6,10-dimethylundeca-3,5,9-trien-2-one

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according to OECD Guideline 415 under GLP, with full report and all individual data.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Reference 2

Reference Type:

secondary source

Title:

No information

Author:

Beekhuizen MEW

Year:

2007

Bibliographic source:

OECD SIDS, Final 04/2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 415 (One-generation reproductive toxicity)

Principles of method if other than guideline:

AccordinhOECD Guideline 415, One-generation reproductive toxicity

GLP compliance:

yes

Remarks:

NOTOX BV

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

6,10-dimethylundeca-3,5,9-trien-2-one

EC Number:

205-457-1

EC Name:

6,10-dimethylundeca-3,5,9-trien-2-one

Cas Number:

141-10-6

Molecular formula:

C13H20O

IUPAC Name:

6,10-dimethylundeca-3,5,9-trien-2-one

Details on test material:

- Name of test material (as cited in study report): Pseudoionone
- Manufacturer: Teranol AG, Lalden
- Lot/batch No.: UU02033826,
- Analytical purity: 95.4% (area, GC).

Test animals

Species:

rat

Strain:

other: Wistar Crl: (WI) BR (outbred, SPF quality)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: males 5 - 6 weeks old; females 11 - 12 weeks old
- Identification: tattoo on the tail
- Housing: suspended stainless-steel cages, 4 animals per sex per cage, with males and females being kept in separate rooms. Mated females and males were housed individually in labelled polycarbonate cages containing sawdust (SAWI bedding, Jelu-Werk, Rosenberg, Germany) as bedding material. During the final stage of the pregnancy period, from day 16 post coitum, and during lactation, paper (Enviro-dri, BMI, Helmond, The Netherlands) was supplied to the dams for incorporation into the nest. The paper was replaced when soiled.
- Diet (e.g. ad libitum): ad libitum, standard pelleted rat diet (Altromin, code VRF1, Lage, Germany)
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Analyses for all batches of feed and quarter-yearly analyses of tap water are retained at NOTOX archives

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

maize oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Pseudoionone was formulated daily

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Formulations were analytically confirmed to be stable for at least 4 hours at room temperature and to correspond to targeted concentrations.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1 from same dose group
- Length of cohabitation: until vaginal plug was found; max. 3 weeks
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- After 21 days of unsuccessful pairing pairs were separated.
- After successful mating each pregnant female was caged (how): individually

Duration of treatment / exposure:

Exposure period: males: mean 106 (range 104-108) days
females: mean 60 (range 36-65) days
Premating exposure period (males): 11 weeks
Premating exposure period (females): 2 weeks
Duration of test: 126 days

Frequency of treatment:

once daily

Duration of test:

Exposure period: males: mean 106 (range 104-108) days;
females: mean 60 (range 36-65) days
Premating exposure period (males): 11 weeks
Premating exposure period (females): 2 weeks
Duration of test: 126 days

Doses / concentrations

Remarks:

Doses / Concentrations:
40, 120 and 360 mg/kg bw/d
Basis:
nominal conc.

No. of animals per sex per dose:

24

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: dose levels were based on a GLP 28-day subchronic toxicity study with the same dose levels that resulted in a NOEL of 50 mg/kg bw/d and a LOEL of 250 mg/kg bw/d with reversible effects (-> 7.5.1 Strobel1997.Repeated dose toxicity: oral rat 28d)

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of exposure and weekly thereafter; Mated females were weighed on days 0, 7, 14 and 21 of gestation and during lactation on days 1, 4, 7, 14 and 21


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption of mated females was recorded on gestation days 0, 7, 14 and 21 and during lactation on days 1, 4, 7, 14 and 21


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes, but only subjective appraisal was maintained

REPRODUCTIVITY
- numbers of animals mated, mating date, confirmation of pregnancy and day of delivery were recorded

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes

Fetal examinations:

- External examinations: Yes: all per litter

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

120 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

360 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

For general results, please refer to Beekhuizen2003.Toxicity to reproduction rat 1 generation

Reproduction
Reproduction parameters were unaffected by treatment up to
360 mg/kg bw/d. In the 40 group, one female did not mate and
one female was non-pregnant. In the 120 group, one female
showed delivery difficulties, and in the 360 group, two
females showed delivery difficulties. Mating performance,
duration of gestation, fertility parameters and number of
pups at birth were similar for the control and treated
groups.
----------------------------------------------------------
Dose group,   Litter size, live births, mean bodyweights,
mg/kg bw/d         n            n              g
----------------------------------------------------------
   0    mean      14.7         14.5            6.8
        SD         2.5          2.72           0.62
        n         24           24             24 
----------------------------------------------------------
  40    mean      15.0         14.1            6.6
        SD         2.5          3.98           0.44
        n         22           22             21
----------------------------------------------------------
 120    mean      15.7         15.1            6.5*
        SD         1.3          2.72           0.45
        n         23           23             23
----------------------------------------------------------
 360    mean      15.4         14.5            6.5
        SD         4.5          5.38           0.59
        n         23           23             22
----------------------------------------------------------
*: p < 0.05, Dunnett's test on pooled variance.
----------------------------------------------------------

Pups
Development of the pups was unaffected by treatment up to
360 mg/kg bw/d. Numbers of pups at birth were similar
between controls and all treatment groups. No teratogenic
malformations are reported. However, postnatal deaths were
significantly increased at 360 mg/kg bw/d during days 0-4
post partum, due to which the viability index was decreased
in this group (91.0 compared to 96.6 in controls).