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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-01-18 till 2007-02-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 414)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Undecylenic Acid / Acide Undecylenique
- Physical state: white solid
- Analytical purity: 98.75
- Lot/batch No.: 0607007 filling 0022/06
- Expiration date of the lot/batch: 2007-12-22
- Storage condition of test material: at RT, protected from light
- Purity test date: 06/04/2006

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS (Caesarian-obtained, barrier-sustaines, virus-antibody free pregnant animals)
- Source: Charles River, L`Arbresle, France
- Age at study initiation: 11 weeks
- Weight at study initiation: 212-312 g
- Fasting period before study:
- Housing: barrier rodent unit, housed individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): ad lib. access to pelleted standard diet
- Water (e.g. ad libitum): ad lib. access to 0.22 um-filtered tap water
- Acclimation period:3,4, or 5 days (delivered as mated females from supplier)
-individual identification by ear tattoo


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 50+/-20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
-mixing: magnetic stirrer
-Rate of preparation of solution (frequency): for up to 4 / 9 days
- Storage temperature of solution: 4°C


VEHICLE
- Justification for use and choice of vehicle (if other than water): not soluble in water
- Concentration in vehicle: 30,90,150 mg/mL
- Amount of vehicle (if gavage): 5 ml/kg BW/day
- Lot/batch no. (if required): batch No. 015K0115 (Sigma)
- Purity:98.79 %
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
by HPLC-UV;
deviations from nominal value: 3-9%;
compound in vehicle stable over 9 days at 4°C;
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug referred to as day 0 post coitum
Duration of treatment / exposure:
from day 6 to day 20 post coitum
Frequency of treatment:
once daily
Duration of test:
15 days
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary study

Examinations

Maternal examinations:
MORBIDITY/MORTALITY/CLINICAL SIGNS: Yes
- Time schedule: once to twice a day during treatment, afterwards once a day

BODY WEIGHT: Yes
- Time schedule for examinations: days 2,4,6,9,12,15,18,21 post coitum

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as mg food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21 (high-dose group between day 8 and 16 p.c.)
- macroscopic examination of the principal thoracic and abdominal organs

OTHER: fixation and collection of macroscopic lesions
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number and ditribution of dead/life fetuses: Yes
- Number and distribution of uterine scars: Yes
- Other: gross evaluation of placentas, macroscopic lesions fixec and collected
Fetal examinations:
- External examinations/fetal weights/sex: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Mean values: one-way ANOVA with Dunnett`s test
Percentage Values: Fisher exact probability test
Indices:
body weight change, net body weight (chnage), total number of resorptions, total number of dead fetuses, % of dead fetuses/litter, total number of live fetuses, % of live fetuses/litter, % of pre-implantation loss, % of post-implantation loss, average fetal body weight, %of pre-implantation loss relative to number of corpora lutea
Historical control data:
no

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
mortality 8/24 in the high dose group, termination before end of study;
reduced body weight gain (see table1) and food consumption as well as hypersalivation (24/24) in the intermediate dose group;
hypersalivation (15/24) in some animals of the low dose group

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
none of the parameters investigated was affected
(one fetus in the low dose group with several malformations was not considered relevant but of spontaneous origin)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (actual dose received)
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

Table 1: Maternal Body Weight Gain (±SD)

 

 

Interval

Dose in mg/kg bw/day (24 of Dams)

Control (N)

LDT (150)

MDT (450)

HDT (750)

Treatment:

Days 6 -12 

 40

37 

32**

 -

Treatment:

Days 6 -15 

63 

 57

 52**

 -

Treatment:

Days 6 -21 

 151

137 

135* 

 -

*  Significantly different (p 0.05) from the control

** Significantly different (p 0.01) from the control

 

Applicant's summary and conclusion

Conclusions:
No hints for developmental toxic effects of undecylenic acid were identified, not even in animals with clear maternal toxicity.
Executive summary:

The potential of the test substance undecylenic acid to induce developmental toxicity was evaluated in the rat according to OECD guideline 414. Pregnant Sprague-Dawley rats were treated daily with the test substance by oral gavage between days 6 and 21 post coitum. The dams were observed during the treatement for signs of toxicity. The animals were sacrificed on day 21 post coitum and fetuses as well as maternal animals were investigated for signs of toxicity.

Unexpectedly high mortality in the high dose group led to the decision to terminate the treatment of this group. All animals of the intermediate dose group exhibited hypersalivation, and a significantly reduced body weight gain compared to control. In the low dose group, no relevant effects were observed. Hypersalivation in half of the animals was not considered as a relevant sign of toxicity.

No effects or uncommon findings were observed in the fetuses of the animals (malformations observed in a single fetus of the low dose group was considered incidental).

Consequently, the NOAEL for maternal toxicity was set to 150 mg/kg bw/day, while the LOAEL for this parameter was 450 mg/kg bw/day based on body weight and clinical signs. No signs of teratogenicity/developmental toxicity were observed in the study, and the NOAEL ws set to the highest dose level, 450 mg/kg bw/day (750 mg/kg bw/day was discontinued before end of study). A LOAEL for teratogenicity was not observed.