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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:
2001-04-25 - 2001-05-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(2000, draft)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1998)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Dodecane-12-lactam of Degussa AG, batch Nos.
3347/24936 (GC purity 99.95 %) and
3347/24977 (GC purity 99.93 %)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: Charles River Laboratories, L'Arbresle (France)
- Strain: Crl CD (SD) IGS BR
- Age: 10-11 weeks
- Weight at study initiation: 190-332 (mean 263) g
- Sex: females (sexually mature and primigravid)
- identification by CIT identity number via ear tattoo
Environmental conditions:
-acclimation period before treatment: 5 days
- room temperature: 22 °C (+/- 2°C)
-humidity: 50% (+/- 20%)
- light /dark cycle: 12h/12h (07:00-19:00)
-ventilation: about 12 cycles/hour of filtered, non-recycled air
-food: free access to A04 C pelleted maintenance diet (batch No. 10227; UAR, Villemoisson, Epinay-sur-Orge, France)
-water: free access to filtered (0.22µm filter) tap water

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: mixture of gum Arabic (10%) and tween 80 (0.5%) in purified water
Details on exposure:
- Treatment: doses based on preliminary study (CIT/Study No. 20870 RSR)
- Concentration in vehicle: 10, 50, or 200 mg/ml (suspensions; homogeneity verified by analysis)
- Total volume applied: 5 ml/kg bw/day
- Type or preparation of particles: Daily. The test substance was ground to fine powder using a mortar and pestle, suspended in the vehicle in order to achieve the desired concentrations, and then homogenized using a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogenity: The lowest and the highest concentrations (10 and 200 mg/ml) were prepared under conditions representative of those of the study. From each dosage forms duplicate samples were taken at three different levels (top, middle, bottom) and analyzed by HPLC analysis (UV detection at 212 nm) for concentration of the test material to evaluate the homogenity.

Concentration: The concentration of samples taken from each doseage form (including the control) prepared for use on the first day of treatment and on the last day of treatment was determined by HPLC analysis (UV detection at 212 nm)
Details on mating procedure:
Females were mated at breeder's facilities. Mating was confirmed by detection of a vaginal plug (day 0 post-coitum). 5 days acclimatization period to the conditions of the study followed.
Duration of treatment / exposure:
day 6 through day 19 post-coitum inclusive
Frequency of treatment:
daily (once a day)
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 per group; only the first 20 pregnant females were taken into consideration for fetal examinations.
Control animals:
yes, concurrent vehicle
Details on study design:
no further relevant details

Examinations

Maternal examinations:
- Body weight gain: days 2, 6, 9, 12, 15, 18, 20 post-coitum
- Food consumption: intervals days 2-6, 6-9, 9-12, 12-15, 15-18, 18-20 post-coitum
- Clinical observations (morbidity and mortality, clinical signs): at least once a day
- Hysterectomies: on day 20 post-coitum all females were killed. weight of gravid uterus was recorded for each pregnant female at hysterectomy (with at least one live fetus). The ovaries and uterus of females were examined. (see chapter: "Ovaries and uterine content")
- After hysterectomy, the females were subjected to a macroscopic post-mortem examination of the principal thoracic and abdominal organs. A gross evaluation of placentas was also performed.
Ovaries and uterine content:
number of corpora lutea; number and distribution of: dead and live fetuses, implantation sites (or uterine scars), early and late resorptions
Fetal examinations:
Examinations of fetuses were carried out only in the first 20 litters (femals with at least one live fetus): body weight, sex, external examination (all visible structures, surfaces and orifices); detailed examination of the soft tissue including all organs and structures of the head, neck, thorax and abdomen (according to Wilson technique, approximately on half of the fetuses per litter) and detailed examination of the skeleton (bone and cartilage of the head, spine, rib cage, pelvis and limbs) on the remaining fetuses per litter; sex of each live fetus was determined at the time of evisceration or at the time of serial sectioning; sex of each dead fetus was determined at the time of hysterectomy
Statistics:
Mean values were compared by one-way analysis of variance and Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous). Percentage values were compared by the Fisher exact probability test.
Indices:
Data are expressed as group mean values +/- standard deviation or as proportions (wherever necessary, the experimental unit of comprison was the litter). Pre-implantation loss was calculated as follows: (number of corpora lutea - number of implantation sites/ number of corpora lutea)x100; Post-implantation loss was calculated as follows: (number of implantation sites-number of live fetuses/number of implantation sites)x100; Fetal findings were analyzed as follows: (number of fetuses with a particular finding/total number of fetuses examined) x 100
Historical control data:
reported for pre-implantation loss and fetal skeletal variation

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There were no treatment-related clinical signs in the 50 and 250 mg/kg/day treated groups.
Severe clinical signs of poor clinical condition were recorded in a notable proportion of the animals given 1000 mg/kg/day.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
There was no treatment-related death at the 50 and 250 mg/kg/day dose-levels.
At the 1000 mg/kg/day dose-level, two females which presented poor clinical condition were prematurely sacrificed on day 8 post-coitum.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight and body weight gain were similar in the control and the 50 mg!kg/day treated groups.
In the 250 and 1000 mg/kg/day, the body weight gain (gross or net) was moderately to markedly lower when compared to the control group over the treatment period.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food consumption was similar in the control and the 50 mg/kg/day treated group.
In the 250 and 1000 mg/kg/day, there was a significant slight to moderate effect on food consumption over the treatment period.
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:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no macroscopic findings in the control and the 50 mg/kg/day treated groups.
In the 250 and 1000 mg/kg/day treated groups, except the findings recorded in the two prematurely killed females (yellowish deposit on the stomach), the few findings recorded were among those commonly reported in rats of this strain and age.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
There were no abortions or total resorptions in any group.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on the pre- or the post-implantation loss, or the sex ratio.
The minimally lower fetal weight recorded at 250 and 1000 mg/kg/day was considered to be secondary to the lower maternal body weight gain and thus, did not represent a direct adverse effect on the embryofetal development.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
- Mortality and day of death: There was no mortality in the 0 (control), 50 and 250 mg/kg bw/day dose levels. At the 1000 mg/kg/day dose level, two females which presented poor clinical condition were prematurely sacrificed on day 8 post-coitum.
- Number aborting: no abortions in any group
- Number of resorptions: no total resorptions in any group
- Body weight: Slight to marked effects in mid- and high-dose groups:
50 mg/kg bw/day: gross 3 % above, net 2 % below control
250 mg/kg bw/day: gross 15 %, net 37 % below control
1000 mg/kg bw/day: gross 26 %, net 50 % below control
(gross = days 6 to 20; net = from day 6, corrected for weight of uterine content)
- Food/water consumption: Slight to marked effects in mid- and high-dose groups:
50 mg/kg bw/day: not affected
250 mg/kg bw/day: food consumption 7 % below control
1000 mg/kg bw/day: food consumption 11 % below control
- Description, severity, time of onset and duration of clinical signs:
50 mg/kg bw/day, 250 mg/kg bw/day: no clinical signs that were related to the treatment with the test substance
1000 mg/kg bw/day: Severe clinical signs of poor clinical condition in a notable proportion of the animals: piloerection, round back, sedation, dyspnea and/or hypokinesia in 14/24 females, generally from the beginning until the end of the treatment.
- Gross pathology incidence and severity: There was no macroscopic finding that was attributed to the treatment with the test substance in any group.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): The minimally lower fetal weight recorded at 250 and 1000 mg/kg/day was considered to be secondary to the lower maternal body weight gain and thus, did not represent a direct adverse effect on the embryofetal development.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on the pre- or the post-implantation loss, or the sex ratio.
The minimally lower fetal weight recorded at 250 and 1000 mg/kg/day was considered to be secondary to the lower maternal body weight gain and thus, did not represent a direct adverse effect on the embryofetal development.
Changes in litter size and weights:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No fetal external malformations or variations that were ascribed to the treatment with the test substance were noted in any group.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No fetal skeletal malformations or variations that were ascribed to the treatment with the test substance were recorded in any group.
Visceral malformations:
no effects observed
Description (incidence and severity):
No fetal soft tissue malformations or variations that were ascribed to the treatment with the test substance were recorded in any group.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Litter size and weights: No treatment-related effects were observed on the pre- and the post-implantation losses, and the sex ratio. The minimally lower fetal weight recoded at 250 and 1000 mg/kg/day was not statistically significant and considered to be secondary to the lower maternal body weight gain, and thus did not represent a direct adverse effect on the embryofetal development. Mean fetal weights:
50 mg/kg bw/day: 4.04 +/- 0.21 g
250 mg/kg bw/day: 3.89 +/- 0.30 g
1000 mg/kg bw/day: 3.87 +/- 0.26 g
control: 3.93 +/- 0.25 g
- Number of viable fetuses: no treatment-related effects
- Sex ratio: no treatment-related effect
- External abnormalities: No treatment-related fetal external malformations or variations were noted in any group.
- Soft tissue abnormalities: No fetal soft tissue malformations or variations that were ascribed to the treatment with the test substance were recorded in any group.
- Skeletal abnormalities: No fetal skeletal malformations or variations that were ascribed to the treatment with the test substance were recorded in any group. Findings were considered to be of no toxicological significance.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

no further relevant remarks

Applicant's summary and conclusion

Conclusions:
The test substance Lauryl lactam, which was administered orally in rats, was not maternotoxic at 50 mg/kg bw/day. At dose-levels of 250 and 1000 mg/kg bw/day, the test substance produced slight to marked maternotoxicity resulting in reduction in food consumption and body weight gain. In addition, some mortality and clinical signs of toxicity were recorded at 1000 mg/kg/day.
No embryo- and fetotoxicity was recorded at any dose-levels, and no teratogenic effects were found. Consequently, the No Observed Effect Level for maternal toxicity is 50 mg/kg/day and the No Observed Effect Level for embryofetal toxicity is 1000 mg/kg/day.
Executive summary:

The objective of this prenatal development toxicity study was to evaluate the potential toxic effects of the test substance Lauryl lactam on the pregnant female Sprague-Dawley rats an on embryonic and fetal development following daily oral administration (gavage) to pregnant female rats from implantation to the day prior to the scheduled hysterectomy: day 6 to day 19 post-coitum inclusive. Three groups of 24 mated female Sprague-Dawley rats, received the test substance Lauryl lactam by oral administration at 50, 250 and 1000 mg/kg/day from day 6 to day 19 post-coitum inclusive. A control group of 24 mated female was given the vehicle alone.

The test substance Lauryl lactam, which was administered orally in rats, was not maternotoxic at 50 mg/kg bw/day. At dose-levels of 250 and 1000 mg/kg bw/day, the test substance produced slight to marked maternotoxicity resulting in reduction in food consumption and body weight gain. In addition, some mortality and clinical signs of toxicity were recorded at 1000 mg/kg/day. No embryo- and fetotoxicity was recorded at any dose-levels, and no teratogenic effects were found. Consequently, the No Observed Effect Level for maternal toxicity is 50 mg/kg/day and the No Observed Effect Level for embryofetal toxicity is 1000 mg/kg/day.