Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-06-24 to 2013-04-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant study.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
(22 March 1996)
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3650 Guideline from the Office of Prevention, Pesticides and Toxic Substances, July 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V., NM Horst / The Netherlands
- Age at study initiation: 11 weeks old
- Weight at study initiation: Males: 288 to 334 g; Females: 183 to 219 g
- Fasting period before study: None
- Housing: In groups of three to four animals
- Diet: Pelleted standard Harlan Teklad 2018C (batch nos. 80/11 and 43/12) rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst/Switzerland) was available ad libitum.
- Water: Community tap-water from Füllinsdorf was available ad libitum in water bottles
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70%
- Air changes: Air-conditioned with 10 - 15 air changes per hour
- Photoperiod: 12-hour fluorescent light / 12-hour dark cycle

IN-LIFE DATES: From: 2012-07-26 To: Males: 2012-08-30 Females: 2012-09-11
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was weighed into a glass beaker on a tared precision balance and approximately 80% of the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous suspension was prepared. Having obtained a homogeneous mixture, the remaining vehicle was added. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Justification for use and choice of vehicle: Common non hazard vehicle
- Lot/batch no.: Batch 1: 499150899, Batch 2: 292189296
- Purity: No data
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Until evidence of copulation was observed
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 0.5 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 0.5 g of each concentration were taken from the middle to confirm the stability for 4 hours. Towards the end of the study, samples were taken from the middle to confirm concentration.The aliquots for analysis of dose formulations were
frozen (-20 ± 5 °C) and delivered on dry ice to Harlan Laboratories Ltd. (Zelgliweg 1, 4452 Itingen / Switzerland) and stored there at -20 ± 5 °C until analysis.The samples were analyzed by GC following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item was used as the analytical standard.
Duration of treatment / exposure:
Males: 28 days weeks
Females: Approximately 6 weeks
Frequency of treatment:
Once daily (within four hours)
Details on study schedule:
- Section schedule rationale: Study Sequence Females/ Males
Acclimatization: 7 days
First Test Item Administration: Day 1 of pre-pairing
Pre-Pairing: 14 days
Gestation (only females): Approximately 21 days
Treatment Ends: Females: On day 4 post partum; Males: On day before sacrifice
Necropsy: Females: On day 5 post partum (pups on day 4 post partum); Males: After treatment of 28 days, when no longer needed for assessment of reproductive effects

OTHER:
Towards the end of the treatment period neurobehavioural examinations were conducted and haematology as well as clinical chemistry parameters were assessed in selected animals from all dose groups (for details, please refer to section 7.5.1).
Remarks:
Doses / Concentrations:
0, 30, 75, 150 mg/kg bw7day
Basis:
actual ingested
No. of animals per sex per dose:
10 animals
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 14-day range-finding study (report number D55063) the dose levels of 30, 75, and 150 mg/kg bw/day were selected for the present study.
- Rationale for animal assignment: The rat is a suitable species for repeated dose and reproduction/developmental toxicity studies required by regulatory authorities. The oral route is one possible route for human exposure.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
Once daily, during acclimatization and up to the day of necropsy. Additionally females were observed for signs of difficult or prolonged parturition, and behavioral abnormalities in nesting and nursing.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once prior to the first administration of the test item (day 6 of acclimatization) and weekly thereafter (in the gestation period on day 0, 6, 13 and 20 post coitum), detailed clinical observations were performed outside the home cage in a standard arena. Animals were observed for the following: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies or bizarre behavior were also reported.

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded daily from treatment start to the day of necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Males: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 – 14, after pairing period days 1 - 2
Females: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; gestation days 0 – 7, 7 - 14 and 14 – 21 and days 1 - 4 of the lactation period.
Oestrous cyclicity (parental animals):
During the pre paring period, cages with males were interspersed amongst those holding females to promote the development of regular estrous cycles. The estrous cycle phase was determined at the histopathological examinations of the vagina.
Sperm parameters (parental animals):
Parameters examined in [all/P/F1] male parental generations:
Sperm stages in testes were checked on completeness of cell populations, completeness of stages and degenerative changes, testis weight, epididymides weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: All surviving pups were necropsied on day 4 postpartum.

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 post partum.

GROSS EXAMINATION OF DEAD PUPS:
Yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.

Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, after treatment of 28 days.
- Maternal animals: All surviving animals (on day 5 postpartum). Since in several females a birth did not occur on the expected date (day 21 post coitum), these dams were sacrificed on day 25 post coitum.

GROSS NECROPSY: Yes
All animals sacrificed were subjected to a detailed macroscopic examination. Specimens of abnormal tissue were fixed in neutral phosphate buffered 4% formaldehyde solution.
At the scheduled sacrifice, all animals were weighed and sacrificed by an injection of sodium pentobarbital. All parent generation animals were exsanguinated. Dead pups, except those excessively cannibalized, were examined macroscopically. All parent animals and pups were examined macroscopically for any structural changes, either at the scheduled necropsy or during the study if death occurred. For the parent animals, special attention was directed at the organs of the reproductive system. The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of apparently non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites.


HISTOPATHOLOGY: Yes
Testes, epididymides, prostate, seminal vesicles, ovaries, oviduct, vagina and uterus from all animals of the control and high-dose group were examined micro microscopically. The same applied to all occurring gross lesions. The remaining organs/tissues of 5 randomly selected males and females of the control and high-dose group, respectively, were examined histopathologically.
In addition, because of possible test item related findings that were noted during the initial histopathologic examination in animals of the high dose group, the stomach including forestomach and glandular stomach from 5 males and 5 females in each of the low and intermediate groups (groups 2 and 3, respectively) were additionally examined to establish a no-effect level. Special emphasis was made on the stages of spermatogenesis and histopathology of interstitial cell structure.
Histological examination of ovaries was carried out on the females that did not give birth.

ORGAN WEIGHT:
At the scheduled sacrifice, the testes and epididymides of all parental males were weighed separately. In addition, from 5 males and 5 females killed at the end of the study which were selected for hematology and clinical chemistry examination from each group, the following organs were
trimmed from any adherent tissue, as appropriate, and their wet weight taken.

Adrenal glands (weighed as pairs), Brain, Heart, Kidneys (weighed as pairs), Uterus (including cervix), Prostate, Liver, Thymus, Spleen, Thyroid (after fixation), Ovaries (weighed as pairs), Seminal vesicles (inclusive coagulating gland)

Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination)

GROSS NECROPSY
Pups were examined macroscopically for any structural changes, either at the scheduled necropsy or during the study if death occurred

HISTOPATHOLOGY / ORGAN WEIGTHS
No
Statistics:
The following statistical methods were used to analyze food consumption, body and organ weights, clinical laboratory and reproduction data and macroscopical findings:
• Means and standard deviations of various data were calculated.
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be dichotomized without loss of information.
PARENTAL ANIMALS
CLINICAL SIGNS AND MORTALITY

One female treated at 150 mg/kg bw/day was killed in extremis on day 21 of its gestation period. Upon microscopic examination, the irritant property of the test item was considered to be the cause of animal’s morbidity. There were no further unplanned deaths during the course of this study.

In females treated at 150 mg/kg bw/day, effects on breathing were noted. Slight breathing noises were noted during the last 1 or 2 days of the lactation period in two females. Also, slight breathing noises accompanied by gasping were noted in the female that was killed in extremis, on the day of sacrifice. These findings were considered to be test item-related. Furthermore, in one female treated at 150 mg/kg bw/day, slightly ruffled fur was noted on days 11 and 12 of the prepairing period. Thereafter, this animal was free from clinical signs until the end of the study.
Incidentally, in one female treated at 75 mg/kg bw/day, slight hair loss was noted towards the end of the prepairing period and the two first days of pairing. From day 3 of pairing onwards, this finding was no longer present. The remainder of females from this group was free from clinical signs.
No clinical signs were noted in males of all dose levels during the whole course of the study and in females up to the dose of 30 mg/kg bw/day.

No findings at detailed weekly clinical observation were noted in males and females at any dose level.


BODY WEIGHT

Body Weights of Males (Pre-pairing, Pairing and After Pairing Periods)
During the prepairing period, there was a slight, but statistically significant decrease in body weight gain in males treated at 150 mg/kg bw/day. No further statistically significant differences were noted thereafter and no effect on mean body weights was observed, therefore this effect at the beginning of treatment was considered not to be adverse. In males treated at 30 and 75 mg/kg bw/day, no effects of the test item were noted. The overall differences in mean body weight gain at the dose levels of 0, 30, 75 and 150 mg/kg bw/day were: +15%, +15%, +14% and +13% during the pre-pairing period and +6%, +7%, +6% and +7% during the pairing period and +1%, +1%, +1% and ±0% during the after pairing period, respectively (percentages refer to the body weight gain within the period).

Body Weights of Females (Pre-pairing, Pairing, Gestation and Lactation Periods)
No test item-related effects on mean body weight and mean body weight gain were noted. The overall differences in mean body weight gain at the dose levels of 0, 30, 75 and 150 mg/kg bw/day were: +8%, +8%, +10% and +8% during the pre-pairing period, +52%, +51%, +58% and +50% during the gestation period and +8%, +4%, +6% and +5% during the lactation period, respectively (percentages refer to the body weight gain within the period).


FOOD CONSUMPTION

Food Consumption of Males (Pre-Pairing and After-Pairing Period)
There were no statistically significant effects on mean food consumption at any dose level and in any study phase. However, in males treated at 150 mg/kg bw/day, there was a slight reduction in mean food consumption when compared with controls (-4.2% during prepairing and -3.4% during after pairing). Since mean body weight gain was statistically significantly decreased during the prepairing period, the slight reduction in mean food consumption was considered to be test item-related but not adverse.

Food Consumption of Females (Pre-pairing, Gestation and Lactation Periods)
There were no effects on mean food consumption at any dose level.


REPRODUCTIVE PERFORMANCE

Reproduction and Breeding Data
Mating Performance and Fertility
No effects on mating performance and fertility were observed at any dose level. All females were mated within the first pairing period. The median and mean precoital times were unaffected by treatment with the test item. Mean (median) precoital times calculated for the first pairing period were 3.5 (3), 2.7 (3), 2.3 (3) and 2.4 (1) days in order of ascending dose levels.
One female each at 0, 30 and 75 mg/kg bw/day was not pregnant. As a result the fertility index in those three groups was 90.9% and 100.0% at 150 mg/kg bw/day. No birth was recorded for one pregnant female at the dose level of 30 mg/kg bw/day (no. 61). At termination on day 25 post coitum, only one implantation site was found in this female.
Gestation index (number of females with living pups as a percentage of females pregnant) was 100% in the control group and at the dose level of 75 mg/kg bw/day, 80.0% at 30 mg/kg bw/day and 90.9% at 150 mg/kg bw/day.

Postnatal Loss Days 0 - 4 Post Partum
No effects on postnatal loss were observed at any dose level. One pup from each group died between days 0 and 4 post partum.


ORGAN WEIGHTS

In males and females no test item-related effects on organ weights were noted.
Absolute testis weights in males at 75 and 150 mg/kg bw/day were statistically significantly higher, confirmed by the values relative to body and brain weight. However, all absolute and relative testes weights were in the range of the historical control data (3.39 g – 3.92 g absolute testes weights, 0.92 % – 1.12 % relative to the body weight, 155.90 % – 193.13 % relative to brain weights). Testes weights from control animals were at the lower end of the historical control data range and the values of the dose group at the upper end. Due to these facts, and since no histopathological correlation was noted, the higher testes weights were considered to be a result of biological variability and not a test item-related effect.
Absolute thyroid weights and thyroid to brain weight ratios were statistically significantly lower in males at 150 mg/kg bw/day. Since this difference occurred in one sex only, and in the absence of histopathological changes, this was considered to be incidental. The same applies to the organ weights showing statistical significant changes only based on relative, but not on absolute weights, and in which no histopathological alterations were noted (brain, liver, epididymis).
No relevant effects on organ weights in females were noted at any dose level. The slightly increased values of relative (to body weight) adrenal weights were well in the range of the historical control data (0.031 g - 0.041 g). The lower relative (to brain) spleen weights noted at 150 mg/kg bw/day were borderline to the historical control data (32.25 % – 40.21 %). In the absence of histopathological findings and since no effects occurred in males, this finding was also considered to be incidental.


GROSS PATHOLOGY

In female no. 83 of the high dose group (150 mg/kg bw/day) that was killed in extremis during the treatment period, gray white and foamy abnormal contents in the stomach, bilateral pale discoloration of the kidney, reddish and pale discoloration of the liver surface, and fetus contents in both uterine horns were recorded. Gastric abnormal contents were considered to represent the stagnation of the dosing solution that arose from animal’s morbidity.
In the survivors, gross lesions attributable to treatment with the test item were recorded in the stomach (nodules, foci, crateriform retractions, discolorations) of three males and three females treated at 150 mg/kg bw/day.
All other gross lesions recorded in the survivors were within the range of normal background alterations which may be recorded in animals of this strain and age.


HISTOPATHOLOGY
Degenerative, necrotic, inflammatory and/or reactive changes were observed in the forestomach and/or glandular stomach of both sexes in all test item treatment groups (i.e. at 30, 75 and 150 mg/kg bw/day). They consisted of mucosal degeneration with or without pustules, ulcer, inflammatory cell infiltrate with or without edema, reactive squamous hyperplasia, and hyperkeratosis and/or parakeratosis with occasional dyskeratosis in the forestomach, and erosion with or without regenerated mucosa and/or increased inflammatory cell infiltrate in the glandular stomach. These histologic changes were considered to be treatment-related adverse effects which were attributable to the irritant property of the test item.
In the high dose female that was killed in extremis, mucosal degeneration as well as inflammatory cell infiltrate with edema, hyperkeratosis and reactive squamous hyperplasia were observed in the forestomach. These lesions that were attributable to the irritant property of the test item were considered to be the cause of animal’s morbidity. Tracheal mucosal abrasion was also recorded. However, this lesion was considered to be incidental, caused by the regurgitation of gastric contents, which occasionally happen in morbid animals. Furthermore tubular dilatation in the kidney and congestion of the liver were recorded in this animal, but these were also considered to be non-specific alterations which are often observed in morbid animals
No microscopic alteration that could be attributed to treatment with the test item was observed by detailed histopathologic evaluation of the testes.


Other:
Corpora Lutea Count
Mean number of corpora lutea per dam (determined at necropsy) was similar in all groups (14.2, 12.4, 14.8 and 13.2 in order of ascending dose level) and gave no indication of a test item-related effect.

Duration of Gestation
The mean duration of gestation was unaffected by exposure to the test item. Mean duration of gestation was 21.7, 22.2, 21.5 and 21.5 days, in order of ascending dose level.

Implantation Rate and Post-implantation Loss
No effects on implantation rate or post-implantation loss were observed at any dose level. The mean number of implantations per dam was 12.8, 10.8, 12.9 and 11.8 in order of ascending dose levels. The mean incidence of post-implantation loss as a percentage of total implantations was 5.5%, 19.6%, 4.7% and 10.2%, in order of ascending dose level. The high incidence of postimplantation loss in group 2 was mainly based on female nos. 59 and 66, which had together 23 implantations, but only 9 live pups. Due to the absence of a dose-dependency, this was considered to be not test item-related.
Post implantation loss was comparable in females treated at 75 and 150 mg/kg bw/day and well within the range of the historical control data.
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No reproductive effects were noted.
VIABILITY
No effects on litter size were observed at any dose level. Mean litter size at first litter check was 12.1, 8.7, 12.4 and 10.6 pups in order of ascending dose levels. One dead pup at first litter check was recorded in the control group as well as at 75 and 150 mg/kg bw/day. At 30 mg/kg bw/day, two pups from the same litter were dead at first litter check.

CLINICAL SIGNS
No test item-related findings were noted for pups during first litter check and lactation at any dose level.
In the control group, one pup showed wound on the neck and a second pup showed localized swelling of the right hindleg. These findings occurred in two different litters.
At 150 mg/kg bw/day, two female pups from the same litter were cold to the touch. However, all animals from this litter (a total of 13 pups) survived until day 4 post partum.

BODY WEIGHT
Mean pup weights on day 1 and 4 post partum were unaffected by treatment with the test item. On day 1 post partum mean pup weights were 6.1, 6.4, 6.2 and 6.0 g in order of ascending dose level. Also mean body weight gain was similar in all groups. On day 4 post partum no effects on mean body weights were observed.

SEXUAL MATURATION
Sex ratios at first litter check and on day 4 post partum were unaffected by exposure to the test item.
The proportion of males at first litter check was 45, 53, 54 and 42%, in order of ascending dose level.


GROSS PATHOLOGY (OFFSPRING)
No findings were noted at macroscopic examination of F1 pups at any dose level.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No developmental effects were noted.
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP and guideline compliant study.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test

The Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat was conducted according to the OECD guideline No. 422.

Benzylamine was administered by oral-gavage to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.

The following dose levels were applied:

Group 1: 0 mg/kg bw/day (control group)

Group 2: 30 mg/kg bw/day

Group 3: 75 mg/kg bw/day

Group 4: 150 mg/kg bw/day

A standard dose volume of 4 mL/kg bw with a daily adjustment to the actual body

weight was used. Control animals were dosed with the vehicle alone (corn oil).

The following results were obtained:

 

Parent Animals

General Tolerability

One female treated at 150 mg/kg bw/day was killed in extremis on day 21 post coitum due to gastric lesions deemed due to the irritant property of the test item. Test item-related clinical signs were limited to females treated at 150 mg/kg bw/day and mainly consisted of breathing noises at the end of lactation period.

 

Food Consumption and Body Weights

In males, slightly reduced mean food consumption and mean body weight gain was noted at 150 mg/kg bw/day during the pre-pairing period. This slight and transient reduction in mean body weight gain at the beginning of the treatment was considered not to be adverse. No test item-related effects on food consumption, body weights and body weight gain of females were observed at any dose level.

 

Clinical Laboratory Investigations

An increase in triglycerides reaching statistical significance in males and females at 150 mg/kg bw/day might be a secondary effect of the irritative potential of the test item in the stomach.

 

Reproduction and Breeding Data

Mean precoital time, fertility index and conception rate were not affected by the treatment with the test item. No effects on implantation loss or postnatal loss were observed.

 

Organ Weights

No relevant effects on organ weights were noted in any group.

 

Macroscopical Findings and Histopathological Examinations

Under the conditions of this study, the test item Benzylamine produced gastric lesions in both sexes of all test item treatment groups (30, 75 and 150 mg/kg bw/day) which were considered to be attributable to the irritant property of the test item. For the female, which was killed in extremis at 150 mg/kg bw/day, microscopically, mucosal degeneration as well as inflammatory cell infiltrate with edema, hyperkeratosis and reactive squamous hyperplasia were observed in the forestomach. These lesions that were attributable to the irritant property of the test item were considered to be the cause of animal’s morbidity. Also in the survivors, degenerative, necrotic, inflammatory and/or reactive changes were observed in the forestomach and/or glandular stomach of both sexes in all test item treatment groups (30, 75 and 150 mg/kg bw/day). They consisted of mucosal degeneration with or without pustules, ulcer, inflammatory cell infiltrate with or without edema, reactive squamous hyperplasia, and hyperkeratosis and/or parakeratosis with occasional dyskeratosis in the forestomach, and erosion with or without regenerated mucosa and/or increased inflammatory cell infiltrate in the glandular stomach. These histologic changes were considered to be treatment-related adverse events which were attributable to the irritant property of the test item.

 

Findings at First Litter Check and during Lactation

The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pup was noted at any dose level.

 

Pup Weights to Day 4 Post Partum

No effects on pup weight and pup weight gain were observed.

 

Macroscopical Findings

At necropsy of pups, there were no abnormal findings.

 

Conclusion

Based on the histopathological findings, a no-observed-adverse effect level (NOAEL) was not obtained under the condition of this study. It was considered that the NOAEL was below the 30 mg/kg bw/day in both sexes.

There were no adverse effects except the local lesions at the stomach, the site of administration. Therefore, the NOAEL for systemic toxicity was considered to be 150 mg/kg bw/day.

The NOAEL for reproduction/developmental toxicity was considered to be 150 mg/kg bw/day.


Short description of key information:
Via oral route: The NOAEL for reproduction/developmental toxicity was considered to be 150 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
GLP and guideline compliant study.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test

The Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in the Han Wistar Rat was conducted according to the OECD guideline No. 422. For details, please refer to section 7.8.1.

Justification for classification or non-classification

Based on the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test under relevant test conditions of the test substance Benzylamine, classification is not warranted according to the criteria of Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).