Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 August 2021 - 03 December 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: • Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2'-(C16-18 (evennumbered, C18 unsaturated) alkyl imino) diethanol
EC Number:
620-540-6
Cas Number:
1218787-32-6
Molecular formula:
No molecular formula
IUPAC Name:
2,2'-(C16-18 (evennumbered, C18 unsaturated) alkyl imino) diethanol
Test material form:
liquid: viscous
Details on test material:
- Chemical name: 2,2'-(C16-18 (evennumbered, C18 unsaturated) alkyl imino) diethanol
- EC number: 620-540-6

To the best of knowledge, the sample used is representative to the boundary composition shared and agreed by each registrant.

Test animals

Species:
rat
Strain:
Wistar
Remarks:
RccHan®:WIST. (Han Wistar) rat
Details on test animals or test system and environmental conditions:
Strain/Species RccHan®:WIST. (Han Wistar) rat.
Supplier Envigo RMS Ltd. (UK)
Number of animals ordered 88 time-mated females.
Duration of acclimatization Four days from arrival on Day 2 after mating to commencement of treatment on Day 6 after mating.
Age of the animals at the start of the study (Gestation Day 2) 11 weeks old.
Weight range of the animals at the start of the study (Gestation Day 3) 171 to 238 g.

3.3.2 Mating
Method Natural mating with Han Wistar males at the supplier’s facility. Males and females were not related.
Day 0 of gestation When positive evidence of mating was detected.
Delivery to Labcorp On Day 2 after mating

3.3.3 Allocation and Identification
Allocation Randomly to each group, on day of arrival.
Method Allocation was controlled to prevent time mated females mated with the same male partner being allocated to the same treatment group.
Identification of animals Each animal was assigned a number and identified uniquely within the study by a microchip inserted subcutaneously in the dorsal cervical region.
Identification of cages Each cage label was color-coded according to group and was numbered uniquely with cage and study number, as well as the identity of the occupant.

3.4 Animal Care and Husbandry

3.4.1 Environmental Control
Animal facility Limited access - to minimize entry of external biological and chemical agents and to minimize the transference of such agents between rooms.
Air supply Filtered fresh air which was passed to atmosphere and not recirculated.
Temperature and relative humidity Monitored and maintained within the range of 20-24C and 40-70%.
There were no deviations from these ranges.
Lighting Artificial lighting, 12 hours light: 12 hours dark.
Electricity supply Public supply with automatic stand-by generators.

3.4.2 Animal Accommodation
Cages Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropriate intervals.
Solid (polycarbonate) bottom cages were used during the acclimatization and gestation periods.
Cage distribution The cages constituting each group were blocked by group and mounted in batteries.
Bedding Solid bottom cages contained softwood based bark-free fiber bedding, which was changed at appropriate intervals each week.
Number of animals per cage One.

3.4.3 Environmental Enrichment
Aspen wood based products A soft white untreated wood block: provided to each cage throughout the study and replaced when necessary.
Plastic shelter Provided to each cage throughout the study and replaced at the same time as the cages.

3.4.4 Diet Supply
Diet SDS VRF1 Certified, pelleted diet.
The diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
Availability Non-restricted.

3.4.5 Water Supply
Supply Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.
Availability Non-restricted.

3.4.6 Supplier Certificates of Analysis
Certificates of analysis for the diet are scrutinized and approved before any batch of diet was released for use. Certificates of analysis were routinely provided by the water supplier.
Certificates of analysis were also received from the suppliers of the softwood based bark-free fiber bedding and Aspen wood based products.
No specific contaminants were known that may have interfered with or prejudiced the outcome of the study and therefore no special assays were performed.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
Route Oral gavage using a suitably graduated syringe and a flexible cannula inserted via the mouth.

Method For each group, the required amount of dose was drawn up into the syringe and cannula. The outside of the cannula was wiped clean of any formulation residue with a clean disposable tissue and the end of the flexible cannula was lightly tapped onto clean tissue to remove any remaining droplets. The cannula was then dipped into a container filled with 5% glucose solution to aid intubation.

Treated at Constant doses in mg/kg/day.

Volume dose 4 mL/kg body weight.

Individual dose volume Calculated from the most recently recorded scheduled body weight.

Control (Group 1) Vehicle at the same volume dose as treated groups.

Frequency Females were treated from Day 6 to Day 20 (inclusive) after mating, once daily at approximately the same time each day.

Formulation A daily record of the usage of formulation was maintained based on weights. This balance was compared with the expected usage as a check of correct administration.
Formulations were stirred using a magnetic stirrer before and throughout the dosing procedure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Correction factor None.

Vehicle Arachis oil

Method of preparation The test material was warmed until melted and gently inverted until homogenous. The required amount of test item was weighed. Approximately 50% of the final volume of vehicle was added and heated to around 60°C in a water bath whilst magnetically stirring until uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer and heated in water bath to around 60°C until homogenous. The formulation was transferred to the final containers, via syringe, whilst magnetically stirring.

Frequency of preparation Twice weekly.

Storage of formulation Refrigerated (2 to 8C).

Test item accounting Detailed records of compound usage were maintained. The amount of test item necessary to prepare the formulations and the amount actually used were determined on each occasion. The difference between these amounts was checked before the formulations were dispensed.


Stability and homogeneity The homogeneity and stability of formulations during storage were determined as part Labcorp Study Number MH28JS. In that study, formulations in the range 1 to 100 mg/mL were determined to be stable for:
• One day at ambient temperature (15 to 25C)
• Four days when stored refrigerated (2 to 8C)

Achieved concentration Samples of each formulation prepared for administration in the first and last weeks of treatment were analyzed for achieved concentration of the test item.

Analysis The method of analysis and results are presented in Attachment 14.2.
Details on mating procedure:
Method Natural mating with Han Wistar males at the supplier’s facility. Males and females were not related.

Day 0 of gestation When positive evidence of mating was detected.

Delivery to Labcorp On Day 2 after mating
Duration of treatment / exposure:
Females were treated from Day 6 to Day 20 (inclusive) after mating, once daily at approximately the same time each day.

Volume dose 4 mL/kg body weight.

Individual dose volume Calculated from the most recently recorded scheduled body weight.
Frequency of treatment:
Once daily
Duration of test:
14 days Day 6 to Day 20 post-coitum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
22 Females
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
3.6.1 Clinical Observations
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. 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.

Signs Associated with Dosing
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.

Clinical Signs
A detailed physical examination was performed on each animal on Days 3, 5, 12, 18 and 21 after mating to monitor general health.

3.6.2 Body Weight
The weight of each adult was recorded on Days 3 and 6-21 after mating.

3.6.3 Food Consumption
The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 3-5, 6-8, 9-11, 12-14, 15-17 and 18-20 after mating inclusive.

All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
Schedule Animals were killed on Day 21 after mating.

Organ Weights
For bilateral organs, left and right organs were weighed together. Requisite organs were weighed for animals killed at scheduled intervals.

Fixation
Tissues were routinely preserved in 10% Neutral Buffered Formalin

3.7.3 Histology
Processing Tissue samples were dehydrated, embedded in paraffin wax and sectioned at a nominal four to five micron thickness. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required.

Thyroid All adult females.

Routine staining Sections were stained with hematoxylin and eosin.

3.7.4 Light Microscopy
Ovaries and uterine content:
The following were recorded for all animals:
Uterus Gravid uterine weight (including cervix and ovaries).

For each ovary/uterine horn Number of:
Corpora lutea.
Implantation sites.
Resorption sites (classified as early or late).
Fetuses (live and dead).

Apparently non pregnant animals and for apparently empty uterine horns
The number of uterine implantation sites were checked after staining with ammonium sulphide (modification of the Salewski staining technique (Salewski, 1964)).

Blood sampling:
3.6.4 Thyroid Hormone Analysis
Blood samples were collected at the following occasion GD 21 at necropsy

Parameters
Triiodothyronine (T3)
Thyroxine (T4)
Thyroid stimulating hormone (TSH)

Sequence of blood sampling on each occasion To minimize any potential confounding effect of the time of day of blood sampling, the time of blood sampling was controlled to allow satisfactory inter-group comparisons. Animals were sampled in a random order, within a two-hour time period, where possible

Conditions No overnight deprivation of food.

Blood sample site Sublingual vein.

Anesthetic Isoflurane.

Anticoagulant None.

Blood tubes Greiner Minicollect tubes with clotting activator.

Blood volume 1.0 mL.

Treatment of samples Samples were kept at ambient temperature (15 to 25°C) for a minimum of 30 minutes prior to centrifugation.

Centrifugation conditions At 2000g for ten minutes at 4°C.
Serum was transferred to appropriately labelled polypropylene “cryo” tubes using plastic disposable pipettes and then mixed by gentle ten-fold inversion. Following mixing, each serum sample was divided in two aliquots.

Number of aliquots Two per animal.
Aliquot 1: 0.2 mL serum for T3/T4
Aliquot 2: residual serum for TSH

Final storage conditions Deep frozen (approximately -60°C to -90C) pending analysis.

Fate of samples Aliquot 1 (T3 and T4): dispatched to the department of LC MS/MS Bioanalysis, Labcorp.
Aliquot 2: dispatched to the Department of Immunology and Immunotoxicology, Labcorp.

T3 and T4 Performed by the department of LC-MS/MS Bioanalysis, Labcorp.
The method of analysis and results are presented in Attachment 14.3.

TSH Performed by the Department of Immunology and Immunotoxicology, Labcorp.
The method of analysis and results are presented in Attachment 14.4.
Fetal examinations:
3.7.6 Fetal Examination and Processing
Examination of all viable fetuses and placentae Dissected from the uterus, individually weighed and identified within the litter using a coding system based on their position in the uterus. Fetuses examined externally with abnormalities recorded. Particular attention was paid to the external genital organs of male fetuses. The sex and ano-genital distance of each fetus was recorded.

50% of fetuses in each litter Sexed internally, eviscerated and fixed in Industrial Methylated Spirit (IMS).

50% of fetuses in each litter Sexed internally and examined for visceral abnormalities by fresh microdissection (Modified Staples technique) and subsequently fixed in Bouin’s solution.

Processing Bouin’s fixed fetuses had heads removed post-fixation and heads were processed by Wilsons free-hand serial sectioning. Torsos were retained in Bouin’s solution.
IMS fixed fetuses were processed and stained with Alizarin Red.

3.7.7 Fetal Pathology Examination
Bouin’s fixed heads Serial sections were examined for visceral abnormalities.

Alizarin Red stained fetuses Assessed for skeletal development and abnormalities.
Statistics:
This report only contains serial observations pertaining to the gestation period (from Day 3 after mating).
Where appropriate, group mean values, each with standard deviation (SD), were calculated from individual data. Summary tabulated data was normally restricted to data derived from females/litters with live young at Day 21 after mating.

For all adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
The following data types were analyzed at each timepoint separately:
Body weight, using absolute weights and gains over appropriate study periods
Gravid uterine weight and adjusted body weight
Food consumption, over appropriate study periods
C-section litter data (corpora lutea, implantations, pre/post implantation loss, live young and sex ratio - percentage male)
Placental, litter and fetal weights
Ano-genital distance, average for each litter adjusted for litter average fetal body weight
Organ weights, absolute

The following comparisons were performed:
Group 1 vs 2, 3 and 4

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

For litter average ano genital distance, analysis of covariance was performed using average fetal weight for each litter as covariate (Angervall and Carlstrom, 1963), unless non parametric methods were applied. The treatment comparisons were made on adjusted group means in order to allow for differences in fetal weight which might influence the ano genital distance.
Indices:
Prenatal losses are separated into pre- and post-implantation phases. Pre-implantation loss was considered to reflect losses due to non-fertilization of ova and failure to implant. It was calculated from the formula:
Pre-implantation loss (%) = (Number of corpora lutea - Number of implantations) / Number of corpora lutea x 100

Where the number of implantations exceeded the number of corpora lutea observed, pre implantation loss was assumed to be zero (i.e. no pre-implantation loss was considered to have occurred).
Post-implantation loss was calculated from the formula:
Post-implantation loss (%) = (Number of implantations - Number of live fetuses) / Number of implantations x 100
All group values and SD were calculated from the individual litter values.
Historical control data:
Available and used for comparison where necessary and to help validate controls.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The appearance and behavior of all animals were unaffected by treatment.

Isolated findings of decreased activity, salivation and piloerection were reported in one animal receiving 150 mg/kg/day, but in view of the low incidence, this was considered unrelated to treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Overall body weight gain (Day 6-21 after mating) was statistically significantly lower than control in females receiving 150 mg/kg/day (overall reduction of 50%). The extent of the reduction from control was greatest from Day 13-21 after mating (55% reduction, compared to a 41% reduction from Day 6-13 after mating).

Body weight gain was unaffected in females receiving 15 or 50 mg/kg/day.

On Day 21 of gestation, gravid uterine weight was statistically significantly lower than control in females receiving 150 mg/kg/day (overall reduction 28%). When adjusted for the contribution of the gravid uterus, there was a mean loss of body weight (-6 g) in females receiving 150 mg/kg/day.

Gravid uterus weight and adjusted body weight gain was unaffected in females receiving 15 or 50 mg/kg/day.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Overall mean food intake during the dosing period (Day 6-21 after mating) was 24% lower than controls in females receiving 150 mg/kg/day. There was no similar finding at 15 or 50 mg/kg/day.
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
The analysis of thyroid hormone concentrations on Day 21 of gestation revealed statistically significantly low triiodothyronine concentration in females receiving 150 mg/kg/day, compared with control.
Thyroxine concentration was slightly lower than control in females receiving 50 or 150 mg/kg/day and thyroid stimulating concentration was slightly high in females receiving 150 mg/kg/day but in each case, there was no dose response and statistical significance was not attained and, as such, this was not attributable to treatment.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were no organ weight differences considered to be related to treatment with 2,2’-(C16-18 (even numbered, C18 unsaturated) alkyl imino) diethanol in the thyroid and parathyroid glands.
Any changes in the absolute thyroid and parathyroid weights of treated females were considered to be incidental and not related to treatment, as there was no microscopic correlate. It is possible that any changes in the absolute thyroid and parathyroid weights of females receiving 150 mg/kg/day were secondary to lower than control bodyweight gain and lower than control food intake seen in females receiving 150 mg/kg/day, and not related to treatment.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no macroscopic findings considered to be related to treatment with 2,2’-(C16-18 (even numbered, C18 unsaturated) alkyl imino) diethanol.
The thyroids of one female treated with 150 mg/kg/day were macroscopically small, and this finding was considered to represent normal biological variation as there was no microscopic correlate.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No test item related microscopic findings were seen in the thyroid gland.
Histopathological findings: neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The number of live offspring was slightly low and pre-and post-implantation loss were slightly high at 150 mg/kg/day, with the mean number of live offspring and pre- and post-implantation losses being outside of the historical control range. However, the pre-implantation loss, although outside the range of the historical control data, was only marginally higher than that at 50 mg/kg/day, did not attained statistical significance and represents a period prior to the start of dosing. The number of live offspring and post-implantation losses did not attain statistical significance and individual values were similar to control. These variations were therefore not attributable to treatment
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
At scheduled termination on Day 21 after mating, two control females (Nos. 14 and 17), three females receiving 15 mg/kg/day (Nos. 34, 35 and 41), one female receiving 50 mg/kg/day (No. 57) and four females receiving 150 mg/kg/day (Nos. 71, 72, 80 and 82) were not pregnant. In addition, one female receiving 15 mg/kg/day (No. 25), one female receiving 50 mg/kg/day (No. 45) and one female receiving 150 mg/kg/day (No. 79) had a total litter resorption
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Total litter weight was 29% lower than control at 150 mg/kg/day, the difference attaining statistical significance. There was no effect on total litter weight for females receiving 15 or 50 mg/kg/day.
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Total litter weight was 29% lower than control at 150 mg/kg/day, the difference attaining statistical significance. There was no effect on total litter weight for females receiving 15 or 50 mg/kg/day.
Anogenital distance of all rodent fetuses:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Placental weight was slightly higher than control in females receiving 150 mg/kg/day. There was no effect of maternal treatment on male, female or overall fetal weight at any dose level investigated

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
Treatment related:
no

Any other information on results incl. tables

Summary of Thyroid Hormone Levels after 13 Weeks of Treatment









































Group/sex



1F



2F



3F



4F



Dose level (mg/kg/day)



0



15



50



150



Thyroxine (pg/mL)



19500



21300



17700



16000



Triiodothyronine (pg/mL)



493



515



494



354**



Thyroid stimulating hormone (pg/mL)



580



725



596



741



** p≤0.01

Applicant's summary and conclusion

Conclusions:
It is concluded that that oral administration of 2,2’-(C16-18 (even numbered, C18 unsaturated) alkyl imino) diethanol to Han Wistar rats during the organogenesis and fetal growth phases of pregnancy at doses of 0, 15, 50 or 150 mg/kg/day was generally tolerated but cause an adverse reduction of weight gain, associated with low food intake, in females receiving 150 mg/kg/day. The number of implantations, resorptions and live young, the pre- and post implantation loss and sex ratio were considered unaffected by treatment. The No-Observed-Adverse-Effect Level (NOAEL) for maternal toxicity was therefore considered to be 50 mg/kg/day, based on the effects on body weight gain and body weight loss when corrected for gravid uterus. The NOAEL for embryo-fetal survival and development was considered to be 150 mg/kg/day.
Executive summary:

The purpose of this study was to assess the influence of 2,2’-(C16-18 (even numbered, C18 unsaturated) alkyl imino) diethanol on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat. Dose levels of 0, 15, 50, 150 mg/kg bw/day. The dose levels for this study were selected based on the results of Labcorp Study Number 8466317. In that study, a dose of 150 mg/kg/day was tolerated by pregnant Han Wistar rats, but resulted in a reduction of weight gain (associated with low food intake), which, when adjusted for gravid uterus weight, resulted in an overall body weight loss. There was no effect on embryo-fetal survival or development. The lower body weight gain was considered not to preclude the use of the 150 mg/kg/day in this main study, which was, therefore, selected as the highest dose.


The purpose of this study was to assess the influence of 2,2’-(C16-18 (even numbered, C18 unsaturated) alkyl imino) diethanol on embryo-fetal survival and development when administered during the organogenesis and fetal growth phases of pregnancy in the Han Wistar rat. This study demonstrated that doses up to 150 mg/kg/day were generally tolerated with no treatment-related clinical signs and no premature deaths, though there was evidence of a toxic response in pregnant females which was manifest as an adverse reduction of body weight gain (50% reduction from control), adjusted weight loss and a sustained reduction in food consumption. There was no treatment-related effect on the number of implantations, resorptions and live young, the pre- and post implantation loss and sex ratio and there were no treatment-related findings at the fetal pathology investigations, indicating that there was no effect on embryo-fetal development. Although there was a statistically significant decrease of triiodothyronine concentration in females receiving 150 mg/kg/day, there was considered to be no effect of treatment on the hormonal control of the thyroid gland, since thyroxine and thyroid stimulating hormone concentrations were unaffected and there was no effect on thyroid gland weight and pathology.


Fetal showed bodyweight reductions of up to 29% in the high dose group when compared with that of control. This effect was not considered adverse. Addtionally, secondary effects of maternal toxicity at 150 mg/kg bw/day  resulting in an average body weight loss of 50% when corrected for gracid uterine weight as this may have contributed to reduced fetal bodyweight. 


The reproductive assessment revealed high pre- and post-implantation loss in females receiving 150 mg/kg/day, resulting in a lower number of implantations and live young, which was adverse, with all values being outside of the background control range. The reduction in live young correlated with lower total litter weights and higher placental weights at this dose level. There was, however, no effect on individual fetal weights and the increased placental weights were likely due to the lower numbers of live young in each litter.


Maternal NOAEL was set to 50 mg/kg bw/day due to severe effects on body weight gain.


Fetal NOAEL is 150 mg/kg/day due to lack of adverse effects seen.