Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid (CAS #2166089-27-4) was not tested in reproduction toxicity study. The following arguments were used: 


- In accordance with Column 2 of REACH Annex VIII, the screening study for reproductive/developmental toxicity does not need to be conducted if a pre-natal developmental toxicity study is available.


- In accordance with REACH Annex IX, the extended one-generation reproductive toxicity study does not need to be conducted at this tonnage band (100-1000 tpy) because there are no results from available repeated dose toxicity studies (28-day and 90-day repeated dose toxicity studies together with a pre-natal developmental toxicity study) that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity.


The NOAELs were determined to be 1000 mg/kg bw/day based on the repeated dose toxicity studies and the pre-natal developmental toxicity study.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Annex IX, the extended one-generation reproductive toxicity study does not need to be conducted at this tonnage band (100-1000 tpy) because there are no results from available repeated dose toxicity studies (28-day and 90-day repeated dose toxicity studies together with a pre-natal developmental toxicity study) that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity.
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Pre-natal developmental toxicity study (OECD 414, GLP, K1)


In a developmental toxicity study conducted similarly to the OECD guideline No. 414 and in compliance with GLP, the test material diluted in propylene glycol was administered to three groups of 20 females receiving the test item at doses of 100, 300 or 1000 mg/kg/day at a dose volume of 5 mL/kg/day by oral gavage administration, from Day 6 to 19 after mating, inclusive.


On Day 12 and 13 of gestation, female No. 34 and 35 that received 100 mg/kg/day were killed for reasons of animal welfare. Clinical signs included irregular breathing, salivation, piloerection, brown staining of the muzzle, and a reduction of body weight gain was also observed. Macropathological examination included a distended esophagus and abnormal contents in the stomach, and these findings were not considered to be related to treatment. There were no other clinical signs observed for the remaining females across all groups or signs following dose administration that were considered to be related to treatment.


Thyroid hormones (T3, T4 and TSH), maternal clinical condition, overall body weight performance and food consumption were not adversely affected at any dose level investigated, and there were no test item-related macroscopic abnormalities or thyroid and parathyroid weights detected at scheduled termination on Day 20 after mating.


There was no effect of maternal treatment on the mean numbers of corpora lutea, implantation, resorption, sex ratio, ano-genital distance or on placental, fetal and litter weights, and there were no major or minor abnormalities or skeletal variants related to treatment at 100, 300 or 1000 mg/kg/day.


Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival was concluded to be 1000 mg/kg/day.


 


Subacute oral toxicity study (OECD 407, GLP, rel. 1)


Under the experimental conditions, SD rats were administered with the test substance Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid daily for 28 days at the dose level of 100, 300 and 1000 mg/kg bw/day. Test item-related hyaline droplet accumulation was evident in the kidneys of the majority of males administered 1000 mg/kg/day, however, this is a male rat-specific phenomenon and full recovery was observed. In the absence of any effects which were deemed to be adverse, within the context of this study, the No Observed Adverse Effect Level (NOAEL) was concluded to be 1000 mg/kg/day.


 


Subchronic oral toxicity study (OECD 408, GLP, rel. 1)


Under the experimental conditions, SD rats were administered with the test substance Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid daily for 90 days at the dose level of 100, 300 and 1000 mg/kg bw/day. No changes related to the exposure of the test substance were noted. The NOAEL of Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid was 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

The test substance was tested for developmental toxicity/teratology in a study in rats according to OECD Guideline 414. It was shown no maternal toxicity, no developmental toxicity and no teratogenicity by administration of the test item by oral gavage up to 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 19 June 2019 To 10 September 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to OECD test guideline No. 414 and in compliance with GLP without any deviations.
Justification for type of information:
Study already available for a registration outside EU, and owned by the company having sold the REACH LoA.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
date of inspection: 02/04/2019
Limit test:
no
Specific details on test material used for the study:
Storage conditions: At ambient temperature (15 to 25°C) in the dark
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD(SD) rat
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Age at study initiation: 69 to 75 days old
- Weight at study initiation: 235-285 g
- Housing:
- females (during pregnancy) were caged individually in polycarbonate bottom cages with stainless steel mesh lid, and grid bottomed cages were used during pairing. Cages were suspended above absorbent paper which was changed daily during pairing.
- during the mating period, 1 Male and 1 females/cage
- Diet (e.g. ad libitum): SDS VRF1 Certified pelleted diet, ad libitum
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 5 days (minimum prior to pairing) under test conditions with an evaluation (up to four animals by cages)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Air supply: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The required amount of test item was weighed into a suitable container. Approximately 50% of the final volume of vehicle was added and magnetically stirred until it was uniformly mixed. It was then made up to the required volume with vehicle and mixed with a magnetic stirrer until homogenous.
A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.

VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg active ingredient/mL
- Dose volume administered (for vehicle and treatment groups): 5 mL/kg bw/day

STABILITY:
- The homogeneity and stability of formulations during storage were confirmed as part of 28-days oral toxicity study, (Covance Study No.: QC98GB). It was demonstrated that formulations were homogenous and stable for one day following ambient storage (15 to 25°C) and for 15 days following refrigerated storage (2 to 8°C).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of each of the first, second and third formulation preparations were analyzed for achieved concentration of the test item.
In addition, of the dose remaining from the second preparation, one pot from each group was sampled and analyzed.
The mean analyzed concentrations were between -11.7% and +1.0% of nominal concentrations, confirming the accuracy of formulation. The percentage difference of individual results from mean values was within 5%, confirming the continued precision of analysis. Associated procedural recovery values were between 97.7% and 100.8% confirming the continued efficiency of the sample extraction process.
Details on mating procedure:
A colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals.
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: until evidence of mating
- Proof of pregnancy: Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm and referred to as day 0 of pregnancy. Only females showing at least two copulation plugs were allocated.

Duration of treatment / exposure:
Females were treated from Day 6 to Day 19 (inclusive) after mating.
Frequency of treatment:
Once daily at approximately the same time each day.
Duration of test:
14 days
Dose / conc.:
0 mg/kg bw/day
Remarks:
Group 1 (vehicle control)
Dose / conc.:
100 mg/kg bw/day
Remarks:
Group 2 (Expressed in terms of material as supplied)
Dose / conc.:
300 mg/kg bw/day
Remarks:
Group 3 (Expressed in terms of material as supplied)
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
Group 4 (Expressed in terms of material as supplied)
No. of animals per sex per dose:
20 females/dose (see Table 7.8.2/1)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels selected for investigation in this main embryo-fetal study were selected in conjunction with the Sponsor and were based on the results of a preliminary embryo-fetal study conducted at these laboratories (Covance Study No. FD84YJ). In that study, dose levels of 250, 500 and 1000 mg/kg/day were investigated. There were no premature deaths,
no signs observed in relation to dose administration, no test item-related changes in clinical condition, no adverse effects on body weight, food consumption or embryo-fetal survival and development and no treatment related macroscopic findings at any dose level investigated. The high dose level for the current OECD414 study was therefore set at 1000 mg/kg/day with intermediate and low dose levels of 300 and 100 mg/kg/day chosen to fulfill the 2-fold to 4-fold dosing interval as specified in the test guideline.
- Rationale for animal assignment (if not random): Random
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatization period, observations of the animals and their cages were recorded at least once per day


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health.
Detailed observations were recorded daily during the treatment period at the following times in relation to dose administration:
Pre-dose observation
One to two hours after completion of dosing
As late as possible in the working day


BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was recorded on Days 0, 3 and 6-20 after mating.


FOOD CONSUMPTION: Yes
The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0-3, 3-6, 6-10, 10-14, 14-18, and 18-20 inclusive after mating.

THYROID HORMONE ANALYSIS
Blood samples were collected at scheduled termination, for all adult females (excluding premature deaths), from the sublingual vein.
- Anaesthetic used for blood collection: Yes, under light general anesthesia induced by isoflurane
- Animals fasted: No
- Parameters checked: T3, T4 and TSH analysis performed by the Department of Bioanalysis LC-MS/MS, Covance CRS Limited Huntingdon

POST-MORTEM EXAMINATIONS: Yes (Each animal was examined externally and internally for macroscopic abnormalities)
- Animals surviving until the end of the scheduled study period were killed on Day 20 after mating, by carbon dioxide asphyxiation. and the fetuses were killed by chilling on a cool plate (nominally 0°C).
- Organs examined: Abnormalities were fixed and gravid uterus (with cervix) was weight. Thyroid with parathyroids were weighed after partial fixation, fixed and examined microscopically. Findings were either reported as "present" or assigned a severity grade.
Then, tissue samples were dehydrated, embedded in paraffin wax and sectioned at a nominal four to five micron thickness. Sections were stained with hematoxylin and eosin.
For bilateral organs, left and right organs were weighed together. Requisite organs were weighed for animals killed at scheduled intervals.
Tissues were routinely preserved in 10% Neutral Buffered Formalin.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes, including cervix and ovaries
- Number of corpora lutea: Yes
- Number of implantations: Yes, checked after staining with ammonium sulphide
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Fetuses live and dead
Fetal examinations:
- All viable fetuses and placentae were dissected from the uterus, individually weighed and identified within the litter using a coding system based on their position in the uterus. External examination with abnormalities and the sex and ano-genital distance of each fetus were recorded.
- 50% of fetuses in each litter were sexed internally and eviscerated. Then fetuses were fixed in Industrial Methylated Spirit (IMS). Remaining fetuses were fixed whole in Bouin’s fluid.
- Bouin’s fixed fetuses were subject to free-hand serial sectioning and examined for visceral abnormalities.
IMS fixed fetuses were processed and stained with Alizarin Red and assessed for skeletal development and abnormalities
Statistics:
The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, pre/post implantation loss, live young, sex ratio - percentage male, placental, litter and fetal weights, ano-genital distance and organ weight data:
- Means and standard deviations of various data were calculated and included in the report.
- Parametric analysis used if Bartlett's test for variance homogeneity was not significant at the 1% level (t-test, Williams' test or Dunnett's test)
- Non-parametric test used if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations (Kruskal-Wallis' test, Wilcoxon test, Shirley's test or Steel's test)
- For organ weight data, analysis of covariance was performed using terminal body weight as covariate, unless non-parametric methods were applied.

Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Indices:
Percentage pre-implantation loss was calculated as:
(Number of corpora lutea - Number of implantations)/ Number of corpora lutea x 100
Percentage post-implantation loss was calculated as:
(Number of implantations - Number of live foetuses)/ Numer of implantations x 100
Historical control data:
Historical control were provided in the study (Fetal examinations: major, skeletal avec visceral findings)
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
On Day 12 of gestation, female No. 34 that received 100 mg/kg/day showed irregular and gasping breathing, salivating and brown staining of the muzzle, and was killed for reasons of animal welfare. Prior to Day 12 of gestation, female No. 34 had shown no clinical signs or signs associated with dose administration. Body weight gain was reduced from Day 11 of gestation and food intake values for this female remained similar to that of the Controls. Macropathological examination revealed distention and food material in the esophagus and firm contents in the stomach. This females was pregnant with 16 fetuses. Given the absence of these findings at higher dose levels, this death is considered not to be related to treatment.

On Day 13 of gestation, female No. 35 receiving 100 mg/kg/day was killed for reasons of animal welfare, showing signs of irregular breathing, piloerection and brown staining of the muzzle on Day 12 and 13 of gestation. Body weight gain was reduced from Day 12 of gestation and food intake values remained similar to that of the Controls. Macropathological investigation revealed distention and frothy pale fluid in the esophagus, yellow contents in the jejunum and pale firm contents in the stomach. This female was pregnant with 17 fetuses.
Given the absence of these findings at higher dose levels, this death is considered not to be related to treatment.

From Day 18 of gestation hair loss on the forelimbs became apparent for a number of females across all groups but were considered not to be related to treatment.
There were no other clinical signs or observations following dose administrations that were considered to be related to treatment
Mortality:
no mortality observed
Description (incidence):
Two females were killed for reasons of animal welfare as mentionned above, but these deaths are considered not to be related to treatment.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was no adverse effect of treatment at any dose level investigated.

It was noted that, during Days 10-15 of gestation, group mean body weight gain at 100 or 300 mg/kg/day was statistically significantly low when compared to Controls, in a non dose-dependent manner, although mean body weight gain during this period at 1000 mg/kg/day was essentially similar to Control. A review of the individual data revealed that occasions of reduced body weight gain and/or weight loss were not confined to a particular day of gestation during this recording period, and in the absence of a similar response in the 1000 mg/kg/day, these apparent effects on body weight performance were considered incidental and unrelated to treatment with the test item.

Overall body weight gain during the treatment period (Days 6 to 19 of gestation) was lower than Controls for females that received 100 or 300 mg/kg/day, however this can be attributed to the body weight loss observed during Days 10 to 15 of gestation. Overall body weight gain for females that received 1000 mg/kg/day during treatment was unaffected when compared to Controls.

There was no adverse effect on mean gravid uterine weight at any dose level investigated.
The gravid uterine weight for females that received 1000 mg/kg/day was slightly higher than Control.
The maternal body weight change adjusted for gravid uterine weight for females that received 100 or 300 mg/kg/day was lower than that of Controls, however, the gravid uterine weight for these females was comparable to Controls, and this can be attributed to the overall bodyweight loss/reduced body weight gain seen during Days 10 to 15 of gestation.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There was no clear effect of treatment on food intake.
The food intake of females that received 100 or 300 mg/kg/day was slightly lower than Controls during Days 10-14 of gestation, however, there was no dose-related response.
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:
no effects observed
Description (incidence and severity):
Thyroid and parathyroid weights were unaffected by treatment for females that received 100, 300 or 1000 mg/kg/day.
Gross pathological findings:
no effects observed
Description (incidence and severity):
The macroscopic examination performed after 20 days of treatment revealed no test item related lesions.
The incidence and distribution of all findings were considered to be unrelated to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Histopathological examination on the thyroid revealed no test item related findings.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
THYROID HORMONE ANALYSIS: There was no clear effect of treatment on mean T3, T4 or TSH concentrations.

- Triiodothyronine (T3) and Thyroxine (T4)
Mean T3 concentrations in serum samples obtained from females that received 100, 300 or 1000 mg/kg/day were found to be similar. T3 concentrations in females receiving 100 mg/kg/day had a significantly higher mean value compared to Control (p=0.004,,Dunnett's test), however, there was no dose-related increase in mean T3 concentrations apparent. Serum T4 concentrations for each group, including Control, were lower than the endogenous levels observed in the control matrix used to prepare the QC samples.
Mean T4 concentrations in serum samples obtained from females that received 100, 300 or 1000 mg/kg/day had significantly higher mean values when compared to Control (p<=0.003,
Dunnett's test), however, there was no dose-related increase in mean T4 concentrations apparent. Serum T3 concentrations for each group, including Control, were lower than the
endogenous levels observed in the control matrix used to prepare the QC samples.

- Thyroid Stimulating Hormone (TSH)
Mean TSH concentrations in serum samples obtained from females that received 100, 300 or 1000 mg/kg/day were increased when compared to Controls. No differences attained statistical significance and the serum TSH concentrations for each group, including Control, were lower than the matrix QC level (2250 pg/mL).
Number of abortions:
no effects observed
Description (incidence and severity):
One control female (No. 8) and one female that received 1000 mg/kg/day (No. 79) were found not to be pregnant at macroscopic examination on Day 20 of gestation. All remaining females (including premature decedents) were found to be pregnant.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The levels of pre- and post-implantation losses were unaffected by maternal treatment.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of resorptions were unaffected by maternal treatment.
Early or late resorptions:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
Dead fetuses:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
Other effects:
not specified
Details on maternal toxic effects:
Litter data were unaffected by maternal treatment.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effect observed
Remarks on result:
other: expressed as active ingredient
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was considered to be no effect of treatment on placental, litter and fetal weights.
Mean placental weight and male, female and hence overall mean fetal weight for females that received 1000 mg/kg/day were slightly higher than Control and attained statistical significance. Total litter weight was also slightly higher than Control, however, statistical significance was not attained. Given the direction of these changes, they are not considered adverse.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the sex ratio were unaffected by maternal treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There was considered to be no effect of treatment on placental, litter and fetal weights.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Litter data, as assessed by the mean numbers of corpora lutea, implantations, resorptions and live young, the levels of pre- and post-implantation losses and sex ratio were unaffected by
maternal treatment.
External malformations:
no effects observed
Description (incidence and severity):
There were no major or minor abnormalities or skeletal variants related to treatment at any dose level investigated.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no major or minor abnormalities or skeletal variants related to treatment at any dose level investigated.
Visceral malformations:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Ano-genital distance was unaffected by treatment at all dose levels.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed
Remarks on result:
other: expressed as active ingredient
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
The oral administration of the test material at dose levels up to 1000 mg/kg bw/d, to pregnant rats from Day 6 to Day 19 of gestation resulted in no significant systemic effects on the adults. Development of embryos and fetuses was not affected by treatment of the dams up to including a dose level of 1000 mg/kg bw/day. Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival was concluded to be 1000 mg/kg/day. Under the test conditions, the test material is not classified according to the annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In a developmental toxicity study conducted similarly to the OECD guideline No. 414 and in compliance with GLP, the test material diluted in propylene glycol was administered to three groups of 20 females receiving the test item at doses of 100, 300 or 1000 mg/kg/day at a dose volume of 5 mL/kg/day by oral gavage administration, from Day 6 to 19 after mating, inclusive. The dose levels selected for investigation in this main embryo-fetal study were selected in conjunction with the Sponsor and were based on the results of a preliminary embryo-fetal study. In that study, dose levels of 250, 500 and 1000 mg/kg/day were investigated. There were no premature deaths,
no signs observed in relation to dose administration, no test item-related changes in clinical condition, no adverse effects on body weight, food consumption or embryo-fetal survival and development and no treatment related macroscopic findings at any dose level investigated. The high dose level for the current OECD 414 study was therefore set at 1000 mg/kg/day with intermediate and low dose levels of 300 and 100 mg/kg/day. A similarly constituted Control group received the vehicle, propylene glycol, at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.


Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight and thyroid weight were recorded and thyroid hormones measured. Microscopic pathology investigations were also undertaken of the maternal thyroid glands. Ano-genital distance was measured for fetuses and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.


 


On Day 12 and 13 of gestation, female No. 34 and 35 that received 100 mg/kg/day were killed for reasons of animal welfare. Clinical signs included irregular breathing, salivation, piloerection, brown staining of the muzzle, and a reduction of body weight gain was also observed. Macropathological examination included a distended esophagus and abnormal contents in the stomach, and these findings were not considered to be related to treatment. There were no other clinical signs observed for the remaining females across all groups or signs following dose administration that were considered to be related to treatment.


Thyroid hormones (T3, T4 and TSH), maternal clinical condition, overall body weight performance and food consumption were not adversely affected at any dose level investigated, and there were no test item-related macroscopic abnormalities or thyroid and parathyroid weights detected at scheduled termination on Day 20 after mating.


There was no effect of maternal treatment on the mean numbers of corpora lutea, implantation, resorption, sex ratio, ano-genital distance or on placental, fetal and litter weights, and there were no major or minor abnormalities or skeletal variants related to treatment at 100, 300 or 1000 mg/kg/day.


 


Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival was concluded to be 1000 mg/kg/day.


Under the test conditions, the test material is not classified according to the annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.


This study is acceptable and satisfies the requirement for developmental toxicity endpoint.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The testing of Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid (CAS #2166089-27-4) for prenatal developmental toxicity/teratogenicity was performed in a study in rats according to OECD 414 and in compliance with GLP.


The test material diluted in propylene glycol was administered to three groups of 20 females receiving the test item at doses of 100, 300 or 1000 mg/kg/day at a dose volume of 5 mL/kg/day by oral gavage administration, from Day 6 to 19 after mating, inclusive. The dose levels selected for investigation in this main embryo-fetal study were selected in conjunction with the Sponsor and were based on the results of a preliminary embryo-fetal study. In that study, dose levels of 250, 500 and 1000 mg/kg/day were investigated. There were no premature deaths,
no signs observed in relation to dose administration, no test item-related changes in clinical condition, no adverse effects on body weight, food consumption or embryo-fetal survival and development and no treatment related macroscopic findings at any dose level investigated. The high dose level for the current OECD 414 study was therefore set at 1000 mg/kg/day with intermediate and low dose levels of 300 and 100 mg/kg/day. A similarly constituted Control group received the vehicle, propylene glycol, at the same volume dose as the treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.


Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and the gravid uterus weight and thyroid weight were recorded and thyroid hormones measured. Microscopic pathology investigations were also undertaken of the maternal thyroid glands. Ano-genital distance was measured for fetuses and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.


 


On Day 12 and 13 of gestation, female No. 34 and 35 that received 100 mg/kg/day were killed for reasons of animal welfare. Clinical signs included irregular breathing, salivation, piloerection, brown staining of the muzzle, and a reduction of body weight gain was also observed. Macropathological examination included a distended esophagus and abnormal contents in the stomach, and these findings were not considered to be related to treatment. There were no other clinical signs observed for the remaining females across all groups or signs following dose administration that were considered to be related to treatment.


Thyroid hormones (T3, T4 and TSH), maternal clinical condition, overall body weight performance and food consumption were not adversely affected at any dose level investigated, and there were no test item-related macroscopic abnormalities or thyroid and parathyroid weights detected at scheduled termination on Day 20 after mating.


There was no effect of maternal treatment on the mean numbers of corpora lutea, implantation, resorption, sex ratio, ano-genital distance or on placental, fetal and litter weights, and there were no major or minor abnormalities or skeletal variants related to treatment at 100, 300 or 1000 mg/kg/day.


 


Based on the results of this study, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and embryo-fetal survival was concluded to be 1000 mg/kg/day.


Under the test conditions, the test material is not classified according to the annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.


This study is acceptable and satisfies the requirement for developmental toxicity endpoint.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.


 


Dodecanoic acid, mixed diesters with dipropylene glycol and nonanoic acid (CAS #2166089-27-4) was not tested in reproduction toxicity study. The following arguments were used: 


In 28-day and a 90-day studies together with a pre-natal developmental toxicity study, No adverse effects on reproductive organs or tissues, or other concerns in relation with reproductive toxicity were identified.


The NOAELs were determined to be 1000 mg/kg bw/day based on the repeated dose toxicity studies and the pre-natal developmental toxicity study.


 


Based on results obtained for reproductive and developmental toxicity, the test material does not require classification, according to Regulation 1272/2008/EC (CLP) as amended for the tenth time.

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