Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
12-Oct-2004 to 06-Dec-2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study OECD 422, Screening test, GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted on 22 March 1996
Deviations:
no
Principles of method if other than guideline:
OECD combined study TG422:
Combined repeated dose toxicity study by the oral route (gavage) with the reproduction/development toxicity screening test. Three groups of 10 
male and 10 female Sprague-Dawley rats received the test item, Lauryl MA, by daily oral (gavage) administration for 15 days before mating, through 
mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 100, 300 and 1000 mg/kg/day. The
control group (10 males and 10 females) received the vehicle only (corn/oil). The dosing volume was 5 mL/kg. Clinical signs and mortality were 
checked daily. Body weight and food consumption were recorded at designated intervals throughout the study. Detailed clinical observations, 
reactivity to different stimuli (Functional Observation Battery; (FOB)) and motor activity were also recorded. Blood was taken from five males and five
females for hematological and blood biochemical investigations at terminal sacrifice (i.e. in week 6 for males and week 7 for females). At the same 
time, urine was collected from five males for analysis. Males were sacrificed approximately two weeks (week 6) after the end of the mating period, 
females on day 6 p.p. The animals were subjected to a  macroscopic examination of the principal thoracic and abdominal organs. Designated organs were weighed and examined microscopically. In addition,  the numbers of corpora lutea and implantation sites were recorded for each female. The 
pups were observed daily for clinical signs, sexed and  weighed on days 1 and 5 p.p.  After sacrifice on day 6 p.p., the pups were examined for gross  abnormalities.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Number: 88 rats (44 males and 44 females)
- Source: Sprague-Dawley, Crl CD® (SD) IGS BR, Caesarian Obtained, Barrier Sustained-Virus Antibody Free, (COBS-VAF®); Charles River Laboratories France, L’Arbresle, France.
- Age at study initiation: males were 8 weeks old and females were 10 weeks old
- Weight at study initiation: males: mean body weight of 317 g (range: 296 g to 345 g); females mean body weight of 223 g (range: 199 g to 261 g)
- Fasting period before study:
- Housing: The animals were individually housed (except during mating) in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metallic tray
containing autoclaved sawdust (SISCA, Alfortville, France) was placed under these cages. During mating, gestation and lactation, the
animals were housed in polycarbonate cages (43.0 x 21.5 x 20.0 cm) containing autoclaved sawdust (SICSA, Alfortville, France), with wood shaving as nesting material.
- Diet: ad libitum (SNIFF R/M-H pelleted maintenance diet, batch No. 2764132 (SNIFF Spezialdiäten GmbH, Soest, Germany) distributed weekly)
- Water: ad libitum (tap water (filtered with a 0.22 μm filter)
- Acclimation period: 7 days before the beginning of the treatment period
- Allocation to group: during the acclimation period, the required number  of animals were selected according to body weight and/or clinical 
condition and allocated by sex to the groups, using a stratification procedure based on body weight (these data are not 
presented in the report). Body weights of the animals assigned to the study at the start of the  treatment period were within 
20% of the mean weight for each sex. Identification: each animal was individually identified by an ear tattoo detailing a unique 
CIT identity number.
- Contaminant analyses: The batches of diet and sawdust were analyzed by the suppliers for composition and contaminant levels. Bacterial and 
chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible  contaminants 
(sawdust: pesticides and heavy metals; diet and water:  pesticides, heavy metals and nitrosamines). No contaminants were present in the diet, drinking water or sawdust at  levels which could be expected to interfere with or prejudice the outcome  of the study. A copy of the appropriate analyses was maintained with the study records.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20 %
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
.PREPARATION OF DOSING SOLUTIONS: The test item dosage formulations were prepared by suspending Lauryl Methacrylate (Lauryl MA; 
CAS: 142-90-5) in corn oil to achieve the concentrations of 20, 60 and 200 mg/mL and were stored at 
+4°C, protected  from light, for up to 9 days prior to use.
- Administration: The dosage formulations were administered by gavage using a plastic syringe fitted with a metal gavage tube (length of gavage 
tube: 7.6 cm),  once a day, at approximately the same time. The quantity of dosage formulation administered to each animal was 
adjusted according to the  most recently recorded body weight with the exception that body weights on day 14 post-coitum were 
used to calculate individual dosages for the  pregnant females from day 14 post-coitum through parturition (day 1 post-partum) to  avoid overdosing the dams because weight gain from GD 14 to 20 (GD: gestation day) is fetal weight. A constant dosage-volume of  5 mL/kg/day was used. Control animals (group 1) received the vehicle alone. The dosage formulations were stirred  continuously 
throughout the dosing procedure.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Lot/batch no. (if required): 122K0131 and 103K0107, supplied by Sigma (Saint-Quentin-Fallavier, France)
- Purity: no data, commercial product
Details on mating procedure:
- M/F ratio per cage: Mating was monogamous (one male to one female).
- Length of cohabitation: maximum of 14 days
- Proof of pregnancy: The presence of a vaginal plug or sperm in the vaginal smear was taken as positive identification of mating, upon which vaginal smearing ceased.
The day of confirmed mating was designated day 0 post-coitum (p.c.).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity
The results of the analyses demonstrated the homogeneity of each dosage formulation analyzed (5 and 300 mg/mL) just after preparation
(protected from light). Furthermore, there was a satisfactory correspondence between the nominal and the measured concentrations of the test
item in the vehicle.
Stability
The results of the analyses demonstrated the satisfactory stability of the two dosage formulations investigated (5 and 300 mg/mL) over a 9-day
period at +4°C (protected from light).
Concentration
A satisfactory agreement was observed between the nominal and actual concentrations of the test item in the dosage formulations analyzed since
the deviations from nominal concentration were in an acceptable range of ± 10%.
Duration of treatment / exposure:
Each animal was given the appropriate dosage formulation once a day, at approximately the same time each day, 7 days a week, according to the
following schedule:
in the males:
- 15 days before mating, during the mating and post-mating periods until sacrifice (approximately 6 weeks in total),
in the females:
- 15 days before mating,
- during the mating period,
- during pregnancy and lactation, until day 5 post-partum inclusive (or until sacrifice, for un-mated females).
Day 1 corresponds to the first day of the treatment period.
Frequency of treatment:
daily, 7 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle alone), 100, 300 and 1000 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
10; 10 male and 10 female per dose group
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The oral route was selected as it is a possible route of exposure of the test item in man. The dose levels of 100, 300
and 1000 mg/kg/day were defined on the basis of the 14 day oral toxicity range finding study.
Positive control:
No positive control.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

MORBIDITY AND MORTALITY:
- Time schedule: Each animal was checked at least twice a day for mortality and signs of morbidity (except during the acclimation period when they
were checked at least once a day).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was observed at least once a day at approximately the same time (i.e. after dosing the animals in the morning), for the
recording of clinical signs. Animals were also observed in the afternoon as part of the mortality check and any clinical signs were recorded.

All animals of each group were observed in the cage, in the hand and in the standard arena, by observers unaware of the animal's treatment, before
the first day of treatment and then once a week thereafter.
The animals were randomized in order to ensure "blind" evaluation, except for examination performed before the first day of treatment.
The following parameters were assessed:
- "touch escape" or ease of removal from the cage,
- in the hand: fur appearance, chromodacryorrhea, chromorhinorrhea, salivation, lachrymation, piloerection, eye, exophthalmia, mucous
membrane, reactivity to handling, pupil size (presence of myosis or mydriasis),
- in the standard arena (two-minute recording): grooming, palpebral closure, defecation and urination counts, tremors, twitches, convulsions,
gait, arousal (hypo- and hyper-activity), posture, stereotypy behaviour and breathing, ataxia, hypotonia.

Reactivity to manipulation or to different stimuli (FOB):
In five males and five females per group, the examinations listed below were conducted shortly before terminal sacrifice, and before blood
sampling for clinical pathology. The observer performing the evaluation was not aware of the treatment group of the animal. The animals were
randomly selected in order to ensure "blind" evaluation.
The following measurements, reflexes and responses were recorded:
. touch response,
. forelimb grip strength qualitative approach,
. pupil reflex,
. visual stimulus,
. auditory startle reflex,
. tail pinch response,
. landing foot splay,
. righting reflex,
. at the end of observation: rectal temperature.

Motor activity
Motor activity was measured in five males and five females using automated infra-red sensor equipment, recording individual animal activity over a
one-hour period. The females were evaluated on or near day 17 post-coitum to avoid removal of the dam from her pups after parturition and the
males were evaluated at approximately the same time as the females and near the time of sacrifice.


BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded on the first day of treatment (day 1), then once a week until sacrifice.
The body weight of each female was recorded on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7,
14 and 20 post-coitum and days 1 and 5 post-partum.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption/Compound intake: Yes
The quantity of food consumed by each animal was recorded once a week, over a 7-day period, from the first day of treatment through gestation
(days 0-7, 7-10, 10-14, 14-17 and 17-20 post-coitum intervals) and lactation (days 1-5 post-partum interval). During the mating period, the food
consumption was not recorded for males or females. Food intake per animal and per day was calculated by noting the difference between the food
given and that remaining in the food-hopper at the end of the specified interval.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: Lithium heparin tubes: Sodium (Na+), Potassium (K+), Chloride (Cl-), Calcium (Ca++), Inorganic phosphorus (I.PHOS),
Glucose (GLUC), Urea (UREA), Creatinine (CREAT), Total bilirubin (TOT.BIL), Total proteins (PROT), Albumin (ALB), Albumin/globulin ratio (A/G),
Total cholesterol (CHOL), Triglycerides (TRIG), Alkaline phosphatase (ALP), Aspartate aminotransferase (ASAT), Alanine aminotransferase (ALAT),
Tubes without anticoagulant: Biles acids (BIL.AC)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: 10; five males and five females (adults) from each group at terminal sacrifice
- Parameters checked: EDTA tubes: Erythrocytes (RBC), Hemoglobin (HB), Mean cell volume (MCV), Packed cell volume (PCV), Mean cell hemoglobin
concentration (MCHC), Mean cell hemoglobin (MCH) Thrombocytes (PLAT), Leucocytes (WBC), Differential white cell count with cell morphology
. neutrophils (N)
. eosinophils (E)
. basophils (B)
. lymphocytes (L)
. monocytes (M)
Sodium citrate tubes: Prothrombin time (PT), Activated partial thromboplastin time (APTT), Fibrinogen (FIB)


URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- How many animals: 5; first surviving five males (adults) from each group at terminal sacrifice
- Parameters checked: Quantitative parameters: Volume (VOLUME), pH (pH), Specific gravity (SP.GRAV)
Semi-quantitative parameters: Proteins (PROT), Glucose (GLUC), Ketones (CETO), Bilirubin (BILI), Nitrites (NITR), Blood (BLOOD), Urobilinogen (UROB)
Cytology of sediment Microscopic:
. Leucocytes (WBC)
. Erythrocytes (RBC)
. Cylinders (CYLIN)
. Magnesium ammonium phosphate crystals (AMM.PH)
. Calcium phosphate crystals (CAL.PH)
. Calcium oxalate crystals (CAL.OX.)
. Cells (CELLS)
Qualitative parameters: Appearance (APP), Color (COLOR)


NEUROBEHAVIOURAL EXAMINATION: No
Sperm parameters (parental animals):
Parameters examined in male parental generation:
Testes and epididymides were weighed for all males.
Special emphasis was paid to the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. In
particular, the evaluation identified treatment-related effects such as retained spermatids, missing germ cell layers or types, multinucleated giant
cells or sloughing of spermatogenic cells into the lumen. Examination of the intact epididymis included the head, corpus, and tail, which was
accomplished by evaluation of a longitudinal section. The epididymis was evaluated for leukocyte infiltration, change in prevalence of cell types,
aberrant cell types, and phagocytosis of sperm. PAS and hematoxylin staining were used for examination of the male reproductive organs.
Histopathological examination of the ovary included detection of any relevant changes in the follicular development, follicular atresia and corpora
lutea formation.
Peer review was performed for at least 10% of histological slides of control and high-dose groups in each sex and on all slides from identified target
organs.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
Litter size
The total litter size and numbers of pups of each sex were recorded as soon as possible after birth.
The litters were observed daily in order to note the number of live, dead and cannibalized pups. A detailed external examination of live pups was
performed on days 1 and 5.
Clinical signs
The pups were observed daily for clinical signs or abnormal behaviour.
Body weight
The weight of each pup was recorded on days 1 and 5 post-partum.
Postmortem examinations (parental animals):
SACRIFICE
Adults
On completion of the treatment period, after at least 14 hours fasting (parents only), all animals were asphyxiated by carbon dioxide and sacrificed by exsanguination.
The males were sacrificed approximately 2 weeks after the end of the mating period (total treatment period was approximately 6 weeks).
The females and their pups were sacrificed on day 6 post-partum. The female showing no evidence of mating was sacrificed 24-26 days after the last day of the mating period.

A complete macroscopic post-mortem examination was performed on all parent study animals. This included examination of the external surfaces,
all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their
associated organs and tissues and the neck with its associated organs and tissues.
The ovaries and uterus of the parent females were examined to determine:
. number of corpora lutea,
. number of implantation sites.
In apparently non-pregnant or un-mated females, the presence of implantation scars on the uterus was checked using an ammonium sulphide
staining technique.
In addition, for any female that was pregnant but did not deliver, the implantation sites were recorded according to the following classification:
. uterine scar: uterine implantation without implant,
. early resorption: evidence of implant without recognizable embryo,
. late resorption: dead embryo or fetus with external degenerative changes,
. dead fetus: non live fetus with discernible digits.


Tissues fixed and preserved
From at least 5 male and female animals per group the following tissues listed below were fixed and preserved in 10% buffered formalin
(except testes and epididymides which were fixed in Bouin's solution) of the control and high-dose groups sacrificed at the end of the treatment
period. Furthermore a microscopic examination was performed on all macroscopic lesions of all the animals of the low- and intermediate-dose
groups sacrificed on completion of the treatment period.
Macroscopic lesions
Adrenal glands Ovaries
Brain Prostate
Caecum Rectumall macroscopic lesions
Colon Sciatic nerve
Duodenum Seminal vesicles (with coagulating glands)
Epidiymides Spinal cord (cervical, thoracic and lumbar)
Heart Spleen, Sternum with bone marrow
Ileum Stomach with forestomach
Jejunum Testes
Kidneys Thymus
Liver Thyroids with parathyroids
Lungs with bronchi Trachea
Lymph nodes (mandibular and mesenteric) Urinary bladder
Uterus (horns and cervix)

Histopathological examination
All tissues required for microscopic examination were embedded in paraffin wax, sectioned at a thickness of approximately four microns and stained with hematoxylin-eosin (except testes and epididymides which were stained with hematoxylin/PAS). A longitudinal section of epididymides was
carried out, including the head, the corpus and the tail parts.
This tissue processing was performed at Histotox under the responsibility of CIT.
Postmortem examinations (offspring):
SACRIFICE
- The pups were sacrificed by subcutaneous injection of Thiopental sodium. Moribund pups were sacrificed in the same manner.The F1 offspring
were sacrificed at 6 days of age.

GROSS NECROPSY
- Pups found dead or sacrificed on day 6 post-partum were carefully examined externally for gross abnormalities through a macroscopic visceral
examination.
Statistics:
Standard deviations will be calculated as appropriate. For contiunous the significance of the differences amongst group means will be assessed by
analysis of variance. Differences between each treated group and the control group will be assessed by Dunnett's test using a pooled error
variance. The homogeneity of the data was verified by Bartlett's Test before Dunnett's Test was performed. If the data were found to be
inhomogeneous, a modified T Test (Cochran and Cox) was applied. The non-parametric Kruskal-Wallis analysis of variance was used for litter and sex ratios data. Intergoup differences between the control and treated groups were assessed by the non-parametric version of the Williams test.
The criterion for statistical sigificance was p<0.05. The mean values, standard deviations and statistical analysis were calculated from actual
values in the computer without rounding off.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Other than hypersalivation (ptyalism), all signs at 300 and 1000 mg/kg/day for males and females were observed during the first week of the
premating dosing period only. Hypersalivation, seen shortly after dosing, was observed in a number of males and females receiving 300 or
1000 mg/kg/day in a dosage-related manner (based on incidence) starting in week 2 of dosing. As dosing continued through gestation and lactation the number of females exhibiting hypersalivation decreased. Hypersalivation was considered to be a reaction of the animals to the dosing procedure and not a toxic response of Lauryl methacrylate. This conclusion is supported by the lack of similar and/or related findings at time periods other than just following dosing. Incidences of chromodacryorrhea, piloerection and loud breathing were sporadic and not dose-related.
A mass was observed on a right mammary gland of female G20493 (100 mg/kg/day) from day 19 post-coitum until necropsy. Based on the age of
the animal, the single incidence, the lack of dose response and the duration of dosing, a relationship to treatment was excluded.

Motor activity
There were no differences in the measured motor activity (horizontal and rearing movements) which could be attributed to treatment with the test
item.

Detailed clinical observations and reactivity to manipulation or different stimuli (FOB)
There was no evidence of disturbance of either autonomal or physiological functions at any dose-level.

Mortality
There were no premature deaths during the study.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The body weight loss between days 29 and 36 for the males in all groups is the result of the 14-hour fasting procedure (for blood collection) prior to the final weight collection on day 36. Females given 1000 mg/kg/day gained 18% less weight than the controls between day 0 and day 7 post-coitum. This variation was not considered to represent an adverse effect since the differences from controls were not statistically significant, were only
observed for the 0-7 interval, and were of minor amplitude. No other treatment-related effects on body weight were noted.

Food consumption
Males
The food consumption of treated males was similar to that of the controls during the study.
Females
There was no effect of treatment on group mean food consumption during the premating or lactation periods. Between day 7 and day 10 post-
coitum, all groups given Lauryl MA consumed less food than the controls, with no dose-relationship trend, achieving statistical significance at 100
and 1000 mg/kg/day (-17%, p<0.05 and -25%, p<0.001, respectively). Due to the lack of dose response and lack of consistency with other time
periods in the study, these differences in food consumption were not considered of toxicological importance.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no effect of treatment on mating at any dose-level.
The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg/day, were pregnant with live
fetuses.
The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of
liveborn pups or on pup death after birth.
There were no gross external abnormalities in the control or test item-treated groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
There were no treatment-related effects on absolute or relative organ weights in any dose groups.

MACROSCOPIC OBSERVATIONS (PARENTAL ANIMALS)
Reproductive organs
Microscopic examination of the testes No treatment-related abnormalities were found in Lauryl MA the treated animals. The tailed and round
spermatids were unaffected and the different stages of spermatogenic cycle were undisturbed by the treatment with the test item.
Sloughing of spermatogenic cells into tubular lumen and vacuoles in seminiferous tubules were noted with minimal severity and equal incidence in
control and test item treated animals. These findings are commonly recorded as spontaneous changes in the rat and were considered to be of
no toxicological importance. Moreover, minimal degeneration of seminiferous tubules was noted in one male given 1000 mg/kg/day. As this finding
can be found in the untreated rat with similar incidence and severity, it was considered of no toxicological importance.

Microscopic examination of the ovaries and uterus
The microscopic examination of the ovaries and uterus did not reveal any treatment-related effects on these organs. The microscopic changes
noted in both control and test item-treated animals correlated well with their status (post-partum).

Other organs and tissues
No treatment-related microscopic findings were noted at the end of treatment in the organs which were examined microscopically.
All microscopic findings reported were those which commonly occur in the rat of this strain and age and were considered to be of no toxicological
importance.

Palpable mass
The palpable mass in one female given 100 mg/kg/day was found to be a ductular carcinoma. Taking into consideration the length of the present
study (12 weeks) and as this neoplastic finding can be found in the young, untreated rat of this strain and age (Attia et. al., 1994; Oishi Y et al. 1995)
as well as the single occurrence in the low dose group, the carcinoma was considered to be unrelated to test article treatment.
No treatment-related findings were observed at necropsy. A palpable mass was found in mammary gland area of one female given 100 mg/kg/day
(see microscopic examination for the toxicological importance). All necropsy findings reported at the end of treatment period were those which
commonly occur in the rat of this strain and age kept under laboratory condition and were considered to be of no toxicological importance.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)


CLINICAL SIGNS (OFFSPRING)
Coldness to the touch was noted in seven pups (one litter) in the control group and four pups (three litters) at 1000 mg/kg/day. This sign was
considered not to be related to treatment since it was observed at a greater incidence in the control group.
The other clinical signs (anouria in one pup from the control group, necrosed forelimb in one pup from the 300 mg/kg/day group) were considered not to be treatment-related as they were isolated findings.

BODY WEIGHT (OFFSPRING)
There was no effect of treatment on mean pup body weight or body weight gain for males or females.

SEX RATIO (OFFSPRING)
The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups, and close to a theoretical value of 50%.
GROSS PATHOLOGY (OFFSPRING)
No relevant findings were observed in the pups sacrificed on day 6 post-partum or in the pups found dead.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the basis of the results the NOEL(reproduction/developmental) was considered to be >= 1000 mg/kg bw/day in males and females.
Executive summary:

Three groups of 10 male and 10 female Sprague-Dawley rats received the test item, Lauryl MA, by daily oral (gavage) administration for 15 days before mating, through mating, gestation and the beginning of the lactation period (until day 5 post-partum, p.p.). The dose-levels were 100, 300 and 1000 mg/kg/day. Another group of 10 males and 10 females received the vehicle, corn oil, alone, under the same experimental conditions and served as a control group. The dosing volume was 5 mL/kg. Clinical signs and mortality were checked daily. Body weight and food consumption were recorded at designated intervals throughout the study. Detailed clinical observations, reactivity to different stimuli (Functional Observation Battery; (FOB)) and motor activity were also recorded. Blood was taken from five males and five females for hematological and blood biochemical investigations at terminal sacrifice (i.e. in week 6 for males and week 7 for females). At the same time, urine was collected from five males for analysis. Males were sacrificed approximately two weeks (week 6) after the end of the mating period, females on day 6 p.p. The animals were subjected to a macroscopic examination of the principal thoracic and abdominal organs. Designated organs were weighed and examined microscopically. In addition, the numbers of corpora lutea and implantation sites were recorded for each female. The pups were observed daily for clinical signs, sexed and weighed on days 1 and 5 p.p. After sacrifice on day 6 p.p., the pups were examined for gross abnormalities.

At 1000 mg/kg/day, hypersalivation was recorded in males and females, lower body weight gain was recorded in females during the GD 0-7 interval and increased plasma glucose concentrations were recorded in males.

At 300 mg/kg/day, a few animals had hypersalivation.

At 100 mg/kg/day, no treatment-related effects were detected.

Hypersalivation was not considered to be a sign of toxicity to Lauryl MA. There were no substance-induced effects on the male and female reproductive performance, nor on the progeny of the parental rats at any dose-level.

There were no treatment-related findings at histopathological examination.

There was no effect of treatment on mating at any dose-level. The male and female fertility indices were unaffected by treatment; all mated females, except one given 1000 mg/kg/day, were pregnant with live fetuses. The duration of gestation was similar between the control and test item-treated groups. There was no effect of treatment on the mean number of liveborn pups or on pup death after birth. There were no external pup abnormalities in the control or test item-treated groups.

There was no effect of treatment on mean pup body weight or body weight gain for males or females. The sex ratios on days 1 and 5 post-partum were similar in the control and test item-treated groups. No relevant findings were observed in the pups sacrificed on day 6 post-partum.

On the basis of these results the NOEL(reproduction/developmental) was considered to be >= 1000 mg/kg bw/day in males and females.

This study is acceptable and satisfies the guideline requirement for a screening reproductive study (OECD 422) in rats.

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