Cinnamyl butyrate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Cinnamyl butyrate (103-64-0). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 462.57mg/kg bw. When male and female Sprague-Dawley rats were exposed with Cinnamyl butyrate (103-64-0)orally. Thus, based on the studies and predictions on Cinnamyl butyrate (103-64-0) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation Cinnamyl butyrate (103-64-0) cannot be classified as reproductive toxicant.

 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of the test material: Cinnamyl butyrate
- IUPAC name: (2E)-3-phenylprop-2-en-1-yl butanoate
- Molecular formula: C13H16O2
- Molecular weight: 204.267 g/mol
- Substance type: Organic
- Smiles: c1(\C=C\COC(CCC)=O)ccccc1

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Throughout maturation, mating, gestation and up to day 4 post partum.

Frequency of treatment:

Once daily

Details on study schedule:

No data available

Dose / conc.:

462.57 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

462.57 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: No effects on reproductive performance was observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

462.57 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

clinical signs

gross pathology

other: overall developmental effects

Remarks on result:

other: No developmental effects was observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and "k" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters OR Vinyl/Allyl Esters by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> 4-alkylphenol-like derivatives (2b-3) by DART scheme v.1.0

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.11

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.8

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 462.57mg/kg bw. When male and female Sprague-Dawley rats were exposed with Cinnamyl butyrate (103-64-0)orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Cinnamyl butyrate (103-64-0). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 462.57mg/kg bw. When male and femaleSprague-Dawleyrats were exposed with Cinnamyl butyrate (103-64-0)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

462.57 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies, Cinnamyl butyrate (103-64-0) has been investigated for developmental toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Cinnamyl butyrate (103-64-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Cinnamyl butyrate (103-64-0). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 462.57mg/kg bw. When male and femaleSprague-Dawleyrats were exposed with Cinnamyl butyrate (103-64-0)orally.

 It is further supported by experimental study conducted by Atsushi Ono ; Katsumi Kobayashi; Hideki Serizawa; Tomoko Kawamura, Hina Kato, Mariko Matsumoto, Mika Takahashi, Mutsuko Hirata-Koizumi, Yuko Matsushima and Akihiko Hirose (Fundamental toxicological sciences vol.2(4)191-200,2015) on structurally similar read across substance β-bromostyrene (103-64-0). In a Sub-acute repeated dose toxicity study, Sprague Dawley [Crl:CD()SD] male and female rats treated with β-bromostyrene orally by gavage in the concentration of 0, 30, 125 and 500 mg/kg/day. One female rat found dead on Day 3 and Decreases in spontaneous movement during weeks 3 and 4 were observed in male and female rats. No clinical signs were observed in any animal during the recovery period. Significantly increased body weight was observed in female rat on days 17-24 during the dosing period and significant decrease in water consumption was observed in female rats during week 4 of the dosing period a 125 mg/kg/day dose group as compared to control. Significant decreased in food consumption at day 4 were observed in male and female rat in dosing period and in females at days 7 and 14 in recovery period at 500 mg/kg/day andsignificant increased in food consumption at days 7-21were observed in female rats at 125 mg/kg/day as compared to control.Decreased mean corpuscular hemoglobin (MCH) during dosing and eosinophils in recovery period were observed in male rat and increased Reticulocyte and decreased mean corpuscular hemoglobin concentration (MCHC) during dosing and increase monocytes at recovery period were observed in female rats and significant increase in total protein level in male and female rats, Ca, P and albumin level and decrease in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and creatinine in male rats and significant increase in total cholesterol, triglycerides, phospholipids and Cl level in female rats at the end of dosing. Significant increased in triglycerides level was observed in female rats after the recovery period at 500 mg/kg/day. Decreased activated partial thromboplastin time and increased fibrinogen level were observed in female rats andsignificant decrease in aspartate aminotransferase, lactate dehydrogenase level and significant increase in Ca level in male rats and significant increase in total cholesterol, phospholipids level in female rats observed at 125 mg/kg/day as compared to control. Significant increases in urine volume in male and female rats, decrease in urine osmolality and small round epithelial cells in sediments were observed in male rats during week 4 of dosing period at 500 mg/kg/day and significant increases in urine volume and significant decrease in urine osmolality were observed in male rats at 125 mg/lg/day as compared to control. No significant differences were seen in urine volume, osmolality and qualitative measurements for either sex compared with the control groups during week 2 of the recovery period. Significant decrease in landing foot splay and forelimb grip strength was observed in male rats during week 2 of the recovery period. However, it was determined to be incidental because this sign was not observed during week 4 of the dosing period at 500 mg/kg/day. Significant decrease in forelimb grip strength was observed in male rats during week 2 of recovery period. No significant change was observed in any male and female rats receiving the test substance during week 4 of the dosing period. Significant increase in hindlimb grip strength was observed in female rats during week 4 of the dosing period at 125 mg/kg/day as compared to control. However, this was not observed in the high dose group. Similarly, Significant increase in absolute and relative liver weight in male and female rats, significant increase in absolute and relative kidney weights and significant decrease in absolute testes weight in male rats and significant increase in relative kidney weights in female rats in dosing period and Significant increase in relative liver and heart weight was observed in female rats at 500 mg/kg/day as compared to control at the end of recovery period. Significant increase in relative liver weight and decrease in brain weight were observed at 125 mg/kg/day in female rats at the end of the recovery period. In addition, excess fluids in the abdominal and thoracic cavities, an enlarged liver, and dark red foci in the glandular stomach and unilateral small thyroids observed in female rat and enlargement of liver was observed in male rats at the end of dosing period. Enlargement of liver was observed in male rats at the end of recovery period in 500 mg/lg/day. Dark red foci in lung in one male rat and dark red foci in the glandular stomach in one female rat were observed at end of the dosing period at 125 mg/kg/day dose group. Minimal to mild degree of eosinophilic bodies in tubular cells, Mild degeneration of renal tubular and minimal hyaline casts in kidneys, minimal to mild centrilobular hypertrophy of hepatocytes in liver and minimal hypertrophy of follicular cells in thyroids were observed in male rats and atrophy of Peyer’s patch in the ileum, dilation of the renal tubes with centrilobular necrosis and congestion in the liver, focal hemorrhage and accumulation of foamy cells in the lung, atrophy of the mesenteric and submandibular lymph nodes, an increase in hematopoiesis and atrophy of white pulp in the spleen, erosion in the glandular stomach, atrophy of the thymus, and a remnant of ultimobranchial bodies in the thyroid were observed in female rats at 500 mg/kg/day as compared to control. Minimal Tubular regeneration, mild to minimal Eosinophilic body in tubular cells interstitial mineralization Kidney and Hypertrophy of follicular cells in thyroid of male rat and Periportal vacuolation of hepatocytes in liver of female rat were observed at the recovery period. Minimal to mild degree of eosinophilic bodies in tubular cells in kidney was observed in male rat and minimal hypertrophy of follicular cells in thyroids was observed in female rats at 125 mg/kg/day as compared to control. No effects were observed on reproductive organs of treated female rats as compared to control. Therefore, NOAEL was considered to be 125 mg/kg/day for male and 500 mg/kg/day for female when Sprague Dawley [Crl:CD()SD] male and female rats treated with β-bromostyrene(103-64-0)orally.

 It is further supported by experimental study conducted by A.M. Api; D. Belsito et.al. (Food and Chemical Toxicology Volume 82, Supplement, August 2015, Pages S20-S28)on structurally similar read across substance α-hexylcinnamaldehyde (CAS No.- 101-86-0).The study was designed to investigate the reproductive toxicity effects of α-hexylcinnamaldehyde (CAS No.- 101-86-0) in rats by the oral route. No effects were observed on mating, fertility, reproductive organ weights, reproductive organ microscopic examination, delivery parameters, pup body weights, and pup clinical and necropsy observations. There were non-significant decreases in maternal body weight gain and feed consumption during lactation. Hence the NOAEL for reproductive and developmental toxicity was considered to be 100 mg/kg/day, the highest dosage tested. When rats were treated with α-hexylcinnamaldehyde (CAS No.- 101-86-0) orally.

Thus, based on the above studies and predictions on Cinnamyl butyrate (103-64-0) and its read across substances it was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation Cinnamyl butyrate (103-64-0) cannot be classified as reproductive toxicant.

 

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation Cinnamyl butyrate (103-64-0) cannot be classified as reproductive toxicant.