Registration Dossier

Administrative data

Description of key information

A combined oral repeated dose study with screening for reproductive and/ or developmental effects was performed according to OECD/EC guidelines and GLP principles. C12-14 Alkyl ethoxylated glycidylether was administered by daily oral gavage to male and female rats at dose levels of 83, 250 and 750 mg/kg bw/day. Based on the results of this study, the parental NOEL was concluded 250 mg/kg/day (based on lower body weight gain and food consumption, increased liver weights in males, a thickened forestomach in males and hyperplasia in the forestomach in males and females at 750 mg/kg/day). As these fefects were considered to be non-adverse, the NOAEL was found to be 750 mg/kg bw/day, the highest dose tested.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 Jan 2019 - 15 Aug 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
2016
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.
Version / remarks:
2000
Deviations:
no
Qualifier:
according to
Guideline:
other: OECD 421, Reproduction/Developmental Toxicity Screening Test.
Version / remarks:
2016
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test.
Version / remarks:
2000
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
2008
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Version / remarks:
2008
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3050, Repeated Dose 28-day Oral Toxicity Study in Rodents.
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Purity/Composition correction factor: No correction factor required (substance is a UVCB)
Species:
rat
Strain:
other: Crl: WI(Han)
Details on species / strain selection:
The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for toxicity testing by regulatory agencies. Charles River Den Bosch has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10-11 weeks old (males), 13-14 weeks old (females)
- Weight at study initiation: between 261 and 313 g (males), between 209 and 248 g (females)
- Fasting period before study: no
- Housing: On arrival and following the pretest (females only) and pre-mating period, animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate Macrolon plastic cages. During the mating phase, males and females were cohabitated on a 1:1 basis in Macrolon plastic cages. During the post-mating phase, males were housed in their home cage (Macrolon plastic cages), with a maximum of 5 males/cage. Females were individually housed in Macrolon plastic cages. During the lactation phase, females were housed in Macrolon plastic cages. Pups were housed with the dam. During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage. The cages contained appropriate bedding (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and were equipped with water bottles.
- Diet: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum. During motor activity measurements, animals had no access to food or water for a maximum of 2 hours. Males were fasted overnight with a maximum of 24 hours before necropsy, females were not fasted.
- Water: Municipal tap water was freely available to each animal via water bottles.
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY:
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Periodic analysis of the water was performed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 21°C
- Humidity (%): 45 to 49%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From 31 Jan 2019 to 8 Apr 2019
Route of administration:
oral: gavage
Details on route of administration:
The oral route of administration was selected because this is a possible route of human exposure during manufacture, handling or use of the test item.
The dose levels were selected based the results of a 14-day Dose Range Finder with oral gavage administration of C12-14 Alkyl ethoxylated glycidylether in rats.
Vehicle:
water
Details on oral exposure:
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared daily as a suspension and dosed within 24 hours after adding the vehicle to the test item. Test item dosing formulations were kept at room temperature until dosing. If practically possible, the dosing formulations and vehicle were continuously stirred until and during dosing.
Dose volume: 5 mL/kg. The dose volume for each animal was based on the most recent body weight measurement.
The dosing formulations were stirred continuously during dose administration.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Duplicate sets of samples (approximately 500 mg) were analysed for concentration and homogeneity. Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 15% of target concentration.
Homogeneity results were considered acceptable if the coefficient of variation (CV) of concentrations was ≤ 10%.
Stability analyses were performed previously in conjunction with the method development and validation study and demonstrated that the test item is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study.
Duration of treatment / exposure:
The test item and vehicle were administered to the appropriate animals by once daily oral gavage 7 days a week for a minimum of 28 days. Males were treated for 29 to 32 days, up to and including the day before scheduled necropsy. This included a minimum of 14 days prior to mating and during the mating period. Females that delivered were treated for 50 to 67 days, i.e. 14 days prior to mating, the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy. Females which failed to deliver or had a total litter loss were treated for 40 to 43 days.
Two females from the control group and 2 females from the mid dose group were not dosed on one occasion as these females were littering at the moment of dosing. The omission of one day of dosing over a period of several weeks was not considered to affect the toxicological evaluation.
Frequency of treatment:
Once daily
Dose / conc.:
83 mg/kg bw/day (actual dose received)
Remarks:
Low dose group
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
Mid dose group
Dose / conc.:
750 mg/kg bw/day (actual dose received)
Remarks:
High dose group
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The doses were selected based on the results of a dose range finder study. Three females were dosed once daily by oral gavage at 500 mg/kg bw/day, and 3 females were dosed at 1000 mg/kg bw/day for 7 days a week for 14 days. The dose levels were selected based on the results of an acute oral toxicity study in rats (LD50 > 2000 mg/kg bw/day). Mortality was checked twice daily throughout the study. Clinical Observations were done at least daily up to the day prior to necropsy, at 0-15 minutes, 1 hour (±15 minutes) and 3 hours (± 30 minutes) after dosing. Body Weights were measured on Day 1 prior to dosing and on Days 4, 8, 11 and 14. Food Consumption was monitored over Days 1-4, 4-8, 8-11 and 11-14. All animals were subjected to an external, thoracic and abdominal examination on Day 15 (scheduled necropsy). Animals were not deprived of food prior to necropsy. Terminal body weight, kidney and liver weight were determined at scheduled necropsy.
Positive control:
Not included
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Twice daily, in the morning and at the end of the working day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Once daily, beginning during the first administration of the test item and lasting throughout the dosing period up to the day prior to necropsy. During the dosing period, these observations were performed after dosing at no specific time point, but within a similar time period after dosing for the respective animals. The peak effect of occurrence of clinical signs occurred directly after dosing. Therefore, clinical observations and functional observation tests were conducted directly after dosing.

BODY WEIGHT: Yes
- Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13.

FOOD CONSUMPTION: Yes
- Food consumption was quantitatively measured weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13.

WATER CONSUMPTION: Yes
- Water consumption was monitored on regular basis throughout the study by visual inspection of the water bottles.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy.
- Anaesthetic used for blood collection: Yes, isofluorane
- Animals fasted: Males were fasted overnight with a maximum of 24 hours before blood sampling, water was available; females were not fasted.
- How many animals: all animals, except for one female with total litter loss.
- Parameters checked: White blood cells (WBC), Red Blood Cell Distribution Width (RDW), Neutrophils (absolute), Haemoglobin, Lymphocytes (absolute), Haematocrit, Monocytes (absolute), Mean corpuscular volume (MCV), Eosinophils (absolute), Mean corpuscular haemoglobin (MCH), Basophils (absolute), Mean corpuscular haemoglobin concentration (MCHC), Red blood cells Platelets, Reticulocytes (absolute).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy.
- Animals fasted: Males were fasted overnight with a maximum of 24 hours before blood sampling, water was available; females were not fasted.
- How many animals: all animals, except for one female with total litter loss.
- Parameters checked: Alanine aminotransferase (ALAT), Creatinine, Aspartate aminotransferase (ASAT), Glucose, Alkaline Phosphatase (ALP), Cholesterol, Total protein, Sodium, Albumin, Potassium, Total Bilirubin, Chloride, Bile Acids, Calcium, Urea, Inorganic Phosphate.

Serum was analyzed for total Thyroxine (T4) for F0-males. For the F0-generation, assessment of T4 (females) and Thyroid Stimulating Hormone (TSH; both sexes) was considered not relevant because no treatment-related changes in T4 were noted in F0-males, no adverse effects on thyroid histopathology and no treatment related changes in thyroid weight were recorded

In addition, coagulation parameters were analysed: Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
Functional tests were performed on the selected 5 males during Week 4 of treatment and the selected 5 females during the last week of lactation (i.e. PND 6-13). These tests were performed after completion of clinical observations.
The following tests were performed: Hearing ability, pupillary reflex, static righting reflex.
- Fore- and hind-limb grip strength, recorded as the mean of three measurements per animal.
- Locomotor activity (recording period: 1-hour under normal laboratory light conditions, using a computerized monitoring system). Total movements and ambulations were reported. Ambulations represent movements characterized by a relocation of the entire body position like walking, whereas total movements represent all movements made by the animals, including ambulations but also smaller or more fine movements like grooming, weaving or movements of the head.

IMMUNOLOGY: No

Sacrifice and pathology:
SACRIFICE
Scheduled euthanasias as follows:
- Males: after completion of mating period, minimum 28 days of administration.
- Females: PND 14-16

GROSS PATHOLOGY: Yes
- All animals were subjected to a full post mortem examination, with special attention being paid to the reproductive organs.

ORGAN WEIGHTS
- On selected 5 animals/sex/group: according to guidelines.
- All remaining animals: epididymis, prostate, seminal vesicles including coagulation glands, testes, thyroid.

HISTOPATHOLOGY: Yes
- On selected 5 animals/sex/group in control and high-dose groups and all animals that were euthanized in extremis: according to guidelines.
- On all animals: all gross lesions.
- All remaining animals, including males that failed to sire and females that failed to deliver pups: Cervix, epididymis, glands (coagulation, mammary, parathyroid, pituitary, prostate, seminal vesicle,and thyroid), gross lesions/masses, ovaries, testes, uterus, vagina.
- For the testes of all selected males of the low and high dose groups, and one male of the control group, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle.
Other examinations:
Estrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage. Daily vaginal lavage was performed for all females beginning 14 days prior to treatment (pretest period), the first 14 days of treatment and during mating until evidence of copulation was observed. Vaginal lavage was continued for those females with no evidence of copulation until termination of the mating period. On the day of necropsy, a vaginal lavage was also taken to determine the stage of estrous.
Statistics:
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% or 5% levels. Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible. Inferential statistics were performed according to the matrix below when possible, but excluded semi-quantitative data, and any group with less than 3 observations.
The following pairwise comparisons were made: Low dose group vs. Control group; mid dose group vs. Control group; High dose group vs. Control group.
Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test). For the motor activity data set (at least 3 groups) parametric (ANOVA) tests on group means was applied with Bonferroni correction for multiple testing. Mixed modelling techniques, comparing six different covariance structures, were used in order to select the best fitting statistical model.
Non-Parametric: Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test).
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using Fisher’s exact test whenever the overall test is significant.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related clinical signs were noted during daily detailed clinical observations up to 83 mg/kg bw/day (low dose group). No findings were noted during the weekly arena observations in this study. Salivation was seen after dosing among animals of the 250 (mid dose group) and 750 mg/kg bw/day (high dose group) from the first week of the treatment period onwards and was considered not toxicologically relevant, taking into account the nature and minor severity of the effect and its time of occurrence (i.e. after dosing). This sign was considered to be a physiological response related to taste of the test item rather than a sign of systemic toxicity.
Any other clinical signs noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Mortality:
no mortality observed
Description (incidence):
One female of the 750 mg/kg bw/day (high dose group) was euthanized on Lactation Day 2, as she had a total litter loss.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
No test item-related changes in body weights and body weight gain were observed up to 250 mg/kg bw/day (mid dose group). At Day 8 of pre mating period, body weight gain in males at 750 mg/kg bw/day (high dose group) was decreased to 0.78x when compared with control. During the following weeks of treatment, body weight gains were considered normal. At the end of the post coitum and lactation period, lower (though non-statistically significant) body weights and body weight gains were observed in females at 750 mg/kg bw/day. In absence of statistically significant findings, these changes were considered non adverse.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption before or after correction for body weight was similar to the control level up to 250 mg/kg bw/day (mid dose group). In males at 750 mg/kg bw/day (high dose group), absolute and relative food consumption was slightly lower compared with controls (0.92x and 0.96x, respectively) during the first week of treatment. In the following weeks, food consumption levels were considered normal. In females at 750 mg/kg bw/day, absolute food consumption was decreased, when compared with control during the first week of treatment and during the lactation period (0.88x and 0.74-0.76x, respectively), but not during the post coitum period. Similar decreases in relative food consumption were observed during the first 2 weeks of treatment (0.84-0.91x) and the lactation period (0.74-0.77x). Also, relative food consumption levels were decreased during the first three weeks of the post coitum period (0.86-0.91x).
Any other statistically significant changes in food consumption before or after correction for body weight were considered to be unrelated to treatment since no trend was apparent regarding dose and duration of treatment.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Hematological parameters of treated rats were considered unaffected by treatment up to 750 mg/kg bw/day (high dose group). For males, the available data of low and high dose groups indicate that there is no dose related trend and that results are within normal range when compared with the historical control data (For males only one control measurement was available, therefore low and high dose groups data was compared with historical control data). In females, any statistically significant changes noted in hematology parameters achieving a level of statistical significance when compared to controls were considered unrelated to administration of the test item due to the minimal magnitude of the change and/or absence of a dose response.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical chemistry parameters of treated rats were considered unaffected by treatment up to 83 mg/kg bw/day (low dose group). In males, albumin levels were increased with 1.04x and 1.06x at 250 and 750 mg/kg bw/day (mid and high dose groups), respectively, when compared to control, and urea levels were increased with 1.29x at 750 mg/kg bw/day. In females, bile acids levels were increased with 2.88x at 750 mg/kg bw/day. As all values remained within normal range, these changes were considered not toxicologically relevant. Any other statistically significant changes in clinical chemistry parameters achieving a level of statistical significance when compared to controls were considered unrelated to administration of the test item due to the minimal magnitude of the change and/or absence of a dose response.
Thyroid hormone analyses: Serum levels of T4 in F0-males were considered unaffected by treatment.
Coagulation parameters: unaffected by treatment up to 750 mg/kg bw/day. For males, the available data of 250 and 750 mg/kg bw/day (mid and high dose groups) indicate that there is no dose related trend and that results are within normal range.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Functional observation parameters were considered unaffected by treatment up to 750 mg/kg bw/day (high dose group). Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals. Grip strength was similar between control and high dose animals. The variation in motor activity did not indicate a relation with treatment. All groups showed a similar habituation profile with very high activity in the first interval and a decreasing trend in activity over the duration of the test period. All values remained within normal range.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Test item-related higher liver weights (absolute and relative to body weights) were noted in the 750 mg/kg bw/day group males (high dose group). There was no microscopic correlate with the increased liver weight. Some organ weight differences were statistically significant when compared to the control group (heart, liver, kidneys in males; relative to body weight only) but were considered to be the result of a test item-related effect on final body weight. There were no other test item-related organ weight changes.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test item-related thickened forestomach was observed in the stomach of 2/10 males treated at 750 mg/kg bw/day (high dose group). The remainder of the recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain. Watery fluid in the uterus, found in one high dose female, is related to a stage in the estrous cycle and is a normal finding.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Minimal to slight hyperplasia of the forestomach was recorded in 3 males and 2 females of the 750 mg/kg bw/day group (high dose group). The remainder of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no test item-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Key result
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to and including highest dose tested (750 mg/kg bw/day)
Key result
Critical effects observed:
no

Results Dose Formulation Analyses:

The concentrations analyzed in the formulations of the low , mid and high dose groups were in agreement with target concentrations (i.e. mean accuracies between 96% and 99%). No test item was detected in the Control group formulation. The formulations of the low dose group and the high dose group were homogeneous (i.e. coefficient of variation ≤ 2.0%).

Results dose range finder study:

No mortality occurred. At 1000 mg/kg bw/day, piloerection was present in all animals during Days 2-8. Hunched posture was present in 2-3/3 animals from Days 3-8 and from Days 11-14. Salivation was observed in 3/3 animals on most days during the second week of treatment. On Day 7, lethargy was observed in 2/3 animals. Body weight was reduced in 1/3 animals during Days 1-4, followed by normal body weights and body weight gain. During Days 1-4, absolute and relative food consumption was reduced. At 500 mg/kg bw/day, a hunched posture was observed in 1/3 animals on Days 13 and 14. Piloerection was seen in 3/3 animals on Day 8. Salivation was observed in 3/3 animals on most days during the second week of treatment. Normal body weights and body weight gain was measured, food consumption was considered within normal range.

At necropsy, no abnormalities were noted at 500 mg/kg bw/day. Kidney weights were within normal range, but relative liver weights were increased with approximately 16% compared with the historical control range. At 1000 mg/kg bw/day, in 1/3 animals the stomach was grown together with the liver and the liver was grown together with the diaphragm. No effects were seen on kidney weights, relative liver weights were increased with approximately 39% compared with the historical control range.

Conclusions:
A combined oral repeated dose study with screening for reproductive and/ or developmental effects was performed according to OECD/EC guidelines and GLP principles. C12-14 Alkyl ethoxylated glycidylether was administered by daily oral gavage to male and female rats at dose levels of 83, 250 and 750 mg/kg bw/day. Based on the results of this study, the parental NOEL was concluded 250 mg/kg/day (based on lower body weight gain and food consumption, increased liver weights in males, a thickened forestomach in males and hyperplasia in the forestomach in males and females at 750 mg/kg/day). As these fefects were considered to be non-adverse, the NOAEL was found to be 750 mg/kg bw/day.
Executive summary:

C12-14 Alkyl ethoxylated glycidylether has been evaluated in a combined 28-day repeated dose toxicity with reproduction/developmental toxicity screening in rats. The animals were dosed for 29-32 days (males) and average 54 days (females, range 50-67 days and 40-43 days in case non-pregnant or total litter loss).

The applied dose levels of 0, 83, 250, 750 mg/kg/day were based on results of a 14-day range finder involving two groups of 3 female rats at 500 and 1000 mg/kg/day. Effects at 1000 mg involved: hunched posture and lethargy; BW reduction in one animal; reduction absolute and relative food consumption; effects on stomach in one animal at macroscopic examination; increase relative liver weights by 39%.

The following parameters and end points were evaluated in this study:  mortality/moribundity, clinical signs, functional observations, body weight and food consumption, estrous cycle determination, clinical pathology, measurement of thyroid hormone T4 (F0-males), gross necropsy findings, organ weights and histopathologic examinations.  In addition, the following reproduction/developmental parameters were determined: mating and fertility indices, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy, measurement of thyroid hormone T4 (PND 14-16 pups)).  

Formulation analyses confirmed that formulations of test item in water were prepared accurately and homogenously.

The observed decrease in body weight gain in males at 750 mg/kg/day on Day 8, was considered non adverse as body weights were normal and the body weight gain recovered to normal levels in the following weeks. The decrease in body weight gain may have been related to the decreased food consumption levels found during the first week of treatment in males at 750 mg/kg/day.

For females, (relative) food consumption levels were decreased during the premating, post coitum and/or lactation period at 750 mg/kg/day. Though not statistically significant, body weight gains were lower at the end of post coitum and lactation period at 750 mg/kg/day. These findings were likely the result of the decreased litter sizes at 750 mg/kg/day and were considered secondary to developmental and reproductive toxicity.

Liver weights were increased in males and at the observed magnitude of the effect (relative increase of 27% at 750 mg/kg/day) and in absence of correlating microscopic findings, this was considered non adverse.

A test item-related thickened forestomach was observed in males treated at 750 mg/kg/day. The microscopic correlate for this finding was hyperplasia in the forestomach. Hyperplasia in the forestomach was observed in both males and females at 750 mg/kg/day. Based on the low severity (minimal to slight) and the absence of any inflammatory response, the hyperplasia in the forestomach was considered not adverse. This forestomach lesion was considered to be a local response and most likely due to the minor irritating properties of the test item.  

Parental toxicity: NOEL = 250 mg/kg bw/day. The main observed effects involve:

1. consistent effects that suggest local irritation:

- Dose related salivation, starting at 250 mg/kg bw

- Consistent slightly lower food intake and BW-gain at 750 mg/kg.

- forestomach effects in 4/5 males and 3/5 females at 750 mg/kg.

2. increase liver weight at least in males, suggesting liver induction involving change of epoxide into diols that are readily further metabolized, as first pass metabolism after uptake. These effects are consistent with adverse effects observed after only 14 days treatment in RF.

These effects were however not considered adverse, resulting to a NOAEL of 750 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP compliant guideline study
System:
gastrointestinal tract

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

(Dosing dissolved in water, 5 mL/kg bw)

The following observed effects in the repeated dose study suggest local irritation in the gastro-intestinal tract starting from 50 g/L (250 mg/kg bw):

- Dose related salivation, starting at 50 g/L (250 mg/kg bw).

- Consistent slightly lower food intake and BW-gain at 150 g/L (750 mg/kg).

- forestomach effects in 4/5 males and 3/5 females at 150 g/L (750 mg/kg).

 

The slight increase liver weight at 750 mg/kg bw at least in males, suggesting liver induction involving change of epoxide into diols that are readily further metabolized, as first pass metabolism after uptake. These effects are consistent with adverse effects observed after only 14 days treatment in RF where a clear increase was observed at 1000 mg/kg bw.

Additional information

ORAL:

C12-14 Alkyl ethoxylated glycidylether has been evaluated in a combined 28-day repeated dose toxicity with reproduction/developmental toxicity screening in rats. The animals were dosed for 29-32 days (males) and average 54 days (females, range 50-67 days and 40-43 days in case non-pregnant or total litter loss).

The applied dose levels of 0, 83, 250, 750 mg/kg/day were based on results of a 14-day range finder involving two groups of 3 female rats at 500 and 1000 mg/kg/day. Effects at 1000 mg involved: hunched posture and lethargy; BW reduction in one animal; reduction absolute and relative food consumption; effects on stomach in one animal at macroscopic examination; increase relative liver weights by 39%.

The following parameters and end points were evaluated in this study:  mortality/moribundity, clinical signs, functional observations, body weight and food consumption, estrous cycle determination, clinical pathology, measurement of thyroid hormone T4 (F0-males), gross necropsy findings, organ weights and histopathologic examinations.  In addition, the following reproduction/developmental parameters were determined: mating and fertility indices, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy, measurement of thyroid hormone T4 (PND 14-16 pups)).  

Formulation analyses confirmed that formulations of test item in water were prepared accurately and homogenously.

The observed decrease in body weight gain in males at 750 mg/kg/day on Day 8, was considered non adverse as body weights were normal and the body weight gain recovered to normal levels in the following weeks. The decrease in body weight gain may have been related to the decreased food consumption levels found during the first week of treatment in males at 750 mg/kg/day.

For females, (relative) food consumption levels were decreased during the premating, post coitum and/or lactation period at 750 mg/kg/day. Though not statistically significant, body weight gains were lower at the end of post coitum and lactation period at 750 mg/kg/day. These findings were likely the result of the decreased litter sizes at 750 mg/kg/day and were considered secondary to developmental and reproductive toxicity.

Liver weights were increased in males and at the observed magnitude of the effect (relative increase of 27% at 750 mg/kg/day) and in absence of correlating microscopic findings, this was considered non adverse.

A test item-related thickened forestomach was observed in males treated at 750 mg/kg/day. The microscopic correlate for this finding was hyperplasia in the forestomach. Hyperplasia in the forestomach was observed in both males and females at 750 mg/kg/day. Based on the low severity (minimal to slight) and the absence of any inflammatory response, the hyperplasia in the forestomach was considered not adverse. This forestomach lesion was considered to be a local response and most likely due to the minor irritating properties of the test item.  

Parental toxicity: NOEL = 250 mg/kg bw/day. The main observed effects involve:

1. consistent effects that suggest local irritation:

- Dose related salivation, starting at 250 mg/kg bw

- Consistent slightly lower food intake and BW-gain at 750 mg/kg.

- forestomach effects in 4/5 males and 3/5 females at 750 mg/kg.

2. increase liver weight at least in males, suggesting liver induction involving change of epoxide into diols that are readily further metabolized, as first pass metabolism after uptake. These effects are consistent with adverse effects observed after only 14 days treatment in RF.

These effects were however not considered adverse, resulting to a NOAEL of 750 mg/kg bw/day.

DERMAL

Manufacture and use are highly controlled. Its use is limited to industrial application as intermediate in chemical production where its classification as skin sensitiser will provide for sufficient protection measures to prevent exposure. Furthermore, systemic toxicity via oral route has shown to be low, and as dermal uptake can be expected to be limited, as consequence, effects will be characterised by local irritation rather than by systemic toxicity following dermal uptake.The skin is therefore not a preferred route for testing to evaluate systemic toxicity following repeated dose.

 

INHALATION

Likelihood of exposures via inhalation is low considering thevapour pressure of ≤ 0.070 Pa at 25°C. Its use is highly controlled, limited to industrial chemical manufacturing and does not involve the forming of aerosols, particles or droplets of an inhalable size. Emission rates to air were measured to be 28 µg/day. So, exposure to humans via the inhalation route will be unlikely to occur.

Justification for classification or non-classification

With NOAEL of 750 mg/kg bw from a sub-acute repeated dose toxicity study no classification for STOT-RE is indicated.