Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
extended one-generation reproductive toxicity - with F2 generation (Cohorts 1A, and 1B with extension)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 Jan 2020 - 02 June 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2021
Report date:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Principles of method if other than guideline:
Variation: Due to the delay in sexual maturation, mating of Cohort 1B animals and production of an F2 generation was triggered.
GLP compliance:
yes (incl. QA statement)
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals
: 10 weeks
- Basis for dose level selection
: see attached range finder study, Charles River Study 490131
- Inclusion/exclusion of extension of Cohort 1B : yes
- Inclusion of F2
: delayed sexual maturation in females pups of the F1 triggered F2 generation,
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B
: no, no signs of neurotoxicity from overall data
- Inclusion/exclusion of developmental immunotoxicity Cohort 3
: no, no signs of immunotoxicity from overall data
- Route of administration
: feeding, as substance leads to irritation in stomach if given in bolus

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-dimethyldecan-1-amide
EC Number:
238-405-1
EC Name:
N,N-dimethyldecan-1-amide
Cas Number:
14433-76-2
Molecular formula:
C12H25NO
IUPAC Name:
N,N-dimethyldecanamide
Test material form:
liquid
Details on test material:
Identification: N, N-dimethyldecan-1-amide
Lot: 0020615289
BASF Compound Number: 10/0294-3
Production Date: 22 Mar 2019
Retest Date: 21 Mar 2021
Physical Description: Liquid
Correction Factors: 1.02
Purity: 97.9 area%
Storage Conditions: Ambient, room temperature

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Han Wistar CRL:WI (Han)
Details on species / strain selection:
Strain: Han Wistar CRL:WI (Han)
The Han Wistar rat was chosen as the animal model for this study as it is a rodent species
accepted by regulatory agencies for toxicity testing.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: On 04 Feb 2020, 115 male (including 3 spares) and 115 female (including 3 spares) Han
Wistar CRL:WI (Han) rats were received from Charles River UK Limited, Margate, Kent,
UK
- Females (if applicable) nulliparous and non-pregnant: yes
- Age and weight at study initiation: At the initiation of dosing, the F0 Animals were 6 to 7 weeks old (males, target approximately 8 to 10 weeks) and 5 to 6 weeks old (females, approximately target 6 to
8 weeks) and weighed between 129 and 234 g (males) and 92 and 149 g (females).
- Fasting period before study: diet study
- Housing:Animals were initially socially housed 2 or 3 per cage by sex (unless reduced by mortality) in appropriately sized suspended polycarbonate cages with stainless steel grid tops and solid
bottoms.Bedding material was sterilised white wood shavings. A few days prior to mating, F0 males (and Cohort 1B males) were transferred to individual cages with solid bottoms. F0 and Cohort 1B females were transferred to these cages for mating. Mated females were transferred to individual solid bottomed cages. White paper tissue was
supplied as nesting material from Gestation Day (GD) 20. Females with un-weaned litters
were retained in this type of cage until weaning or termination. On a suitable day after completion of mating, the males were re-housed with their original cage mates. Cohort 1A and 1B were socially housed 2 or 3 per cage by sex per cage in appropriately sized suspended polycarbonate cages with stainless steel grid tops and solid bottoms.
- Diet (e.g. ad libitum): SDS VRF-1 breeder diet in ground format was provided ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The F0 animals were allowed to acclimate to the Test Facility rodent toxicology accommodation for a period of 2 weeks before the commencement of dosing.
ENVIRONMENTAL CONDITIONS
Husbandry practices and environmental enrichment were carried out as per Test Facility
SOPs and protocol. Each batch of diet, bedding, and all environmental enrichment items were
supplied with a Certificate of Analysis. Water from the public supply is routinely analysed
for quality (including microbiological burden). Copies of the certificates for all materials and
the water analysis are retained centrally at the Test Facility. It was considered that there were
no contaminants in any of these materials that influenced the outcome of this study.
- Temperature (°C): 17 to 24°C
- Humidity (%): 32 to 78%
- Air changes (per hr): Ten or greater air changes per hour were maintained in the animal rooms
- Photoperiod (hrs dark / hrs light):12-hour light/12-hour dark cycle
There were occasions where the target environmental conditions for temperature and
humidity were not maintained. These occasions were transient and the health of the animals
was unaffected on any occasion, therefore, these excursions were considered not to impact
the outcome or integrity of the study.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: VRF-1 Diet
Details on exposure:
DIET PREPARATION
Test item dosing formulations were prepared based on a method established at the Test
Facility (Formulation Process Document 998849-19-098) at appropriate concentrations to
meet dose level requirements. The dosing formulations were prepared at least weekly, stored
at -20oC, dispensed as required, and allowed to thaw at ambient temperature.
Any residual volumes were discarded. Details of the preparation and dispensing of the test
item have been retained in the study records
Dose formulation samples were collected for analysis (Thomson, 2020, CRL 422966).
VEHICLE
VRF-1 Diet ; common rodent diet
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration Analysis

Duplicate sets of top, middle, and bottom samples (duplicate middle only for control) for
each sampling time point were sent to the appropriate laboratory for analysis. Samples for
analysis were 10 g and were taken into appropriately sized amber glass jars. Triplicate sets of
top, middle, and bottom samples (triplicate middle only for control) were collected and
maintained at the Test Facility as back-up samples. Back-up samples were 20 g and were
taken into polypropylene bags. Samples were stored at ambient room temperature.
Concentration results were considered acceptable if mean sample concentration results were
within or equal to ±10% of theoretical concentration. For homogeneity, the criteria for
acceptability was a relative standard deviation (RSD) of concentrations of <= 10% for each
group. Any residual/retained analytical samples and back-up samples were discarded
following completion of analysis.

Stability Analysis

Stability analyses performed previously in conjunction with Thomson, 2020, 422966
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. Stability data
have been retained in the study records for Thomson, 2020, 422966.
Duration of treatment / exposure:
The test or control items were administered ad libitum in the diet. The first day diets available
to the animals was designated as Day 1.
Treatment
F0 Males: 10 weeks prior to mating and throughout mating until termination.
F0 Females: 10 weeks prior to mating, throughout mating and gestation until at
least Lactation Day (LD) 21.
Cohort 1A: From PND 21 until the day before necropsy (at least PND 90).
Cohort 1B Males: From PND 21 until the day before necropsy (at least PND 97).
Cohort 1B Females: From PND 21 to mating, throughout mating and gestation until at
least LD 21.
Frequency of treatment:
continous
Details on study schedule:
Mating Procedure – F0 and Cohort 1B
Pairing was on a 1 male to 1 female basis. Females were housed with their allocated
co-group male partner during the evening (after 5 pm). For F0 animals, this commenced on
Study Day 71 and for Cohort 1B animals this commenced on Study Day 204 (nominally 16
weeks old).
Vaginal lavages were taken early each morning from the day of pairing until mating had
occurred and the stage of estrous observed in each vaginal lavage was recorded. The day of
detection of a copulatory plug in situ and/or of sperm in the lavage was designated GD 0.
The pairing period for each pair of animals was a maximum of 14 nights.
If evidence of mating was not observed by the end of the pairing period, the female was
separated from the male during the morning following the last night of pairing and treated as
if mating had occurred during that night. Procedures for that female continued as if it had
mated on the last night of pairing.
For each female the time taken to show a positive mating sign and the number of failed
opportunities to mate (estruses passed without a sign of mating) were evaluated.

Observations of Females and Litters - F0 and Cohort 1B Animals
The females were allowed to litter normally. Any observed difficulty or prolongation of
parturition was recorded. The day of birth of the litter (day on which first pups were born)
was designated LD 0. The duration of gestation in days was calculated.
The numbers of live and dead pups born in each litter was recorded as soon as possible after
completion of parturition on LD 0. The live pups were counted, sexed, weighed individually
on PND 1 and examined daily for the presence of milk in the stomach and for any externally
visible abnormalities daily up to and including PND 4 . On
PND 4, litter size was standardised to 8 pups, where possible 4 males and 4 females, by
culling of extra pups via random selection. Extra pups were necropsied. Where 4 males or 4 females were not available, extra pups of the opposite sex were retained to ensure a total number of 8 pups. An exception was made for Litter 2704, where the litter of 8 males and 4 females was reduced to 5 males and 3 females due to one female having an abnormal hindlimb (black/swollen) and not expected to survive. When the total number of pups in a litter on PND4 was ≤ 8 pups, no litter size adjustment occurred.
From PND 5, the total live pups were counted daily, and were sexed and examined for
abnormality again on PND 7, 14 and 21 . These pups were weighed individually.
Where practicable, any pups that were found dead or were killed during lactation were sexed
and appropriately examined as above. Any externally abnormal decedent pup was preserved
in fixative; externally normal pups were discarded.
Deficiencies in maternal care was recorded: inadequate construction or cleaning of the nest,
pups left scattered and cold, physical abuse of pups, or apparently inadequate lactation or
feeding. White paper tissue was supplied to each mother for incorporation in the nest. This
was replaced when it had become soiled.
Females which failed to produce a litter by their expected GD 24 were sent for necropsy. Any
female that had a total litter loss was sent for necropsy at the earliest appropriate time.

Pre-weaning Physical Development of F1 and F2 Pups Only
Ano-genital distance was measured on PND 1 using a calibrated caliper, the anogenital
distance was measured from the caudal margin of the anus to the caudal margin of the genital
tubercule. Measurements were recorded to the nearest 0.01 mm.
Nipple retention was assessed in males on PND 13. Nipple retention assessment was not
required on PND 21.

Weaning and Selection of F1 animals for Cohorts 1A and 1B
From each group, F1 animals were selected at random on PND 20 and identified on that day
for post-weaning assessments, nominally by selecting up to 4 males and 4 females from each
litter, where possible. Where fewer than 8 pups were weaned, the necessary additional
animals were obtained by selecting an additional pup from appropriate litters; these
appropriate litters would normally be selected arbitrarily but attention would be paid to the
retention of as wide a genetic pool as possible.
These pups were removed from their mother on PND 21 and housed in their new cages.
Pups that were not selected for post-weaning assessments (Cohorts 1A and 1B or up to
20 surplus pups per sex per group) remained with their mother until termination.

Assessment of Sexual Maturation (Cohorts 1A and 1B)
Commencing at PND 28, females were examined daily for vaginal opening. The day on
which the vagina became open was recorded, as was the body weight on that day.
Commencing at PND 35, males were examined daily for balano-preputial separation. The day
on which separation occurred was recorded, as was the body weight on that day.
Doses / concentrationsopen allclose all
Dose / conc.:
500 ppm (nominal)
Remarks:
F0 Animals (Lactation Phase), F1 Animals Cohort 1B Post-weaning (Reproductive, Lactation Phase)
Dose / conc.:
2 000 ppm (nominal)
Remarks:
F0 Animals (Lactation Phase), F1 Animals Cohort 1B Post-weaning (Reproductive, Lactation Phase)
Dose / conc.:
6 250 ppm (nominal)
Remarks:
F0 Animals (Lactation Phase), F1 Animals Cohort 1B Post-weaning (Reproductive, Lactation Phase)
Dose / conc.:
1 000 ppm (nominal)
Remarks:
F0 Animals (main Phase), F1 Animals Cohort 1A Post-weaning, F1 Animals Cohort 1B Post-weaning (Reproductive, non Lactating Phase)
Dose / conc.:
4 000 ppm (nominal)
Remarks:
F0 Animals (main Phase), F1 Animals Cohort 1A Post-weaning, F1 Animals Cohort 1B Post-weaning (Reproductive, non Lactating Phase)
Dose / conc.:
12 500 ppm (nominal)
Remarks:
F0 Animals (main Phase), F1 Animals Cohort 1A Post-weaning, F1 Animals Cohort 1B Post-weaning (Reproductive, non Lactating Phase)
No. of animals per sex per dose:
F0 = 28
F1 Cohort 1A = 20
F1 Cohort 1B = 25
Control animals:
yes, plain diet
Details on study design:
Justification of Route and Dose Levels
The oral (dietary) route of administration was selected for this study as this route has been
defined by the Sponsor as a possible route of human exposure. The highest dose
(12,500 ppm) was tested under Bain, 2020, 490131.
As food intake was expected to be considerably higher in lactating females, dietary
concentration was lowered by 50% during the lactation period to maintain similar dosage.
- Fasting period before blood sampling for clinical biochemistry: Animals were fasted overnight prior to blood sampling
- Other: Blood was collected from via orbital sinus under non-recoverable isoflurane anaesthesia or via venous collection either from the jugular vein or tail vein (without anaesthetic).
Additional blood samples were obtained (e.g. due to clotting of non-serum samples) as
required. Urine was collected in ascending animal order over 6 hours with absence of food
and presence of water.

Examinations

Parental animals: Observations and examinations:
In-life Procedures, Observations, and Measurements – F0 Animals
The in-life procedures, observations and measurements listed below were performed for all
F0 animals and their litters.
Mortality/Moribundity Checks
Animals were observed twice daily, once at the start and once towards the end of the working
day throughout the study for general health/mortality and moribundity.
Clinical Observations
Cage Side Observations
Animals were observed from the cage side at least once daily, beginning Week -1.
Detailed Clinical Observations
Animals were removed from the cage and subjected to detailed clinical observations weekly,
beginning Week -1. The examinations included, but were not limited to, changes in skin, fur,
eyes, mucous membranes, palpebral closure, vocalisation, rearing, arousal, stains and
autonomic activity (lacrimation, salivation, piloerection, unusual respiratory pattern).
Changes in gait and posture, as well as the presence of clonic or tonic movements, stereotypy
or bizarre behaviour were assessed.
Body Weights
Males were weighed weekly beginning Week -1. Females were weighed weekly beginning
Week -1 until pairing for mating and then on GD 0, 7, 14 and 20 and on LD 1, 4, 7, 14 and 21. F1 Pups were weighed individually on PND 1, 4, 7, 14 and 21. A weight was also recorded on the day of scheduled necropsy.
Food Consumption
Food consumption was quantitatively measured for both sexes weekly, beginning Week -1
until pairing for mating, for the mated females on the GD periods 0 to 7, 7 to 14 and 14 to 20
and on LD periods 1 to 7, 7 to 14 and 14 to 21. Food consumption was resumed weekly for the males from Study Day 78 after mating and re-housing.
Water Consumption
Water consumption was monitored on a regular basis throughout the study by visual
inspection of the water bottles. No intergroup differences were noted.

Oestrous cyclicity (parental animals):
Estrous Cycle Monitoring
Vaginal lavages were taken early each morning and the stages of estrous observed were
recorded from 2 weeks prior to pairing (Study Day 57) until the day of detection of a
copulatory plug in situ and/or of sperm in the lavage.
Vaginal smears were examined on the morning of necropsy to determine the stage of the
estrous cycle to allow correlation with histopathology of the ovaries.
Sperm parameters (parental animals):
Sperm Evaluation – F0 and Cohort 1A Males
Computer Aided Sperm Assessment (CASA)
From all F0 and Cohort 1A males only, the right cauda epididymis was placed in 0.3% BSA
in Medium 199 as per Test Facility SOPs and the sperm was allowed to “swim out” into the
medium. An appropriate dilution of the sperm suspension was prepared and examined using a
Hamilton Thorne sperm motility analyser.
Sperm Count and Morphological Analysis
The cauda epididymis was minced and suspended. Dilutions of this sperm suspension was
counted using a haemocytometer to obtain a total sperm count which was expressed per
cauda epididymis and per gram of cauda epididymis. Optionally, the cauda epididymis was
frozen prior to assessment.
From all samples of the sperm suspension described in the preceding paragraph, a sperm
smear was prepared and stained with eosin Y solution. At least two hundred sperm per animal
was evaluated for morphological abnormalities using criteria described by Wyrobek and
Bruce (1975).
Spermatid Count
The right testis was decapsulated and homogenised. The homogenate may be sonicated to
reduce tissue debris etc., if required. The number of homogenisation resistant spermatids in
dilutions of this suspension was counted using a haemocytometer to obtain a total spermatid
count which was expressed per testis and per gram of testis. Optionally, the testis was frozen
prior to assessment.
Litter observations:
In-life Procedures, Observations, and Measurements – F1 Cohorts
The in-life procedures, observations, and measurements listed below were performed for all
applicable Cohort 1A and 1B animals, including Cohort 1B litters (i.e. F2 generation).
Mortality/Moribundity Checks
Animals were observed twice daily, once at the start and once towards the end of the working
day throughout the study for general health/mortality and moribundity.
Clinical Observations
Cage Side Observations
Animals were observed from the cage side at least once daily, beginning Week -1.
Detailed Clinical Observations
Animals were removed from the cage and subjected to detailed clinical observations weekly,
from weaning on PND 21, starting on a suitable day within one week of weaning of all litters
(Nominal Week 4).
Body Weights
Cohort 1A (both sexes) and Cohort 1B males were weighed weekly from weaning, starting
on a suitable day within one week of weaning of the majority of litters (Nominal Week 4).
Cohort 1B females were weighed weekly from weaning until pairing for mating and then on
GD 0, 7, 14 and 20 and on LD 1, 7, 14 and 21. F2 Pups were weighed individually, by sex, on
PND 1, 4, 7, 14 and 21. A weight was also recorded on the day of scheduled necropsy.
Food Consumption
Food consumption was quantitatively measured for Cohort 1A and 1B (both sexes) animals
weekly, starting on a suitable day within one week of weaning of all litters (Nominal Week 4)
and for the mated females (Cohort 1B only) on the GD periods 0 to 7, 7 to 14 and 14 to 20
and on LD periods 1 to 7, 7 to 14 and 14 to 21. Food consumption was resumed weekly for the Cohort 1B males on a suitable day after mating and re-housing.
Water Consumption
Water consumption was monitored on a regular basis throughout the study by visual
inspection of the water bottles. No intergroup differences were noted.
Estrous Cycle Monitoring
Vaginal lavages were taken early each morning and the stages of estrous observed were
recorded from the day after vaginal patency, continuing until the first confirmed estrous was
determined (from PND 75 for at least 14 consecutive days) for Cohort 1A females and from 2
weeks prior to mating until detection of a copulatory plug in situ and/or of sperm in the
lavage for Cohort 1B females.
Vaginal smears were also examined on the morning of necropsy to determine the stage of the
estrous cycle to allow correlation with histopathology of the ovaries for Cohort 1A females
only.
Postmortem examinations (parental animals):
Terminal procedures are summarised in Table 16; 17, 18 and 19 below.
Tissue Collection, Preservation and Processing are summarised in Table 21, 22, 23 and 24 below.

Postmortem examinations (offspring):
Terminal procedures are summarised in Table 16; 17, 18 and 19 below.
Tissue Collection, Preservation and Processing are summarised in Table 21, 22, 23 and 24 below.
Statistics:
STATISTICAL ANALYSIS
All results presented in the tables of the report are calculated using non-rounded values as per
the raw data rounding procedure and may not be exactly reproduced from the individual data
presented.
All statistical analyses were performed within the respective study phase, unless otherwise
noted. Numerical data collected on scheduled occasions was summarised and statistically
analysed as indicated below according to sex and occasion or by litter.
Constructed Variables
The following constructed variables were calculated and are reported.
Body weight gains: calculated against appropriate intervals
Organ weight relative to body weight: calculated against the terminal body weight
Organ weight relative to brain weight: calculated against the brain weight
Descriptive Statistical Analysis
Means, standard deviations, percentages, numbers, and/or incidences have been reported, as
appropriate by dataset.
Inferential Statistical Methods
All statistical tests were conducted at the 5% significance level. All pairwise comparisons
were conducted using two sided tests and are reported at the 1% and 5% levels, unless
otherwise noted.
The pairwise comparisons of interest are listed below:
Group 2 vs. Group 1
Group 3 vs. Group 1
Group 4 vs. Group 1
Analyses were performed according to the matrix below when possible, but excluded any
group with less than 3 observations.

Statistical Matrix
Variables for Inferential Analysis Statistical Method with Parametric/ Non-Parametric
Body Weighta X
Body Weight Gainsa X
Food Consumptiona X
Haematology Variables X
Coagulation Variables X
Clinical Chemistry Variables X
T4 X
TSH (Performed at Test Site) X
Urinalysis Variables X
Organ Weights X
Organ Weight relative to Body Weight X
Organ Weight relative to Brain Weight X
Ovarian Scoring (total number of oocytes per animal) X

Parametric/Non-Parametric
Levene’s test was used to assess the homogeneity of group variances.
The groups were compared using an overall one-way ANOVA F-te

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no test item related clinical signs on the study.
Clinical observations observed occurred at a low rate, didn’t follow a dose-related trend or
were of the type commonly observed in this species and were consequently considered
unrelated to administration of the test item.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no test item related deaths on the study.
There was one unscheduled death of a Control animal during the course of this study. Animal
1001M (F0 Generation receiving 0 ppm) was euthanised on Day 114 due to a persistent skin
scab/lession on the right dorsal thorax which correlated microscopically with marked
ulceration.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
F0 Generation animals

There were no test item related differences in body weight or body weight gain in the F0
Generation Males during any period of the study. A statistically significant effect in body
weight change (Day 1-134) in the intermediate group (4000/2000 ppm) of F0 Generation
males was considered artefactual as it did not follow a dose-related trend.
There was a small test item related effect on the F0 Generation females of the high dose
group between Day 1 to the mating period, where body weight gain was lower (-9.8%
compared with Control).
Statistically, a difference in body weight was seen during the gestation period and up to
Lactation Day 14 for females at 12,500/6250 ppm; however the differences were minor and
therefor considered not toxicologically relevant.
There were no effects in the F0 generation females at 4000/2000 ppm or 1000/500 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The initiation of dosing 12,500 ppm (Day 1-8) showed a significantly lower daily average
food consumption in both males (16.58 g compared with 19.26 g in the control) and females
(11.19 g compared with 13.22 g in the control). Following this, at 12,500/6250 ppm food
consumption in males and in female animals (including during gestation and lactation), was
lower than the control and (excluding lactation) frequently this difference was also
statistically significant.
In female animals prior to mating, there was evidence of a test item effect at 12500 ppm
where food consumption was lower than control. The difference was considered
toxicologically relevant as it frequently exceeded 2 grams and was statistically significant. At
4000/2000 ppm, there was no evidence of a toxicologically relevant effect during gestation or
during lactation.
At 4000/2000 ppm (males only) and 1000/500 ppm (males and females), there were no
toxicologically relevant differences in food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In F0 generation, lower levels of white blood cells (specifically lymphocytes, monocytes and
basophils) were found in male animals at 4000 ppm and 12,500 ppm. This difference
however was not seen in the male animals of Cohort 1A, therefore it was considered unlikely
to be attributable to the test item.
Differences in some parameters attained statistical significance, however they were either not
part of a dose-related trend and/or were minor and of insufficient magnitude to be considered
toxicologically relevant.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no effects on coagulation parameters following administration of the test item.
All clinical chemistry parameter of F0 where statistical significance was attained, were either
not part of a dose-related trend and/or were minor and of insufficient magnitude to be
considered toxicologically relevant.
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
Concentrations of T4 were higher in male F0 Generation animals than the concurrent control
at all dose levels, Cohort 1A (male and female) animals both had higher levels of T4 at
12,500/6250 ppm. In the F1 generation (Cohort 1A) however, the control level of T4 was higher in all groups, however an increase in T4 was also apparent slight trend, with higher T4 levels at higher test item concentrations (see tabel 29; T4 concentration).There were no differences in the concentration of T4 in female animals of the F0 Generation, the unselected F1 pups culled on PND 4 or the F2 generation females.
In F0 there were no evident test item related effects on TSH levels.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no relevant effects on urine analysis following administration of the test item.
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Test item-related microscopic findings were limited to the thyroid gland in males only.
Minimal follicular cell hypertrophy was observed in the thyroid gland of males at
12500 ppm. This correlated with the higher thyroid gland weights described above and higher
T4 levels. The low incidence of follicular cell hypertrophy at 1000 ppm and 4000 ppm was
considered insufficient evidence of a test item-related effect at these dietary concentrations.
Test item-related microscopic findings are summarised in Text Table 33.
The remaining microscopic findings observed were considered incidental, of the nature
commonly observed in this strain and age of rat, or occurred at a similar incidence in control
and treated animals,

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
There were no test item related changes to the estrous cycle of female animals in any group.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There were no test item related effects on sperm motility parameters (% Motile, %
Progressive motility and straight line velocity), morphological abnormalities, epididymal
sperm or testicular spermatid reserves, in either the F0 Generation or F1 (Cohort 1A) males.
Reproductive performance:
no effects observed
Description (incidence and severity):
Mating Performance, Fertility and Duration of Gestation

In both the F0 Generation and Cohort 1B animals, there were no test item related effects on
mating, fertility or pregnancy rates. Gestation length was normal in all dose groups.

Litter Survival and Survival Indices

In both the F0 Generation and Cohort 1B animals, there were no effects on litter survival,
with birth, live birth, viability (Day 0-4) and lactation (Day 4-21) indices similar over all
groups. Maternal and pup observations indicated there were no deficiencies in maternal care
at all doses tested.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 12 500 ppm (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: only adaptive and not adverse effects observed up to top dose
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
Reproductive NOAEL (F0 and F1): 12,500/6250 ppm
Key result
Dose descriptor:
NOAEL
Effect level:
>= 12 500 ppm (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: only adaptive and not adverse effects observed up to top dose
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
Parental toxicity (F0 and F1): 12,500/6250 ppm

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no test item related clinical signs on the study.
Clinical observations observed occurred at a low rate, didn’t follow a dose-related trend or
were of the type commonly observed in this species and were consequently considered
unrelated to administration of the test item.
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Cohort 1A
At the high dose level (12,500/6500 ppm) there were lower body weights in Cohort 1A. At
weaning, the animals in Cohort 1A fed diet containing test item at 12,500 ppm were
significantly lighter than control (Males -14.6% and Females -16.9%). Over time the
difference in weight between the these animals and control reduced. By nominal Week 6 of
age, the difference in females was not significant (-4.9% compared with control) and by
nominal Week 10 the males no longer showed a significant difference (-5.9% compared with
control). Between weaning and the start of necropsies, Cohort 1A male and female animals
showed no overall difference in body weight gain.
There were no effects at 4000/2000 ppm or 1000/500 ppm.
Cohort 1B
A similar effect to that seen in the Cohort 1 animals was observed in the Cohort 1B. Whilst in
males statistical significance was observed until the end of the dosing period, the relative
difference was considered minor (below 10% difference from nominal Week 7), however the
overall difference in body weight gain remained statistically significant, but minor (-7.7%
between Day 1 and 120 after weaning).
In female animals no effect was observed prior to mating. Over the period of gestation (GD0-
20) body weight gain was lower in animals in the high dose group (12,500 ppm), where
animals gained 89.9 g on average compared with 114.7 g in the Control (-21.6%). This
rebounded during lactation, where body weight gains were on average higher (19.4 g
compared with 10.1 g in the control). At the end of the lactation period the difference in
body weight was minimal at 12,500/6250 ppm (-4.69% compared with control).
There were no effects at 4000/2000 ppm or 1000/500 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Cohort 1A
At 12500 ppm the food consumption post weaning was lower than control. This was most
notable over the first 3 weeks where the difference was greater than 10% and was statistically
significant. Between the 4th week and necropsy, food consumption continued to be lower at
every collection point however the magnitude of the difference was lower (<3 g per animal
per day) and no longer statistically significant. No effect was seen at 4000 ppm or 1000 ppm.
A greater difference was observed in female animals at this dose level where all data points
showed lower food consumption that was >10% and statistically significant. Evidence of an
effect was also seen at 4000 ppm where food consumption was consistently lower than the
control, however the difference was more modest (typically between 5-10% and not
statistically significant).
No effect was seen in males at 4000 ppm or in male and females at 1000 ppm.
Cohort 1B
A food consumption pattern similar to Cohort 1A was observed, with male animals having
sustained lower food consumption at 12,500/6250 ppm for the whole dosing period (weaning
to necropsy). Female animals also had a lower food consumption from weaning at
12,500/6250 ppm, most notable at the end of gestation where food consumption was 23.3%
lower than the control. In female animals a more modestly lower food consumption was also
observed at 4000 ppm. In female animals during lactation, the difference in food
consumption was only toxicologically relevant at 6250 ppm.
No effect was seen in males at 4000 ppm or in male and females at 1000 ppm.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Differences in some parameters attained statistical significance, however they were either not
part of a dose-related trend and/or were minor and of insufficient magnitude to be considered
toxicologically relevant.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
In Cohort 1A the male animals only, there was a dose-related trend was observed in the bile
acids (1.53x, 1.98x and 2.54x control at 1000, 4000 and 12,500 ppm, respectively), however
there was no equivalent finding in the F0 generation.
In female animals in Cohort 1A there was a small increase in cholesterol at 4000 ppm (1.35X
control) and 12,500 ppm (1.45x control). There was no effect in the males of cohort 1A or the
females of the F0 generation. Therefore, this finding is considered to be incidental.
For all other parameters differences where statistical significance was attained, were either
not part of a dose-related trend and/or were minor and of insufficient magnitude to be
considered toxicologically relevant.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no relevant effects on urine analysis following administration of the test item.
Sexual maturation:
effects observed, non-treatment-related
Description (incidence and severity):
A delay in sexual maturity was evident in female animals at 12,500/6250 ppm in both
Cohort 1A (average 38.5 days compared to 32.3 days in the concurrent control) and
Cohort 1B (average of 37.7 days compared with 33.4 in the concurrent control).
Notwithstanding this, the number of days after vaginal opening that the first estrous was
detected was similar over all treatment groups.
Male animals at 12,500/6250 also showed a slightly longer time to reach sexual maturity,
(although the difference was smaller than in females). The difference was seen in Cohort 1A
(42.9 days vs 41.1 in the Control) and Cohort 1B (43.9 days vs 41.0 days in the Control).
These differences can be attributed to the decreased body weight development in the high
dose group. Mean body weight at the time of sexual maturity were comparable in males and
females and also within the historical control range of the rat strain used. See attached pdf for historical control data.
Anogenital distance (AGD):
no effects observed
Description (incidence and severity):
There were no test item effects on anogenital distance.
Nipple retention in male pups:
no effects observed
Description (incidence and severity):
There were no male pups with retained nipples on PND 13.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Cohort 1A - Test item-related Organ Weight Differences:
Test item-related organ weight differences were noted in the liver. Liver weights were higher
than controls at ≥ 4000 ppm in males and at 12500 ppm in females. See Table 31.
Mandibular lymph node weights were higher in females at 12500 ppm. Given that there was
no microscopic correlate and only females were affected, this was also considered to be
unrelated to the administration of the test item.
Other organ weight differences, including those with statistical significance, were also
considered not to be test item-related as they had no microscopic correlate and were often a
reflection of lower mean terminal body weights in the affected group.
Cohort 1B - Test item-related Organ Weight Differences:
There were no test item-related organ weight differences. Liver weights were higher than
controls at ≥ 1000 ppm in males and at 12500 ppm in females. See Table 32.
Other organ weight differences, including those with statistical significance, were also considered not to be test item-related because the organs had no microscopic correlate in F1 Cohort 1A animals and, for the most part, were considered to be a reflection of lower mean terminal body weight.
F1 Unselected Pups (PND 22-24)
There were no test item-related organ weight differences.
Spleen weight was lower than controls in females at 12500 ppm. These tissues were not examined microscopically. However, given that only one sex was affected and the lack of correlating microscopic findings in F0 and F1 Cohort 1A animals, this was considered not to be test item-related and was considered most likely a reflection of the lower mean terminal body weight in this group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item-related gross findings in the F0 Generation, F1 animals (Cohort 1A,
Cohort 1B or unselected pups on PND 22-24 used for thyroid hormone analysis) or the F2
pups (on PND 22).
All gross findings observed were considered incidental, of the nature commonly observed in
this strain and age of rat, or occurred at a similar incidence in control and treated animals,
and, therefore, were considered not to be related to the test item.
Histopathological findings:
no effects observed
Description (incidence and severity):
Cohort 1A: There were no test item-related microscopic findings.
Microscopic findings were considered incidental, of the nature commonly observed in this
strain and age of rat or occurred at a similar incidence in control and treated animals, and,
therefore, were considered not to be related to the administration of the test item.
F1 Unselected Pups (PND 22-24): Only the mammary gland was examined microscopically. There were no microscopic abnormalities evident in the tissue examined to support the presence of a test item-related effect.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Thyroxine (T4)
In the F1 generation (Cohort 1A) however, the control level of T4 was higher in all groups,
however an increase in T4 was also apparent trend, with higher T4 levels at higher test item
concentrations. There were no differences in the concentration of T4 in female animals of the F0 Generation, the unselected F1 pups culled on PND 4 or the F2 generation females. See Table 29 below
Thyroid Stimulating Hormone (TSH)
There were no evident test item related effects on TSH levels. It was noted that in Cohort 1A
males levels of TSH were notably higher in all groups, including control. There was no test
item effect however this elevation was similar to the higher levels of T4 observed in
Cohort 1A.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

The delayed sexual maturation in females pups of the F1 generation is considered to be a
consequence of delayed body weight development. The body weights at the time of sexual
maturity were within the historical control range. Nevertheless, this finding was a trigger for
a second mating, which showed that fertility parameters and maternal performance were
unaffected by test item as the Cohort 1B animals went on to produce normal litters. The
viability and survival of the F2 generation was also unaffected by the test item.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
4 000 ppm (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
sexual maturation
body weight and weight gain
food consumption and compound intake

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Overall, females in gestation and young animals (F1 and F2 pups) exposed to the test item in
the high dose group (12,500/6250 ppm) showed a lower body weight gain than control. This
effect was seen to be reversible over time. No relevant body weight differences were seen in
the intermediate (4000/2000 ppm) or low (1000/500 ppm) dose groups. Pups in both F1 (litters of the F0 Generation) and F2 (Cohort 1B litters) showed reduced preweaning
body weight gains at the high dose level (administered at 6250 ppm during lactation)
than the controls. The greatest effects were observed at the end of lactation (LD 21) where
the difference exceeded 10% as follows: see table 28
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
F2 Unselected Pups (PND 22)
There were no test item-related organ weight differences.
Compared to controls, there were differences in brain, spleen and thymus weight in males and
brain weight in females at 12500 ppm. These tissues were not examined microscopically.
However, they were considered not to be test item-related because there was no microscopic
correlate in other cohorts examined and, for the most part, were considered a reflection of
lower mean terminal body weight in this group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test item-related gross findings in the F0 Generation, F1 animals (Cohort 1A,
Cohort 1B or unselected pups on PND 22-24 used for thyroid hormone analysis) or the F2
pups (on PND 22).
Histopathological findings:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Thyroxine (T4)
In the F1 generation (Cohort 1A) however, the control level of T4 was higher in all groups,
however an increase in T4 was also apparent trend, with higher T4 levels at higher test item
concentrations. There were no differences in the concentration of T4 in female animals of the F0 Generation, the unselected F1 pups culled on PND 4 or the F2 generation females. See Table 29 below
Thyroid Stimulating Hormone (TSH)
There were no evident test item related effects on TSH levels. It was noted that in Cohort 1A
males levels of TSH were notably higher in all groups, including control. There was no test
item effect however this elevation was similar to the higher levels of T4 observed in
Cohort 1A.

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Details on results (F2)

The delayed sexual maturation in females pups of the F1 generation is considered to be a
consequence of delayed body weight development. The body weights at the time of sexual
maturity were within the historical control range. Nevertheless, this finding was a trigger for
a second mating, which showed that fertility parameters and maternal performance were
unaffected by test item as the Cohort 1B animals went on to produce normal litters. The
viability and survival of the F2 generation was also unaffected by the test item.

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Table 29
Thyroxine (T4) Concentrations (ng/mL)


























































Generation/Sex



Group 1
(0 ppm)



Group 2
(1000/500 ppm)



Group 3
(4000/2000 ppm)



Group 4
(12,500/6250 ppm)



F0 Generation – Males



39.86



51.30
(+29%)



47.08
(+18%)



54.35%
(+36%)



F1 Unselected – Males (PND 22-24)



33.44



32.12
(-4%)



34.46
(+3%)



41.90
(+25%)



F1 Surplus – Females (PND 21-24)



34.11



31.31
(-8%)



34.21
(0%)



40.02
(+17%)



Cohort 1A – Males



49.44



52.14
(+5%)



57.18
(+16%)



61.73
(+25%)



Cohort 1A – Female



34.70



36.64
(+6%)



37.61
(+8%)



41.64
(+20%)



F2 Generation – Males (PND 22)



31.94



33.45
(+5%)



34.13
(+7%)



43.09
(+35%)



 



Table 30
Summary Group Mean Organ Weight Data – Scheduled Euthanasia F0 Males












































































































































































Males



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



27



28



28



28



Gland, Thyroid


(No. weighed)



(27)



(28)



(28)



(28)



Absolute value (g)



0.02274



0.02366



0.02564



0.02720**



% of body weight



0.00516



0.00526



0.00564



0.00635**



% of brain weight



1.08740



1.11478



1.22262



1.28982**



Liver


(No. weighed)



(27)



(28)



(28)



(28)



Absolute value



12.8133



13.9206



14.7870**



15.0387**



% of body weight



2.89638



3.10046*



3.23424**



3.49326**



% of brain weight



612.20483



656.93197



704.97523**



713.01143**



Females



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



28



28



28



28



Gland, Thyroid


(No. weighed)



(28)



(28)



(28)



(28)



Absolute value (g)



0.02216



0.02136



0.02241



0.02263



% of body weight



0.00886



0.00843



0.00900



0.00941



% of brain weight



1.17154



1.11777



1.17373



1.20291



Liver


(No. weighed)



(28)



(28)



(28)



(28)



Absolute value



12.4046



12.9997



13.0981



14.2145**



% of body weight



4.93420



5.11378



5.26092



5.87962**



% of brain weight



653.95826



680.25642



686.43030



754.40465**



Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01


Table 33
Summary Test Item-related Microscopic Findings – Scheduled Euthanasia F0 Males















































 



Males



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals examined



27



28



28



28



Gland, Thyroid (No. Examined)



(27)



(28)



(28)



(28)



Hypertrophy, follicular cell, minimal



0



2



4



9



Table 31
Summary Group Mean Organ Weight Data – Scheduled Euthanasia F1 Cohort 1A




















































































































Males



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



20



20



20



20



Liver


(No. weighed)



(20)



(20)



(20)



(20)



Absolute value



13.5999



13.5419



14.5869



14.9228*



% of body weight



3.65022



3.67897



3.89964*



4.32421**



% of brain weight



666.66881



653.65769



710.89335



747.92891**



Females



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



20



20



20



20



Liver


(No. weighed)



(20)



(20)



(20)



(20)



Absolute value



8.1019



8.0103



8.2154



8.1057



% of body weight



3.90270



3.76515



3.99996



4.20932*



% of brain weight



430.71382



423.49596



436.18854



441.05572



Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01


 


Table 32
Summary Group Mean Organ Weight Data – Scheduled Euthanasia F1 Cohort 1B




















































































































Males



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



25



25



25



25



Liver


(No. weighed)



(25)



(25)



(25)



(25)



Absolute value



15.1339



15.9292



16.6796*



16.1066



% of body weight



3.33411



3.53799*



3.69083**



3.88985**



% of brain weight



725.86628



748.24734



789.19268



771.03969



Females



Group



1



2



3



4



Nominal Dietary Concentration (ppm)



0



1000



4000



12500



No. animals per group



25



25



25



25



Liver


(No. weighed)



(25)



(25)



(25)



(25)



Absolute value



14.1927



14.4609



14.3412



15.0251



% of body weight



5.15096



5.26507



5.22560



5.73997**



% of brain weight



736.76337



750.11143



744.52945



789.93815



Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Applicant's summary and conclusion

Conclusions:
Parental toxicity (F0 and F1): 12,500/6250 ppm (770,3 - 1148,1 mg/kg)
Reproductive NOAEL (F0 and F1): 12,500/6250 ppm (770,3 - 1148,1 mg/kg)
Post-Natal Developmental NOAEL: 4000/2000 ppm. (252,3 - 379,0 mg/kg)
Executive summary:

The objective of this study was to determine the potential toxicity of N, N‑Dimethyldecan‑1‑amide, when given by oral dietary administration to rats to assess the reproductive function in adult animals and their offspring according to OECD 443 (BASF SE 2021). This study was designed to provide an evaluation of the pre and postnatal effects of chemicals on development as well as a thorough evaluation of systemic toxicity in pregnant females, lactating females, young and adult offspring. Detailed examination of key developmental endpoints, such as offspring viability, neonatal health, developmental status at birth, and physical and functional development until adulthood, was expected to identify specific target organs in the offspring. In addition, the study provided information about the effects of the test item on the integrity and performance of the adult male and female reproductive systems.


The study design was as follows:


Text Table 1
Experimental Design – F0 Animals






























































Group No.



Treatment



Nominal Dietary Concentration (ppm)



Formulated Dietary Concentration (ppm)a



Number of Animals



Main Phase



Lactation Phaseb



Main Phase



Lactation Phaseb



M



F



1



Control



0



0



0



0



28



28



2



N-N-dimethyldecan-


1-amide



1000



500



1020



510



28



28



3



4000



2000



4080



2040



28



28



4



12500



6250



12750



6375



28



28



M=Males; F=Females


a Correction factor of 1.02 applied.
b During the lactation phase, as the maternal food consumption increased, the dietary concentration for females only was lowered by 50%.



Text Table 2
Experimental Design – F1 Animals Cohort 1A Post-weaning




























































Group No.



Treatment



Nominal Dietary Concentration (ppm)



Formulated Dietary Concentration (ppm)a



Number of Animals



M



F



1



Control



0



0



20



20



2



N-N-dimethyldecan-
1-amide



1000



1020



20



20



3



4000



4080



20



20



4



12500



12750



20



20



M=Males; F=Females


a Correction factor of 1.02 applied.



 


       

Text Table 3
Experimental Design – F1 Animals Cohort 1B Post-weaning (Reproductive)






























































Group No.



Treatment



Nominal Dietary Concentration (ppm)



Formulated Dietary Concentration (ppm)a



Number of Animals



Main Phase



Lactation Phaseb



Main Phase



Lactation Phaseb



M



F



1



Control



0



0



0



0



25



25



2



N-N-dimethyldecan-


1-amide



1000



500



1020



510



25



25



3



4000



2000



4080



2040



25



25



4



12500



6250



12750



6375



25



25



M=Males; F=Females


a Correction factor of 1.02 applied.


b During the lactation phase, as the maternal food consumption increased, the dietary concentration for females only was lowered by 50%.



The following parameters and end points were evaluated in this study:  clinical observations, body weights, food consumption, estrous cycles, estimated achieved doses, mating performance and fertility indices (F0 and Cohort 1B), duration of gestation and overall litter performance (F0 and Cohort 1B), F1 and F2 survival indices, litter and pup weights, pre- weaning physical development of F1 and F2 pups, assessments of sexual maturation of F1 animals (Cohorts 1A and 1B), clinical pathology parameters (haematology, coagulation, clinical chemistry and urinalysis [F0 and Cohort 1A]), thyroid stimulation hormone (TSH) and thyroxine (T4) analysis, gross necropsy findings, organ weights, immunophenotyping analysis (Cohort 1A), sperm evaluation (F0 and Cohort 1A males), ovarian follicle counts (Cohort 1A) and histopathological examinations.


Administration of the test item via the diet at 12,500/6250 ppm was associated with toxicity as evidenced by lower food consumption in males and females at 12,500/6250 ppm and in female animals only at 4000/2000 ppm. Effects on development were observed with a lower in body weight gain during lactation at the high dose group (6250 ppm).  In the high dose (12,500/6250 ppm) there was also evidence of a delayed sexual maturation in the F1 generation pups (Cohort 1A and Cohort 1B pups) average time to vaginal opening was 38.5 days compared to 32.3 days (Cohort 1A) and 37.7 days compared with 33.4 days (Cohort 1B). This delay is considered to be a consequence of delayed body weight development. The body weights at the time of sexual maturity were within the historical control range. The delay in vaginal opening did not adversely affect the time to the first estrous. Due to the delay in sexual maturation, mating of Cohort 1B animals and production of an F2 generation was triggered. This evaluation demonstrated that despite the delay in sexual maturation, there were no adverse changes on the fertility and maternal performance of the Cohort 1B animals, nor was the viability and survival of the F2 generation affected.


Adaptive changes in the form of follicular cell hypertrophy, were observed in the thyroids of rats following administration of the test item in the diet.


In conclusion, administration of N,N-Dimethyldecan-1-amide by diet was tolerated in male and female rats at doses up to 12,500/6250 ppm.  Toxicity was manifest through lower food consumption and lower body weight gains, including in the offspring of rats administered N,N‑Dimethyldecan-1-amide at 12,500/6250 ppm as well as delays in sexual maturation in female offspring as the consequence of lower body weights. However these delays in sexual maturation did not go on to affect the fertility or maternal performance of the animals.


The administration of N, N-dimethyldecan-1-amide was associated with effects on the thyroid gland of F0 Generation males only at 12,500 ppm, which was not considered to be adaptive and not adverse based on the minimal grade of severity and incidence.


Based on the results of this extended one generation reproductive toxicity study (Cohort 1), the following no-observed-adverse-effect level (NOAEL) of N,N-Dimethyldecan-1-amide were established:


Parental toxicity (F0 and F1):  12,500/6250 ppm
Reproductive NOAEL (F0 and F1):  12,500/6250 ppm
Post-Natal Developmental NOAEL:  4000/2000 ppm.

Categories Display