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Diss Factsheets

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:
08 Sep 2021 - 10 Nov 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2022
Report date:
2022

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 2018
Deviations:
no
Principles of method if other than guideline:
The humidity values were outside the targeted range for 5 days with a maximum of 80% and were without a noticeable effect on the clinical condition of the animals or on the outcome of the study, the deviation was considered acceptable.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alcohols, C12-15, branched and linear, ethoxylated
EC Number:
500-294-5
EC Name:
Alcohols, C12-15, branched and linear, ethoxylated
Cas Number:
106232-83-1
IUPAC Name:
Alcohols, C12-15, branched and linear, ethoxylated (1-2.5 EO)

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:Wl(Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 11 - 15 weeks
- Weight at study initiation: 177 - 254 g
- Fasting period before study: not applicable
- Housing: Polycarbonate cages (Makrolon type MIII, height 18 cm) containing sterilized wooden fibers as bedding material (Lignocel S 8-15, JRS-J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany)
- Diet: SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 - 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 41 - 80%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 08 Sep 2021 To: 1 Oct 2021

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The appropriate amount of the test material was mixed with the vehicle. The dose volume for each animal was based on the most recent body weight measurement and the dose formulations were stirred continuously during dosing.

VEHICLE
- Concentration in vehicle: 25 mg/mL (for 100 mg/kg bw/day), 75 mg/mL (for 300 mg/kg bw/day), 250 mg/mL (for 1000 mg/kg bw/day)
- Amount of vehicle (if gavage): 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulation analyses confirmed that formulations of the test item in corn oil were prepared accurately and homogenously.
In the Group 1 formulations prepared for use in Weeks 1 and 2, no test item was detected.
The concentrations analyzed in the Groups 2, 3, and 4 formulations prepared for use in Week 1 and Week 2 were in agreement with target concentrations (i.e. mean accuracies between 85% and 115% of target concentration).
The formulations of Groups 2 and 4 prepared for use in Weeks 1 and 2 were homogeneous (i.e. coefficient of variation = 10%).
Details on mating procedure:
- Impregnation procedure: not reported
Females were time-mated and arrived at the testing facility as such. Day 0 of gestation is the day of mating, and was decribed as Day 0 post-coitum.
Duration of treatment / exposure:
Day 6 - 20 post-coitum
Frequency of treatment:
once daily, 7 days/week
Duration of test:
until necropsy on Day 21 post-coitum
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Remarks:
Group 2
Dose / conc.:
300 mg/kg bw/day
Remarks:
Group 3
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
Group 4
No. of animals per sex per dose:
22 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels in this study were selected to be 100, 300, 1000 mg/kg/day, based on a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening with oral exposure of Alcohols, C12-15, Ethoxylated <= 2.5 EO in rats, (Test Facility Study No. 20219689).
- Fasting period before blood sampling for (rat) dam thyroid hormones: No
- Time of day for (rat) dam blood sampling: Day 21 post-coitum

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily; starting on Day 6 post-coitum up to the day prior to necropsy, performed directly post dosing.

CHECK FOR MORTALITY: Yes
- Time schedule: At least twice daily beginning on arrival through termination/release. Except on days of receipt and necropsy where frequency will be at least once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On Days 2, 6, 15 and 21 post-coitum

BODY WEIGHT: Yes
- Time schedule for examinations: On Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: Over Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: on a regular basis throughout the study (monitored by visual inspection).

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 21 post-coitum
All animals from all groups were subjected to a gross necropsy. All gross lesions were collected.
- Organs weighed: thyroid
- Tissues collected for histopathology: thyroid gland and macroscopic abnormalities.
- Fixative: 10% buffered formalin
- Embedding media: paraffin
- Thickness of sections: 2 - 4 µm
- Staining: hematoxylin and eosin
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of live and dead fetuses: Yes
Blood sampling:
- Plasma: Yes
- Serum: Yes
- Volume collected: 1.0 mL
- Parameters checked: triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH).
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups: Yes (all per litter)
- Body weight: Yes, all per litter
- Sex: Yes, all per litter
Statistics:
Means, standard deviations (or % coefficient of variation or standard error, when deemed appropriate), percentages, numbers, and/or incidences are reported as appropriate by dataset. All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels, unless otherwise noted. All pairwise comparisons were conducted against the control group (Group 1).
The following statistical tests were used: Levene’s test, ANOVA F-test, Kruskal-Wallis Dunnett’s and Dunn’s test, ANCOVA and Fisher's exact test.
Indices:
Pregnancy rate (%): (No. of pregnant females)/(No. of mated females) * 100
Male fetuses (%): (No. of male fetuses)/(No. of fetuses) * 100
Female fetuses (%): (No. of female fetuses)/(No. of fetuses) * 100
Pre-implantation loss (%): (No. of corpora lutea – No. of implantations)/(No. of corpora lutea) * 100
Post-implantation loss (%): (No. of implantations – No. of live fetuses)/(No. of implantations) * 100
Litter % of fetuses with abnormalities: (No. of fetuses in litter with a given finding)/(No. of fetuses in litter examined) * 100
Historical control data:
Historical control data regarding fetal pathology was provided and can be found in Attachment 3 under "Overall remarks, attachments".

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of toxicity that were noted were salivation in 1/22, 12/22 and 22/22 animals of the 100, 300 and 1000 mg/kg bw/day group. This was considered treatment-related, but non-adverse as they were a physiological response rather than a sign of systemic toxicity.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
not applicable
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No significant difference was observed regarding body weight between the control and 100 mg/kg bw/day group.
At 300 mg/kg bw/day, slightly lower body weight gain compared to control was observed on Day 12 - 15 post-coitum. After this period and over the whole dosing period, comparable body weight gain was noted. Furthermore, body weight gain corrected for gravid uterus weight was comparable to control.
In the 1000 mg/kg bw/day group, slightly lower mean body weight gain was noted at start of dosing
(Days 6 - 9 post-coitum) and end of dosing (Days 18 -21 post-coitum), with mean body weight remaining slightly lower than for controls from Day 9 post-coitum onwards (not statistically significant). Terminal body weight was 4% lower compared to control (not statistically significant). Mean body weight gain corrected for mean gravid uterus weight was 7% compared to 13% in control.

As the differences were slight and below 10%, they were not considered adverse.

Summarized results can be found in Attachment 2 (tables) and 1 (figures) under "Overall remarks, attachments".
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
No treatment-related difference was observed regarding food consumption between the control and 100 mg/kg bw/day group.
At 300 mg/kg bw/day, mean food consumption was lower compared to control from Day 12 post-coitum onwards (reaching statistical significance over Days 18-21 post-coitum with a maximum of -9% in the Day 18 - 21 interval).
In the 1000 mg/kg bw/day group, mean food consumption was lower compared to control throughout the dosing period. The difference was statistically significant from Day 6 - 15, with a maximum difference of -15% compared to the control in the first interval (Days 6 - 9 post-coitum). Overall food intake during the dosing period was 10% lower in high dose dams, compared to control.

As the differences were slight, they were not considered adverse.

Summarized results can be found in Attachment 2 (tables) and 1 (figures) under "Overall remarks, attachments".
Food efficiency:
not examined
Description (incidence and severity):
not applicable
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No differences were observed regarding water consumption between the control and treatment groups up to and including the highest dose level.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Ophthalmological findings:
not examined
Description (incidence and severity):
not applicable
Haematological findings:
not examined
Description (incidence and severity):
not applicable
Clinical biochemistry findings:
not examined
Description (incidence and severity):
not applicable
Endocrine findings:
effects observed, treatment-related
Description (incidence and severity):
No treatment-related differences were observed regarding T3, T4 and TSH between the control and 100 mg/kg bw/day group.
At 300 and 1000 mg/kg bw/day, decreased serum levels of total T3 were noted (0.85x and 0.75x of control, respectively, corresponding to 0.381 ng/mL for the 300 mg/kg bw/day group and 0.336 ng/mL for the 1000 mg/kg bw/day group compared to 0.45 ng/mL in the control group). Although, both means remained within the available historical control data (total T3 (ng/mL): mean = 0.439; P5 – P95 = 0.280 – 0.616 (n = 263) in the period of 2020 - 2021), a dose response is present. Therefore, a decrease in total T3 level was considered test item related. However, as no other associated effect was noted and as both mean values were within the historical data range, the effect on total T3 level in serum is considered as non-adverse.


Summarized results can be found in Attachment 2 under "Overall remarks, attachments".
Urinalysis findings:
not examined
Description (incidence and severity):
not applicable
Behaviour (functional findings):
not examined
Description (incidence and severity):
not applicable
Immunological findings:
not examined
Description (incidence and severity):
not applicable
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related differences were observed regarding thyroid weights between the control and treatment groups up to and including the highest dose level.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related differences were observed during gross pathology between the control and treatment groups up to and including the highest dose level.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Neuropathological findings:
not examined
Description (incidence and severity):
not applicable
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related differences were observed in histopathology examination of the thyroid between the control and treatment groups up to and including the highest dose level.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
not applicable
Other effects:
not examined
Description (incidence and severity):
not applicable

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No abortions occurred in this study.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant difference regarding pre- and post-implantation loss was observed between the control and treatment groups up to and including the highest dose level.
At 1000 mg/kg bw/day, mean pre-implantation loss was higher compared to the control group (12.71% vs 7.65% in the control group; not statistically significant). However, as the treatment started on Day 6 post-coitum (after implantation), the effect is not considered treatment-related.
Post-implantation loss was higher in all treatment groups (7.54, 6.51 and 6.15% for the 100, 300 and 1000 mg/kg bw/day group, respectively), compared with 3.90% in control; none of these differences was statistically significant. However, all mean values remained within the historical data (mean: 5.2, P5 – P95 = 2.1 – 9.0 (n = 706)) and no dose-response was observed. Therefore, the higher post-implantation loss is considered not related to treatment with the test-item.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding total litter losses by resorption was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Early or late resorptions:
no effects observed
Description (incidence and severity):
No treatment-related differences regarding resorptions were observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Dead fetuses:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding the number of dead fetuses was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding the pregnancy duration was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding the number of pregnant females was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Other effects:
not examined
Description (incidence and severity):
not applicable

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects were observed up to and including the highest dose level.

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No treatment-related differences regarding fetal body weights were observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding the number of live offspring was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding sex ratio was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding litter size was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Anogenital distance of all rodent fetuses:
no effects observed
Description (incidence and severity):
No treatment-related difference regarding anogenital distance was observed between the control and treatment groups up to and including the highest dose group.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Changes in postnatal survival:
not examined
Description (incidence and severity):
not applicable
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related external malformations and variations were observed.
The malformations that occurred in this study were a generalized subcutaneous edema in one fetus of the 100 mg/kg bw/day group and a cleft palate in one fetus of the control group. These incidences were considered to be single occurrences and therefore not treatment-related.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related skeletal malformations were observed.
Skeletal malformations that were not considered treatment-related were bent humeri (in 1 control fetus, 1 fetus of the 300 mg/kg bw/day group), multiple malformations relating the lower jaw, skull, vertebrae and sternum (1 additional fetus of the 300 mg/kg bw/day group). The observed sternal anomaly above (sternoschisis) also occurred in the fetus with generalized subcutaneous edema at 100 mg/kg bw/day. Due to single occurrence and lack of a dose-response, a relationship with the test-item was considered unlikely.
Skeletal variations that were observed in all treatment groups were increased incidences of misaligned ilia (pelvic girdle), but the difference to the control group did not reach statistical significance and occurred without any dose-response. Therefore, it was not considered related to treatment.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related visceral malformations were observed in this study.
Only one visceral malformation was observed in 1 control female (dilated brain ventricles), this was considered spontaneous in origin.
The variations that were noted affected the liver (supernumerary lobes) and ureters (convoluted and dilatation) at low incidences or in isolated cases, which did not indicate that they were treatment-related.

Summarized data can be found in Attachment 2 under "Overall remarks, attachments".
Other effects:
not examined
Description (incidence and severity):
not applicable

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed up to and including the highest dose level.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The present study was conducted under GLP and according to OECD test guideline 414 (2018).
Under the conditions of the study, administration of the test substance once daily by oral gavage for Days 6 - 20 post coitum was well tolerated in pregnant rats at levels up to 1000 mg/kg bw/day. No adverse effects on dams were observed up to and including the highest dose level. No test item-related adverse findings were observed causing developmental toxicity. Therefore, the NOAEL for maternal systemic and developmental toxicity was set at 1000 mg/kg bw/day. No teratogenicity was observed (NOAEL = 1000 mg/kg bw/day).