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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 Jul - 26 Aug 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
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alcohols, C9-11, branched and linear, ethoxylated
EC Number:
500-446-0
EC Name:
Alcohols, C9-11, branched and linear, ethoxylated
Cas Number:
160901-09-7
Molecular formula:
n.a.
IUPAC Name:
Alcohols, C9-11, branched and linear, ethoxylated (1-2.5 moles ethoxylated)

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 10 - 13 weeks
- Weight at study initiation: 183 - 258 g
- Fasting period before study: not applicable
- Housing: individually in 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: municipal tap water, ad libitum
- Acclimation period: 5 - 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 58 - 67
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21 Jul 2021 To: 26 Aug 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.
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. Chemical analyses of formulations were conducted twice during the study to assess accuracy and homogeneity.
The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with target concentrations (i.e. mean sample concentration results were within or equal to 85-115% of target concentration).
No ammonium adduct of the C10E6 compound in the test item was detected in the Group 1 formulation.
The formulations of Groups 2 and 4 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 post-mating (Day 0 of gestation) is the day of mating.
Duration of treatment / exposure:
Day 6 - 20 post-mating
Frequency of treatment:
once daily, 7 days/week
Duration of test:
until necropsy on Day 21 post-mating
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.:
800 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 and 800 mg/kg bw/day, based on the results of a Combined 28-day Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test with Alcohols, C9-11, branched and linear, ethoxylated in rats (Test Facility Study No. 20219839), and in an attempt to produce graded responses to the test item.
- Fasting period before blood sampling for (rat) dam thyroid hormones: no
- Time of day for (rat) dam blood sampling: Day 21 post-mating

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily; starting on Day 6 post-mating up to the day prior to necropsy, morbidity and mortality were performed twice daily, observations were performed directly post dosing.

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

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

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-mating.

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-mating
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 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):
Various clinical signs were observed throughout the treatment period. Abnormal breathing sounds observed in some animals of all treatment group were considered incidental as they occurred sporadically. Erected fur in 3/22 females of the 800 mg/kg bw/day group, 1/22 female of the 300 mg/kg bw/day and 1/22 female of the control group was also considered incidental as well as slight salivation seen in 11/22 and 3/22 females after dosing at 800 and 300 mg/kg bw/day, respectively, mostly on incidental occasions, with a maximum of 4 consecutive days. All clinical signs were considered treatment-related but not adverse.

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:
mortality observed, treatment-related
Description (incidence):
At 800 mg/kg bw/day, one female was sacrificed in extremis on Day 12 post-mating, as it was noted with labored breathing, lateral recumbent position, a weak appearance and decreased activity, cold to the touch and slight salivation after dosing. Slight body weight loss (3%) was noted between Days 6 - 9 post-mating, followed by no recovery thereafter. In addition, food consumption was lower between Days 6 - 12 post-mating (11 g/day vs. 20 g/day during the acclimatization period from Days 2 - 6 post-mating). At necropsy, no macroscopic alterations were found. This female was non-gravid. The death was considered treatment-related.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the low- and mid- dose group, no statistically significant difference in body weight was observed between control and treatment groups. In the high-dose group, a general trend towards slightly lower mean values for body weight gain and consequently body weight was observed from start of treatment onwards (3% lower body weight at Day 21 post-mating, compared to control), this was considered treatment related but not adverse.

Summarized data 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):
In the low- and mid- dose group, no difference regarding food consumption was observed between control and treatment groups. In the high-dose group, mean food consumption was statistically significantly decreased during the first 6 days of treatment (in the intervals Days 9 - 12 and 12 - 15, up to 15% lower than control between Days 9 - 12 post-mating), followed by complete recovery to control levels up to the end of the treatment period. Over the whole treatment-period (Day 6 - 21 post-mating), food consumption in the high dose group was 8.85% decreased compared to the control group (statistically significant). These differences were considered treatment related but not adverse.

Summarized data 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 difference regarding water consumption was observed between control and treatment groups up to and including the highest dose level of 800 mg/kg bw/day.
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):
In the low- and mid- dose group, no difference in thyroid hormones was observed between control and treatment groups.
In the 800 mg/kg bw/day group, slightly increased serum levels of TSH were noted (1.4x of control). Even though, the difference did not reach statistical significance, a relation to treatment cannot be excluded. Levels of T3 and T4 were comparable to the control group. The differences were not considered adverse.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Urinalysis findings:
not examined
Description (incidence and severity):
not applicable
Behaviour (functional findings):
no effects observed
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):
Thyroid weights and thyroid to body weight ratios of treated females were considered to be similar to those of control females.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Irregular surface of the non-glandular stomach was noted in 5/22 females at 800 mg/kg bw/day, and for 1/22 females at 300 mg/kg bw/day. As the test item is characterized as an irritant compound, a relation to treatment with the test item could not be excluded.

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 difference regarding histopathology of the thyroid was observed between control and treatment groups.

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.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No toxicologically relevant difference in pre- and post-implantation loss was observed between the control and treatment groups up to and including the highest dose level.
At 800 and 100 mg/kg bw/day, mean pre-implantation loss was slightly higher (10% and 8% vs 5% in the control group; not statistically significant), mainly attributed to 2 females each in the low- and high-dose group. However, as the treatment started on Day 6 post-mating (after implantation), the effect is not considered treatment-related.
In the high-dose group, mean post-implantation loss was slightly higher (7% vs 1% in the control group; not statistically significant). This was attributed mainly to one female with a relatively high number of early resorptions compared to the total number of implantations (n=6/10, respectively). As the post-implantation loss of all remaining high-dose females was either in the same range as for concurrent control females or only marginally higher and in absence of other developmental findings in this study, no toxicological significance was attached to this isolated finding.

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 difference in total litter loss by resorption was observed between the control and treatment groups.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no late resorptions fetuses in this study.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no dead fetuses in this study.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No pre-mature deliveries occurred in this study
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
No difference in pregnancy rate was observed between the control and treatment groups. At scheduled necropsy, 1/22 females of the control group, and 2/22 females of the 100 mg/kg bw/day group were non-gravid. The prematurely sacrificed female in the 1000 mg/kg bw/day group was non-gravid at early sacrifice.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Other effects:
no effects observed
Description (incidence and severity):
The number of females with viable litters was comparable between the control and treatment groups (21, 20, 22 and 21 in the control, 100, 300 and 800 mg/kg bw/day groups, respectively).

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No adverse effects were observed up to and including this dose level.
Key result
Dose descriptor:
LOAEL
Remarks:
systemic toxicity
Effect level:
800 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No differences in fetal body weight were observed between the control and treatment groups up.

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 toxicologically relevant differences in the number of live fetuses were observed between the control and treatment groups.
In the high-dose group, mean litter size was slightly lower compared to the control group (-13%, not statistically significant) as a result of the lower number of implantation sites for 2 dams in this dose group. Therefore, the mean number of live fetuses at this high dose level was considered to reflect normal biological variation.

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 in 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 toxicologically relevant differences in the number of live fetuses were observed between the control and treatment groups up to and including the highest dose group.
In the high-dose group, mean litter size was slightly lower compared to the control group (-13%, not statistically significant) as a result of the lower number of implantation sites for 2 dams in this dose group. Therefore, the mean number of live fetuses at this high dose level was considered to reflect normal biological variation.

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 difference in anogenital distance was observed between the control and treatment groups.

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 toxicologically relevant differences in the number of external malformations were observed between the control and treatment groups up to and including the highest dose group.
Two fetuses presented with external malformations. A single fetus at 100 mg/kg bw/day had exencephaly, and a single fetus at 800 mg/kg bw/day had a cleft palate and small upper jaw, but these were considered incidental.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant differences in the number of skeletal malformations were observed between control and treatment groups up to and including the highest dose group. 1 fetus of the 100 mg/kg bw/day group and 1 fetus of the 800 mg/kg bw/day group had multiple skeletal malformations consistent with their external findings (exencephaly and a cleft palate and a small upper jaw, respectively). The fetus of the 100 mg/kg bw/day group as well as one additional fetus of the 800 mg/kg bw/day group had sternoschisis. Due to the single occurrence in each group, these malformations were considered to be incidental findings. Additionally, the fetus from the 100 mg/kg bw/day group had limb malformations associated with the fibulas. Based on the single occurrence and the absence of a dose-related trend this finding was considered not treatment-related.

Summarized data can be found in Attachment 2 under "Overall Remarks, Attachments".
Visceral malformations:
no effects observed
Description (incidence and severity):
No visceral malformations were observed in this study.
Visceral variations noted were supernumerary liver lobes (all groups) and a single discolored lung (several red spots; 300 mg/kg bw/day group). At the low incidence and in absence of a dose-related trend, these were considered not related to treatment with the test item.

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 and teratogenicity
Effect level:
800 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 tested.

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 300 mg/kg bw/day. Based on mortality and lower body weight at 800 mg/kg bw/day, the NOAEL for maternal systemic toxicity was set at 300 mg/kg bw/day. No test item-related adverse findings were observed regarding developmental toxicity and teratogenicity. Therefore, the NOAELs for developmental toxicity and teratogenicity were set at 800 mg/kg bw/day.