to 19. Due to unexpected mortality at 1000 mg/kg, an additional group of 25 pregnant Wistar rats treated at 125 mg/kg bw/day from GD 5 to 19 was included. The study was performed according to OECD 414 (adopted in 2018) and GLP.Results (adults):All animals treated at 0, 125, and 250 mg/kg survived to planned death. At 500 mg/kg, one animal was found dead on GD 9. No clinical signs of toxicity were observed at 125 or 250 mg/kg. At 500 mg/kg, at least two of the following symptoms were observed in all animals from GD 7 and onwards: hypothermia, lethargy, prostration, and excessive salivation.No significant changes in body weight or body weight gain were observed at 125 or 250 mg/kg. At 500 mg/kg, a significant decrease in maternal body weight (by 6.4%) was found on GD 17 as compared to the control group. On GD 20, a trend of lower maternal body weight (by 6.9%) was found at 500 mg/kg as compared to the control group. These body weight effects were preceded bysignificant decreases in maternal food intake at 500 mg/kg on GD 8 (by 31.2%) and on GD 11 (by 13.9%) as compared to the control group.No significant changes in T3, T4 or TSH levels were observed.Pregnancy rates at termination were 72% (18/25), 96% (24/25), 68% (17/25), and 54% (13/24) at 0, 125, 250 and 500 mg/kg, respectively. For pregnant animals, no significant changes in the numbers of corpora lutea, implantation sites, resorptions, pre-implantation loss, or post-implantation loss were observed. No significant changes in absolute or relative weight of the uterus, ovary, or thyroid and parathyroid were observed. No remarkable effects on placenta weight were observed.No gross findings were made at 0 or 125 mg/kg. At 250 mg/kg, two non-pregnant animals showed pathological alterations in stomach which included white spots of muscular portion, increased size/swelling of muscular portions, and swelling of glandular portion. At 500 mg/kg, a total of 15 pregnant/non-pregnant animals showed pathological alterations in stomach which included white spots of muscular tissue, increased size of muscular portion, and increased size/swelling of glandular portion.Microscopic findings at 250 mg/kg included focal hyperkeratosis in stomach in one animal (minimal in severity). At 500 mg/kg, microscopic findings included focal/multifocal hyperkeratosis in stomach; focal alveolar haemorrhage; diffuse degeneration of glandular tissue in stomach; focal erosion of muscular tissue in stomach; leukocyte infiltration in muscular tissue in stomach; and oedema of muscular tissue in stomach.Results (foetuses):No significant changes in litter size or sex ratio were observed.At 500 mg/kg, a significant decrease in female foetal weight (by 8.2%) and a significant decrease in sex-combined foetal weight (by 6.4%) were observed as compared to the control group. No other significant changes in foetal weight were observed. No significant differences in anogenital distance were observed.Gross foetal findings occurred at low incidences at all dose levels and were not attributed to the test item. No variations or malformations were observed during visceral and head razor examinations. A number of skeletal variations/malformations were observed, however none of them were attributed to the test chemical since they lacked dose dependency and (or) were considered common to developing foetuses.Conclusion:NOAEL for maternal systemic toxicity was considered at 250 mg/kg bw/day. This effect level was based on mortality, clinical signs of toxicity, statistically/biologically significant decreases in body weight on GD 17 and 20, significant decreases in food intake on GD 8 and 11, and several gross/histopathology findings. NOAEL for developmental toxicity was considered at 250 mg/kg bw/day. This effect level was based on lower foetal body weights at 500 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 250 mg/kg bw/day
Study duration:: subacute
Species:: rat
Quality of whole database:: Klimisch 1

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

OECD 414 with source substance (Cinnamaldehyde; CAS 104-55-2):

The substance was given by oral gavage to 25 pregnant Wistar rats at 0 (vehicle), 250, 500 and 1000 mg/kg bw/day from GD 5 to 19. Due to unexpected mortality at 1000 mg/kg, an additional group of 25 pregnant Wistar rats treated at 125 mg/kg bw/day from GD 5 to 19 was included. The study was performed according to OECD 414 (adopted in 2018) and GLP.Results (adults):All animals treated at 0, 125, and 250 mg/kg survived to planned death. At 500 mg/kg, one animal was found dead on GD 9. No clinical signs of toxicity were observed at 125 or 250 mg/kg. At 500 mg/kg, at least two of the following symptoms were observed in all animals from GD 7 and onwards: hypothermia, lethargy, prostration, and excessive salivation.No significant changes in body weight or body weight gain were observed at 125 or 250 mg/kg. At 500 mg/kg, a significant decrease in maternal body weight (by 6.4%) was found on GD 17 as compared to the control group. On GD 20, a trend of lower maternal body weight (by 6.9%) was found at 500 mg/kg as compared to the control group. These body weight effects were preceded bysignificant decreases in maternal food intake at 500 mg/kg on GD 8 (by 31.2%) and on GD 11 (by 13.9%) as compared to the control group.No significant changes in T3, T4 or TSH levels were observed.Pregnancy rates at termination were 72% (18/25), 96% (24/25), 68% (17/25), and 54% (13/24) at 0, 125, 250 and 500 mg/kg, respectively. For pregnant animals, no significant changes in the numbers of corpora lutea, implantation sites, resorptions, pre-implantation loss, or post-implantation loss were observed. No significant changes in absolute or relative weight of the uterus, ovary, or thyroid and parathyroid were observed. No remarkable effects on placenta weight were observed.No gross findings were made at 0 or 125 mg/kg. At 250 mg/kg, two non-pregnant animals showed pathological alterations in stomach which included white spots of muscular portion, increased size/swelling of muscular portions, and swelling of glandular portion. At 500 mg/kg, a total of 15 pregnant/non-pregnant animals showed pathological alterations in stomach which included white spots of muscular tissue, increased size of muscular portion, and increased size/swelling of glandular portion.Microscopic findings at 250 mg/kg included focal hyperkeratosis in stomach in one animal (minimal in severity). At 500 mg/kg, microscopic findings included focal/multifocal hyperkeratosis in stomach; focal alveolar haemorrhage; diffuse degeneration of glandular tissue in stomach; focal erosion of muscular tissue in stomach; leukocyte infiltration in muscular tissue in stomach; and oedema of muscular tissue in stomach.Results (foetuses):No significant changes in litter size or sex ratio were observed.At 500 mg/kg, a significant decrease in female foetal weight (by 8.2%) and a significant decrease in sex-combined foetal weight (by 6.4%) were observed as compared to the control group. No other significant changes in foetal weight were observed. No significant differences in anogenital distance were observed.Gross foetal findings occurred at low incidences at all dose levels and were not attributed to the test item. No variations or malformations were observed during visceral and head razor examinations. A number of skeletal variations/malformations were observed, however none of them were attributed to the test chemical since they lacked dose dependency and (or) were considered common to developing foetuses.Conclusion:NOAEL for maternal systemic toxicity was considered at 250 mg/kg bw/day. This effect level was based on mortality, clinical signs of toxicity, statistically/biologically significant decreases in body weight on GD 17 and 20, significant decreases in food intake on GD 8 and 11, and several gross/histopathology findings. NOAEL for developmental toxicity was considered at 250 mg/kg bw/day. This effect level was based on lower foetal body weights at 500 mg/kg bw/day.

Justification for classification or non-classification

The substance is regarded to be classified as Not Classified for Toxicity to reproduction under regulation EC 1272/2008. This decision is based largely on the results from the OECD 421 study with the substance and the OECD 414 study with cinnamaldehyde (CAS 104-55-2). In the OECD 421 study, no adverse effects on reproduction or development were observed up to the highest dose tested of 350 mg/kg bw/day. In the OECD 414 study with cinnamaldehyde, the only observed effect on development was a slight decrease in foetal body weight at the top dose level (by 6 to 8% vs. controls) and this occurred in the presence of marked systemic toxicity as evident by mortality, significant clinical signs of toxicity, lower maternal body weights, reduced food intake, and gross/histopathology findings. The amount of maternal body weight reduction at the top dose level (by 6 to 7% vs. controls) was comparable to the amount of foetal body weight reduction and it occurred during late gestation, i.e. on GD 17 and 20. Considering this and that the maternal body weight effect was accompanied by reduced food intake, it is not unreasonable to assume that the lower foetal body weights at 500 mg/kg in the study were secondary or partially secondary to maternal undernutrition (1). By also considering other toxic effects at 500 mg/kg, such as mortality and significant clinical signs of toxicity in all animals from GD 7, the slight decrease in foetal weight at 500 mg/kg was considered to secondary to maternal systemic toxicity and not relevant for the classification for toxicity to reproduction as per CLP criteria (refer to sections 3.7.2.2 and 3.7.2.2.1 in Regulation EC 1272/2008). In the OECD 407 study with the substance, no gross or microscopic lesions were observed in any of the reproductive organs from the male or female rats treated at 1000 mg/kg bw/day, and no significant changes in organ weight were observed. Overall, considering the results of the OECD 421 study with the substance, the results from the OECD 414 study with cinnamaldehyde, and the lack of adverse effects on reproductive organs in the OECD 407 study with the substance, the substance is regarded to be classified, as mentioned above, as Not Classified for Toxicity to reproduction under Regulation EC 1272/2008.

1. Chernoff et al.The relationship of maternal and fetal toxicity in developmental toxicology bioassays with notes on the biological significance of the "no observed adverse effect level". Reprod Toxicol 2008; 25: 192-202.

Additional information

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Group, Sex & Dose (mg/kg body weight/day)	Total No. of Animals	Clinical Signs of Toxicity^a: Observation (No. of Animals revealed)	Mortality^b: No. of Mortalities (Total No. of Animals)
G1, M & 0	12	Day 1 to till termination: N (12)	0 (12)
G2, M & 87.5	12	Day 1 to till termination: N (12)	0 (12)
G3, M & 175	12	Day 1 to till termination: N (12)	0 (12)
G4, M & 350	12	Day 1 to till termination: N (12)	0 (12)

Group, Sex & Dose (mg/kg body weight/day)	Total No. of Animals	Clinical Signs of Toxicity^a: Observation (No. of Animals revealed)	Mortality^b No. of Mortalities (Total No. of Animals)
G1, F & 0	12	Day 1 to till termination: N (12)	0 (12)
G2, F & 87.5	12	Day 1 to till termination: N (12)	0 (12)
G3, F & 175	12	Day 1 to till termination: N (12)	0 (12)
G4, F & 350	12	Day 1 to till termination: N (12)	0 (12)

Group, Sex & Dose (mg/kg body weight/day)		Body Weight (g) on Day
Group, Sex & Dose (mg/kg body weight/day)		1	7	14	21	28	35
G1, M & 0	Mean	356.09	372.81	387.92	398.69	409.25	425.76
	±SD	32.00	32.70	30.15	27.25	26.40	27.23
	n	12	12	12	12	12	12
G2, M & 87.5	Mean	358.49	370.19	381.21	390.71	401.02	415.55
	±SD	32.01	34.46	34.35	34.44	37.75	42.38
	n	12	12	12	12	12	12
G3, M & 175	Mean	356.80	365.21	382.45	388.26	402.14	421.50
	±SD	32.59	34.49	34.76	33.04	30.90	42.93
	n	12	12	12	12	12	12
G4, M & 350	Mean	355.70	368.06	387.58	396.80	399.99	420.44
	±SD	30.80	32.95	32.47	31.78	32.65	32.27
	n	12	12	12	12	12	12

Group, Sex & Dose (mg/kg body weight/day)		Body Weight (g) on Day
Group, Sex & Dose (mg/kg body weight/day)		1	7	14	21 #	28 #
G1, F & 0	Mean	251.78	264.14	280.34	281.47	301.49
	±SD	16.80	15.26	15.26	23.03	-
	n	12	12	12	5
G2, F & 87.5	Mean	253.35	262.96	278.62	281.35	281.79
	±SD	16.57	17.80	15.52	20.41	-
	n	12	12	12	6
G3, F & 175	Mean	253.98	265.26	285.68	291.18	-
	±SD	16.90	17.63	16.42	16.66	-
	n	12	12	12	6
G4, F & 350	Mean	253.12	263.60	281.77	282.04	298.38
	±SD	13.95	18.08	17.55	19.19	3.66
	n	12	12	12	7

Group, Sex & Dose (mg/kg body weight/day)		Percent Change in Body Weight (%) during Day
Group, Sex & Dose (mg/kg body weight/day)		1 to 7	1 to 14	1 to 21	1 to 28	1 to 35
G1, M & 0	Mean	4.73	9.11	12.25	15.29	20.01
	±SD	1.73	3.82	5.04	6.20	7.67
	n	12	12	12	12	12
G2, M & 87.5	Mean	3.26	6.39	9.06	11.88	15.88
	±SD	2.91	3.73	3.84	3.96	4.81
	n	12	12	12	12	12
G3, M & 175	Mean	2.37	7.31	9.00	13.03	18.44
	±SD	2.51	5.03	5.49	7.01	10.52
	n	12	12	12	12	12
G4, M & 350	Mean	3.50	9.10	11.75	12.82	18.65
	±SD	3.18	5.10	5.52	8.60	9.35
	n	12	12	12	12	12

Group	Clinical Signs occurrence	Dose Related (Yes/No)	Vehicle Related (Yes/No)
G1	No	NA	NA
G2	No	NA	NA
G3	No	NA	NA
G4	No	NA	NA

Group	Increase/Decrease/No Effect	Significance	Dose Related (Yes/No)	Vehicle Related (Yes/No)
G1	NA	NA	NA	NA
G2	No Effect	NA	NA	NA
G3	No Effect	NA	NA	NA
G4	No Effect	NA	NA	NA

Group, Sex & Dose (mg/kg body weight/day)		Feed Consumption (g/animal/day) during Pre-mating Period
Group, Sex & Dose (mg/kg body weight/day)		Week 1	Week 2
G1, M & 0	Mean	24.77	26.30
	±SD	2.43	1.77
	n	12	12
G2, M & 87.5	Mean	22.36	25.43
	±SD	2.59	3.00
	n	12	12
G3, M & 175	Mean	23.31	26.39
	±SD	2.10	1.38
	n	12	12
G4, M & 350	Mean	22.49	25.64
	±SD	1.80	1.00
	n	12	12

Determination of Oestrus Cyclicity during Pre-Mating Treatment Period
Group, Sex & Dose (mg/kg body weight/day)	Total No. of Females Evaluated		No. of Females with Complete Regular Oestrus Cycle	No. of Females with atleast one Irregular Oestrus Cycle	Average Length of Oestrus Cycle (Days)
G1, F & 0	12	n	12	0	Mean	4.44
		%	100.0	0.0	±SD	0.15
					n	12
G2, F & 87.5	12	n	12	0	Mean	4.46
		%	100.0	0.0	±SD	0.14
					n	12
G3, F & 175	12	n	12	0	Mean	4.43
		%	100.0	0.0	±SD	0.15
					n	12
G4, F & 350	12	n	12	0	Mean	4.44
		%	100.0	0.0	±SD	0.15
					n	12

Group	Effect/No Effect	Dose Related (Yes/No)	Vehicle Related (Yes/No)
G1	NA	NA	NA
G2	No Effect	NA	NA
G3	No Effect	NA	NA
G4	No Effect	NA	NA

Group, Sex & Dose (mg/kg body weight/day)		Body Weight (g) on Gestation Day (GD)
Group, Sex & Dose (mg/kg body weight/day)		0	7	14	20
G1, F & 0	Mean	284.26	300.40	330.06	392.16
	±SD	18.62	18.48	21.44	21.73
	n	12	12	12	12
G2, F & 87.5	Mean	283.29	296.22	326.72	387.94
	±SD	16.64	17.28	19.13	21.02
	n	11	11	11	11
G3, F & 175	Mean	286.76	301.03	329.86	393.44
	±SD	21.06	23.00	22.63	22.36
	n	11	11	11	11
G4, F & 350	Mean	280.94	295.65	325.19	387.94
	±SD	17.62	18.83	20.56	23.36
	n	11	11	11	11

Group	Increase/Decrease/ No Effect	Dose Related (Yes/No)	Vehicle Related (Yes/No)
G1	NA	NA	NA
G2	No Effect	NA	NA
G3	No Effect	NA	NA
G4	No Effect	NA	NA

Group, Sex & Dose (mg/kg body weight/day)		Feed Consumption (g/animal/day) during Gestation Day (GD)
Group, Sex & Dose (mg/kg body weight/day)		0 to 7	7 to 14	14 to 20
G1, F & 0	Mean	19.15	23.07	26.34
	±SD	0.78	1.84	2.22
	n	12	12	12
G2, F & 87.5	Mean	18.70	21.85	24.96
	±SD	1.23	1.61	1.66
	n	11	11	11
G3, F & 175	Mean	18.98	21.79	24.92
	±SD	0.61	1.05	1.63
	n	11	11	11
G4, F & 350	Mean	18.48	20.52*	23.25*
	±SD	0.99	1.86	2.59
	n	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Body Weight (g) on Lactation Day (LD)
Group, Sex & Dose (mg/kg body weight/day)		1	4	7	13
G1, F & 0	Mean	309.42	314.59	327.96	339.36
	±SD	18.33	16.28	15.55	15.15
	n	12	12	12	12
G2, F & 87.5	Mean	305.41	310.08	321.42	336.29
	±SD	20.58	21.69	22.60	24.81
	n	11	11	11	11
G3, F & 175	Mean	305.06	311.55	321.66	333.13
	±SD	18.40	15.37	15.55	15.23
	n	11	11	11	11
G4, F & 350	Mean	301.50	309.75	319.89	332.04
	±SD	16.25	17.43	18.06	19.05
	n	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Feed Consumption (g/animal/day) during Lactation Day (LD)
Group, Sex & Dose (mg/kg body weight/day)		1 to 4	4 to 7	7 to 13
G1, F & 0	Mean	29.25	32.24	36.60
	±SD	2.77	2.55	0.99
	n	12	12	12
G2, F & 87.5	Mean	29.69	33.07	35.77
	±SD	2.58	2.64	1.64
	n	11	11	11
G3, F & 175	Mean	29.93	33.21	36.30
	±SD	1.69	2.08	1.76
	n	11	11	11
G4, F & 350	Mean	28.78	33.55	36.27
	±SD	1.97	2.02	0.95
	n	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Litter Size (No.)	Live Pups (No.)			Dead Pups (No.)			Cannibalized (No.)				Sex Ratio (M/F) at Birth	Live Birth Index (%)	% of offspring
Group, Sex & Dose (mg/kg body weight/day)		Litter Size (No.)	Male	Female	Total	Male	Female	Total	Undetermined	Male	Female	Total	Sex Ratio (M/F) at Birth	Live Birth Index (%)	Male	Female
G1, F & 0	Mean	11.33	5.50	5.75	11.25	0.08	0.00	0.08	0.00	0.00	0.00	0.00	1.05	99.40	48.83	51.17
	±SD	2.53	1.78	1.82	2.45	0.29	0.00	0.29	0.00	0.00	0.00	0.00	0.50	2.06	11.53	11.53
	n	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12
G2, F & 87.5	Mean	10.82	5.91	4.73	10.64	0.00	0.18	0.18	0.00	0.00	0.00	0.00	1.50	98.48	55.51	44.49
	±SD	1.60	2.02	1.85	1.57	0.00	0.60	0.60	0.00	0.00	0.00	0.00	0.92	5.03	14.84	14.31
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G3, F & 175	Mean	10.82	5.09	5.73	10.82	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.95	100.00	47.13	52.87
	±SD	1.72	1.30	1.42	1.72	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.32	0.00	12.71	16.12
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G4, F & 350	Mean	11.09	6.36	4.73	11.09	0.00	0.00	0.00	0.00	0.00	0.00	0.00	1.66	100.00	56.90	43.10
	±SD	2.88	2.54	2.05	2.88	0.00	0.00	0.00	0.00	0.00	0.00	0.00	1.18	0.00	10.43	14.62
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Male Live Pups (No.)	Female Live Pups (No.)	No. of Live Pups At Birth	During Lactation Day 1 to 4									Sex Ratio (M/F) at LD 4	Pup Survival Index (%) LD 1 to 4
					Live Pups (No.)			Dead Pups (No.)			Cannibalized (No.)
					Male	Female	Total	Male	Female	Total	Male	Female	Total
G1, F & 0	Mean	5.50	5.75	11.25	5.50	5.75	11.25	0.00	0.00	0.00	0.00	0.00	0.00	1.05	100.00
	±SD	1.78	1.82	2.45	1.78	1.82	2.45	0.00	0.00	0.00	0.00	0.00	0.00	0.50	0.00
	n	12	12	12	12	12	12	12	12	12	12	12	12	12	12
G2, F & 87.5	Mean	5.91	4.73	10.64	5.91	4.73	10.64	0.00	0.00	0.00	0.00	0.00	0.00	1.50	100.00
	±SD	2.02	1.85	1.57	2.02	1.85	1.57	0.00	0.00	0.00	0.00	0.00	0.00	0.92	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G3, F & 175	Mean	5.09	5.73	10.82	5.09	5.73	10.82	0.00	0.00	0.00	0.00	0.00	0.00	0.95	100.00
	±SD	1.30	1.42	1.72	1.30	1.42	1.72	0.00	0.00	0.00	0.00	0.00	0.00	0.32	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G4, F & 350	Mean	6.36	4.73	11.09	6.36	4.73	11.09	0.00	0.00	0.00	0.00	0.00	0.00	1.66	100.00
	±SD	2.54	2.05	2.88	2.54	2.05	2.88	0.00	0.00	0.00	0.00	0.00	0.00	1.18	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11

Group & Dose (mg/kg body weight/day)	Animal No.	Mean no. of Live Pups (No.) on LD 4			Pups Sacrificed for Blood Collection on LD 4 (No.)			Live Pups (No.) on LD 4 after Sacrificed for Blood Collection			During Lactation Day 4 to 7									Sex Ratio (M/F) at LD 7	Pup Survival Index (%) during LD 4 to 7
		Mean no. of Live Pups (No.) on LD 4			Pups Sacrificed for Blood Collection on LD 4 (No.)						Live Pups per litter (No.)			Dead Pups per litter (No.)			Cannibalized (No.)
		Male	Female	Total	Male	Female	Total	Male	Female	Total	Male	Female	Total	Male	Female	Total	Male	Female	Total
G1, F & 0	Mean	5.50	5.75	11.25	0.00	1.08	1.08	5.50	4.67	10.17	5.50	4.67	10.17	0.00	0.00	0.00	0.00	0.00	0.00	1.41	100.00
	±SD	1.78	1.82	2.45	0.00	1.00	1.00	1.78	1.50	1.70	1.78	1.50	1.70	0.00	0.00	0.00	0.00	0.00	0.00	1.05	0.00
	n	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12	12
G2, F & 87.5	Mean	5.91	4.73	10.64	0.00	0.55	0.55	5.91	4.18	10.09	5.91	4.18	10.09	0.00	0.00	0.00	0.00	0.00	0.00	2.23	100.00
	±SD	2.02	1.85	1.57	0.00	0.82	0.82	2.02	1.72	0.83	2.02	1.72	0.83	0.00	0.00	0.00	0.00	0.00	0.00	2.96	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G3, F & 175	Mean	5.09	5.73	10.82	0.00	0.91	0.91	5.09	4.82	9.91	5.09	4.82	9.91	0.00	0.00	0.00	0.00	0.00	0.00	1.15	100.00
	±SD	1.30	1.42	1.72	0.00	1.04	1.04	1.30	1.33	0.94	1.30	1.33	0.94	0.00	0.00	0.00	0.00	0.00	0.00	0.42	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G4, F & 350	Mean	6.36	4.73	11.09	0.00	1.18	1.18	6.36	3.55	9.91	6.36	3.55	9.91	0.00	0.00	0.00	0.00	0.00	0.00	2.94	100.00
	±SD	2.54	2.05	2.88	0.00	0.98	0.98	2.54	1.75	1.97	2.54	1.75	1.97	0.00	0.00	0.00	0.00	0.00	0.00	3.12	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)	Animal No.	Live Pups (No.) on LD 7			During Lactation Day 7 to 13									Sex Ratio (M/F) at LD 13	Pup Survival Index (%) during LD 7 to 13
		Live Pups (No.) on LD 7			Live Pups (No.)			Dead Pups (No.)			Cannibalized (No.)
		Male	Female	Total	Male	Female	Total	Male	Female	Total	Male	Female	Total
G1, F & 0	Mean	5.50	4.67	10.17	5.50	4.67	10.17	0.00	0.00	0.00	0.00	0.00	0.00	1.41	100.00
	±SD	1.78	1.50	1.70	1.78	1.50	1.70	0.00	0.00	0.00	0.00	0.00	0.00	1.05	0.00
	n	12	12	12	12	12	12	12	12	12	12	12	12	12	12
G2, F & 87.5	Mean	5.91	4.18	10.09	5.91	4.18	10.09	0.00	0.00	0.00	0.00	0.00	0.00	2.23	100.00
	±SD	2.02	1.72	0.83	2.02	1.72	0.83	0.00	0.00	0.00	0.00	0.00	0.00	2.96	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G3, F & 175	Mean	5.09	4.82	9.91	5.09	4.82	9.91	0.00	0.00	0.00	0.00	0.00	0.00	1.15	100.00
	±SD	1.30	1.33	0.94	1.30	1.33	0.94	0.00	0.00	0.00	0.00	0.00	0.00	0.42	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11
G4, F & 350	Mean	6.36	3.55	9.91	6.36	3.55	9.91	0.00	0.00	0.00	0.00	0.00	0.00	2.94	100.00
	±SD	2.54	1.75	1.97	2.54	1.75	1.97	0.00	0.00	0.00	0.00	0.00	0.00	3.12	0.00
	n	11	11	11	11	11	11	11	11	11	11	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)	No. of Males with Evidence of Mating (Total No. of Males used for Mating)	Male Mating Index (%)	No. of Males Capable of Impregnating a Female (No. of males used for Mating)	Male Fertiltiy Index (%)
G1, M & 0	11 (12)	91.7	11 (12)	91.7
G2, M & 87.5	11 (12)	91.7	11 (12)	91.7
G3, M & 175	12 (12)	100.0	12 (12)	100.0
G4, M & 350	10 (12)	83.3	10 (12)	83.3

Group, Sex & Dose (mg/kg body weight/day)		Copulatory interval / Pre-coital interval (Mean Time to Mating) / Cohabitation Record				Gestation Length / Duration of Pregnancy (Days)
Group, Sex & Dose (mg/kg body weight/day)		Pre-coital Interval		Concieving Days (1 to 5)	Concieving Days (5 to More)	Gestation Length / Duration of Pregnancy (Days)
G1, F & 0	Mean	6.75	n	6	6	22.58
	±SD	5.33	%	50.0	50.0	0.51
	n	12	%	50.0	50.0	12
G2, F & 87.5	Mean	8.08	n	5	7	22.55
	±SD	5.12	%	41.7	58.3	0.52
	n	12	%	41.7	58.3	11
G3, F & 175	Mean	7.83	n	5	7	22.55
	±SD	5.04	%	41.7	58.3	0.52
	n	12	%	41.7	58.3	11
G4, F & 350	Mean	8.92	n	5	7	22.73
	±SD	5.73	%	41.7	58.3	0.47
	n	12	%	41.7	58.3	11

Group, Sex & Dose (mg/kg body weight/day)	No. of Females with Evidence of Mating (No. of Females used for Mating)	Female Mating Index (%)	No. of Females Confirmed as Fertile (No. of Females used for Mating)	Female Fertility Index (%)
G1, F & 0	12 (12)	100.0	12 (12)	100.0
G2, F & 87.5	12 (12)	100.0	11 (12)	91.7
G3, F & 175	12 (12)	100.0	11 (12)	91.7
G4, F & 350	12 (12)	100.0	11 (12)	91.7

Group, Sex & Dose (mg/kg body weight/day)	Pregnancy Index (%)			Gestation Index (%)			Parturition Index (%)
Group, Sex & Dose (mg/kg body weight/day)	No. of Pregnant Females	No. of Females Confirmed with Mating	Female Fecundity or Pregnancy Index (%)	Females with Live Born Pups at Parturition	No. of Females with Evidence of Pregnancy	Gestation Index (%)	No. of females littered	No. of Females with Evidence of Pregnancy	Parturition Index (%)
G1, F & 0	12	12	100.0	12	12	100.0	12	12	100.0
G2, F & 87.5	11	12	91.7	11	11	100.0	11	11	100.0
G3, F & 175	11	12	91.7	11	11	100.0	11	11	100.0
G4, F & 350	11	12	91.7	11	11	100.0	11	11	100.0

Group, Sex & Dose (mg/kg body weight/day)		Post-implantation Loss (%)				Post-natal Loss (%)
Group, Sex & Dose (mg/kg body weight/day)		No. of Implantations	No. of Viable Pups	Post-implantation Loss (No.)	Post-implantation Loss (%)	Total No. of Deaths/ Cannibalized during Lactation Period	Post-natal Loss (%)
G1, F & 0	Mean	11.75	11.25	0.50	4.01	0.00	0.00
	±SD	2.53	2.45	0.80	6.33	0.00	0.00
	n	12	12	12	12	12	12
G2, F & 87.5	Mean	11.18	10.64	0.55	4.51	0.00	0.00
	±SD	1.60	1.57	1.04	8.42	0.00	0.00
	n	11	11	11	11	11	11
G3, F & 175	Mean	10.91	10.82	0.09	0.91	0.00	0.00
	±SD	1.64	1.72	0.30	3.02	0.00	0.00
	n	11	11	11	11	11	11
G4, F & 350	Mean	11.55	11.09	0.45	4.12	0.00	0.00
	±SD	2.70	2.88	0.82	7.71	0.00	0.00
	n	11	11	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Testes	Epididymes	Prostate + Seminal vesicles with coagulating glands (PSC)	Thyroid along with parathyroid #
G1, M & 0	Mean	3.5615	1.4352	3.3812	0.0230
	±SD	0.2510	0.0970	0.4057	0.0029
	n	12	12	12	12
G2, M & 87.5	Mean	3.6884	1.4706	3.2724	0.0210
	±SD	0.1675	0.1051	0.3946	0.0018
	n	12	12	12	12
G3, M & 175	Mean	3.4426	1.4507	3.3433	0.0250
	±SD	0.3112	0.0971	0.4443	0.0037
	n	12	12	12	12
G4, M & 350	Mean	3.6953	1.4694	3.4254	0.0224
	±SD	0.2992	0.1037	0.3306	0.0029
	n	12	12	12	12

Organ Weight	Sex	Dose	Increase/Decrease/ No Effect	Significance in terms of relative organ Weight Increase/Decrease/ No Effect	Correlation with Gross Necropsy/Histopathology Increase/Decrease/ No Effect	Dose Related (Yes/No)	Vehicle Related (Yes/No)
Testes	M	87.5 mg/kg, 175 mg/kg, 350 mg/kg	No Effect	No Effect	No effect	NA	NA
Epididymis	M	87.5 mg/kg, 175 mg/kg, 350 mg/kg	No Effect	No Effect	No effect	NA	NA
PSC	M	87.5 mg/kg, 175 mg/kg, 350 mg/kg	No Effect	No Effect	No effect	NA	NA
Thyroid along with parathyroid	M	87.5 mg/kg, 175 mg/kg, 350 mg/kg	No Effect	No Effect	No effect	NA	NA

Group, Sex & Dose (mg/kg body weight/day)		Ovaries	Thyroid along with parathyroid #
G1, F & 0	Mean	0.1264	0.0201
	±SD	0.0323	0.0033
	n	12	12
G2, F & 87.5	Mean	0.1181	0.0214
	±SD	0.0192	0.0028
	n^@	11	11
G3, F & 175	Mean	0.1355	0.0205
	±SD	0.0317	0.0035
	n^@	11	11
G4, F & 350	Mean	0.1063	0.0209
	±SD	0.0256	0.0030
	n^@	11	11

Group, Sex & Dose (mg/kg body weight/day)		Terminal Body Weight (g)	Testes	Epididymes	Prostate+Seminal vesicles with coagulating glands (PSC)	Thyroid along with parathyroid
G1, M & 0	Mean	409.46	0.8717	0.3511	0.8249	0.0057
	±SD	25.71	0.0659	0.0225	0.0729	0.0009
	n	12	12	12	12	12
G2, M & 87.5	Mean	398.21	0.9345	0.3726	0.8288	0.0053
	±SD	39.84	0.0980	0.0450	0.1264	0.0006
	n	12	12	12	12	12
G3, M & 175	Mean	399.68	0.8687	0.3664	0.8426	0.0063
	±SD	44.44	0.1070	0.0403	0.1228	0.0010
	n	12	12	12	12	12
G4, M & 350	Mean	402.31	0.9225	0.3663	0.8528	0.0056
	±SD	28.75	0.0950	0.0294	0.0755	0.0008
	n	12	12	12	12	12

Group, Sex & Dose (mg/kg body weight/day)		Serum T4 Levels (ng/mL)
G1, M & 0	Mean	54.775
	±SD	5.262
	n	12
G2, M & 87.5	Mean	52.626
	±SD	4.612
	n	12
G3, M & 175	Mean	56.175
	±SD	7.082
	n	12
G4, M & 350	Mean	53.380
	±SD	3.874
	n	12

Registration Dossier

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Diss Factsheets

Cinnamyl alcohol

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Link to relevant study records

Reference

Effect on fertility: via oral route

Effect on fertility: via inhalation route

Effect on fertility: via dermal route

Additional information

Effects on developmental toxicity

Description of key information

Link to relevant study records

Referenceopen allclose all

Reference 1

Reference 2

Effect on developmental toxicity: via oral route

Effect on developmental toxicity: via inhalation route

Effect on developmental toxicity: via dermal route

Additional information

Justification for classification or non-classification

Additional information

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Group, Sex & Dose (mg/kg body weight/day)		At Birth (PND 1)	PND 1 to 4	Pups Sacrificed for Blood Collection on PND 4 (No.)*	PND 4 to 7^$	PND 7 to 13^$
G1, F & 0	No. of Dams / Litters^#	12	12	7	12	12
	No. of Live Pups	135	135	13	122	122
	Pup Observation/ No. of Pups observed	N/135	N/135	-	N/122	N/122
G2, F & 87.5	No. of Dams / Litters^#	11	11	4	11	11
	No. of Live Pups	117	117	6	111	111
	Pup Observation/ No. of Pups observed	N/117	N/117	-	N/111	N/111
G3, F & 175	No. of Dams / Litters^#	11	11	5	11	11
	No. of Live Pups	119	119	10	109	109
	Pup Observation/ No. of Pups observed	N/119	N/119	-	N/109	N/109
G4, F & 350	No. of Dams / Litters^#	11	11	7	11	11
	No. of Live Pups	122	122	13	109	109
	Pup Observation/ No. of Pups observed	N/122	N/122	-	N/109	N/109

Group, Sex & Dose (mg/kg body weight/day)		PND 1		PND 4		PND 7		PND 13
		Mean Pup Weight (g)		Mean Pup Weight (g)		Mean Pup Weight (g)		Mean Pup Weight (g)
		Male	Female	Male	Female	Male	Female	Male	Female
G1, F & 0	Mean	6.34	5.49	10.73	9.82	15.15	13.86	26.37	24.61
	±SD	0.49	0.32	0.29	0.30	0.79	1.14	0.53	0.23
	n	12	12	12	12	12	12	12	12
G2, F & 87.5	Mean	5.99	5.29	10.85	9.82	15.44	14.01*	26.32	24.69
	±SD	0.33	0.18	0.41	0.43	0.56	0.67	0.37	0.16
	n	11	11	11	11	11	11	11	11
G3, F & 175	Mean	6.19	5.41	10.85	9.93	15.47	14.17*	26.39	24.87
	±SD	0.42	0.21	0.35	0.45	0.71	0.86	0.45	0.46
	n	11	11	11	11	11	11	11	11
G4, F & 350	Mean	6.10	5.41	10.83	10.00	15.51	14.20*	26.22	24.92
	±SD	0.28	0.16	0.55	0.56	0.65	0.99	0.45	0.52
	n	11	11	11	11	11	11	11	11

Group, Sex & Dose (mg/kg body weight/day)		Mean Male Pup AGD Measurement (mm)	Mean Female Pup AGD Measurement (mm)	Mean Male Pup AGD Ratio	Mean Female Pup AGD Ratio
G1, F & 0	Mean	4.38	2.40	1.99	1.12
	±SD	0.13	0.11	0.06	0.06
	n	12	12	12	12
G2, F & 87.5	Mean	4.32	2.43	1.95	1.13
	±SD	0.08	0.15	0.05	0.07
	n	11	11	11	11
G3, F & 175	Mean	4.36	2.47	1.97	1.15
	±SD	0.09	0.07	0.05	0.04
	n	11	11	11	11
G4, F & 350	Mean	4.35	2.39	1.97	1.11
	±SD	0.07	0.11	0.06	0.06
	n	11	11	11	11

Group & Dose (mg/kg body weight/day)		Mean No. of Pups with Retention of Nipples/ Areolae on Post-natal Day 13
Group & Dose (mg/kg body weight/day)
G1 & 0	Mean	0.00
	±SD	0.00
	n	12
G2 & 87.5	Mean	0.00
	±SD	0.00
	n	11
G3 & 175	Mean	0.00
	±SD	0.00
	n	11
G4 & 350	Mean	0.00
	±SD	0.00
	n	11

Group & Dose (mg/kg body weight/day)		Serum T4 Levels (ng/mL)
Group & Dose (mg/kg body weight/day)		Serum T4 Levels (ng/mL)
G1 & 0	Mean	49.644
	±SD	5.616
	n	12
G2 & 87.5	Mean	49.473
	±SD	3.935
	n	11
G3 & 175	Mean	47.117
	±SD	3.680
	n	11
G4 & 350	Mean	46.835
	±SD	4.650
	n	11

Groups	Control	Low Dose	Mid Dose	High Dose
Dose (mg/kg body weight)	0	125	250	500
Initial animals per group	25	25	25	25
Confirmed Pregnancy at necropsy	18	24	17	13
Pregnancy rate (%)	72	96	68	52
No. of Corpora lutea	14.50 ± 2.62	13.33 ±1.97	13.94 ± 2.73	13.15 ± 2.34
No. of implantation sites	12.44 ± 3.17	12.92 ± 1.84	12.24 ± 3.17	11.08 ± 3.80
No. of resorptions	1.83 ± 2.81	0.83 ± 1.01	1.65 ± 2.26	1.92 ± 3.48
Pre-implantation loss (%)	13.15 ± 20.98	2.91 ± 5.41	12.82 ±15.23	16.66 ± 25.53
Post-implantation loss (%)	14.11 ± 22.04	6.19 ± 6.77	15.23 ± 22.21	18.66 ± 34.90
Litter size	10.61 ± 3.81	12.08 ± 1.69	10.59 ± 4.18	8.83 ± 4.95
No of live foetuses	10.61 ± 3.81	12.08 ± 1.69	10.59 ± 4.18	8.83 ± 4.95
No of dead foetuses	0	0	0	0
Live Foetuses (%)	100	100	100	100

Pregnant Females
Group	Dose (mg/kg)		Day of gestation and body weight in grams
Group	Dose (mg/kg)		0	5	8	11	14	17	20
Control	0	Mean	215.56	236.39	245.11	257.50	272.56	298.06	332.00
		SD	13.26	13.14	13.53	14.36	14.97	17.06	25.65
		N	18	18	18	18	18	18	18
Low Dose	125	Mean	214.25	234.92	243.00	256.83	273.13	298.08	334.58
		SD	12.81	9.66	10.44	10.87	12.16	14.10	15.37
		N	24	24	24	24	24	24	24
Mid Dose	250	Mean	213.94	237.00	244.94	258.06	272.41	294.35	330.18
		SD	12.23	14.83	16.37	17.83	21.72	25.19	32.90
		N	17	17	17	17	17	17	17
High Dose	500	Mean	215.54	237.54	241.69	247.67	263.83	279.08↓	309.00
		SD	11.64	15.23	13.93	10.80	13.03	21.94	30.36
		N	13	13	13	12	12	12	12

Non-Pregnant Female
Group	Dose (mg/kg)		Day of gestation and body weight in grams
Group	Dose (mg/kg)		0	5	8	11	14	17	20
Control	0	Mean	215.14	233.57	240.29	244.29	244.14	246.14	250.14
		SD	11.96	12.22	10.27	17.04	16.93	17.14	20.45
		N	7	7	7	7	7	7	7
Low Dose	125	Mean	211.00	219.00	219.00	223.00	225.00	230.00	238.00
		SD	./.	./.	./.	./.	./.	./.	./.
		N	1	1	1	1	1	1	1
Mid Dose	250	Mean	222.00	240.38	242.25	249.88	247.75	250.25	253.00
		SD	6.72	16.10	10.65	11.21	9.38	9.91	11.30
		N	8	8	8	8	8	8	8
High Dose	500	Mean	223.33	242.58	242.50	245.33	242.83	242.25	248.33
		SD	15.20	22.44	19.64	20.83	15.80	15.78	16.74
		N	12	12	12	12	12	12	12

Non-Pregnant Females
Group	Dose (mg/kg)		Gestation Day and body weight change (%)
Group	Dose (mg/kg)		5	8	11	14	17	20
Control	0	Mean	8.66	11.85	13.66	13.51	14.43	16.27
		SD	4.35	5.23	7.35	5.65	5.52	7.20
		N	7	7	7	7	7	7
Low Dose	125	Mean	3.79	3.79	5.69	6.64	9.00	12.80
		SD	./.	./.	./.	./.	./.	./.
		N	1	1	1	1	1	1
Mid Dose	250	Mean	8.19	9.12	12.55	11.60	12.73	13.95
		SD	4.42	3.38	3.52	2.32	3.06	3.15
		N	8	8	8	8	8	8
High Dose	500	Mean	8.88	8.92	10.15	9.00	8.65	11.34
		SD	9.71	9.58	9.78	7.38	5.89	5.80
		N	12	12	12	12	12	12

Pregnant
Group	Dose (mg/ Kg)		Body weight	Uterus	Ovaries
Group	Dose (mg/ Kg)		Body weight	Uterus	Right	Left
Control	0	Mean	332.00	61.73	0.0878	0.0818
		SD	25.65	20.64	0.0152	0.0208
		N	18	18	18	18
Low dose	125	Mean	334.58	66.61	0.0791	0.0828
		SD	15.37	8.57	0.0197	0.0145
		N	24	24	24	24
Mid dose	250	Mean	330.18	62.60	0.0860	0.0854
		SD	32.90	25.27	0.0138	0.0183
		N	17	17	17	17
High dose	500	Mean	309.00	49.70	0.0861	0.0753
		SD	30.36	24.55	0.0202	0.0112
		N	12	12	12	12