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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Fragrance material review on Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and 4-(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
Author:
J. Lalko, A. Lapczynski , D. McGinty, S. Bhatia, C.S. Letizia, A.M. Api
Year:
2007
Bibliographic source:
Food and Chemical Toxicology, 45, (2007) S251–S257
Reference Type:
publication
Title:
A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients
Author:
D. Belsito et al.
Year:
2007
Bibliographic source:
Food and Chemical Toxicology 45 (2007) S130–S167
Reference Type:
publication
Title:
Inhibition of cyclophosphamide-induced teratogenesis by b-ionone
Author:
M.R. Gomes-Carneiro, A.C.A.X. De-Oliveira, R.R. De-Carvalho,
I.B. Araujo, C.A.M. Souza, S.N. Kuriyama, F.J.R. Paumgartten
Year:
2003
Bibliographic source:
Toxicology Letters 138 (2003) 205-213

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of the test chemical was performed on rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and 4-(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
- IUPAC name: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and 4-(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
- Molecular formula: C13H20O
- Molecular weight: 192.3 g/mole
- Smiles : C1([C@@H](C(=CCC1)C)\C=C\C(C)=O)(C)C
- Inchl: 1S/C13H20O/c1-10-6-5-9-13(3,4)12(10)8-7-11(2)14/h6-8,12H,5,9H2,1-4H3/b8-7+
- Substance type: Organic
- Physical state: Solid (yellow)
Specific details on test material used for the study:
- Name of test material: Reaction mass of 4-(2,6,6-trimethylcyclohex-2-ene-1-yl)-but-3-ene-2-one and -(2,6,6-trimethylcyclohex-1-ene-1-yl)-but-3-ene-2-one
- Molecular formula: C13H20O
- Molecular weight: 192.3 g/mole
- Smiles : C1([C@@H](C(=CCC1)C)\C=C\C(C)=O)(C)C
- Inchl: 1S/C13H20O/c1-10-6-5-9-13(3,4)12(10)8-7-11(2)14/h6-8,12H,5,9H2,1-4H3/b8-7+
- Substance type: Organic
- Physical state: Liquid

Test animals

Species:
rat
Strain:
not specified
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: oil
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
2 mg of test material in 0.1 ml oil solution was prepared


DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material form a solution in oil
- Concentration in vehicle: 8-10mg/kg bw/day
- Amount of vehicle (if gavage): No data available

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
8 months
Frequency of treatment:
On alternate daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
8-10 mg/kg bw
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data available
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum:No data available
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, other:]Number of offspring, live pups, weight of pups at birth and after 7 and 21 days, and the viability of the pups after birth were observed.

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]No data available

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:No data available

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.The F1 generation (offspring) were
allowed to reach maturity and Their offspring, the F2 generation were evaluated for reproduction parameters.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]Reproductive parameters were observed

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
yes ,offspring viability were observed

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
no effect was observed on body weight.
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
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 / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
no effects was observed on number of pregnancies, number of offspring

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: No effect was observed in given dose

Target system / organ toxicity (P0)

Critical effects observed:
no
System:
female reproductive system
Organ:
not specified

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P1)

Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: No effects was observed at given dose

Target system / organ toxicity (P1)

Critical effects observed:
no
System:
female reproductive system
Organ:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
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:
not specified
Histopathological findings:
not specified
Other effects:
no effects observed
Description (incidence and severity):
No effects were observed on Number of offspring, live pups, weight of pups at birth and after 7 and 21 days, and the viability of the pups after birth.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
body weight and weight gain
other: reproductive parameters
Remarks on result:
other: No effects was observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
no
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 10mg/kg bw. When rats were treated with the test chemical orally.
Executive summary:

The reproductive toxicity study of the test chemical was performed on rats . The test material was given 2 mg in 0.1 ml oil solution on alternate days for 8 months (equivalent to a dose of approximately 8–10 mg/kg body weight/day). The female rats were observed through three reproduction cycles for number of pregnancies, weight, number of offspring, live pups, weight of pups at birth and after 7 and 21 days, and the viability of the pups after birth. The F1 generation (offspring) were allowed to reach maturity and treated with 15 mg/kg of test material prior to being subject to reproductive toxicity testing. Their offspring; the F2 generation were evaluated for reproduction parameters. No adverse effect on any of the parameters measured. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 10mg/kg bw. When rats were treated with the test chemical orally.