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Description of key information

Repeated dose oral: The NOAEL for systemic toxicity was considered to be 150 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
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.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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:

 

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.

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.

 

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 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.

 

 

14-Day Dose Range-Finding Study

 

The purpose of this study was to select suitable dosages to be used in the subsequent combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in the rat. Three groups of 4 males and 4 females were treated by oral gavage with Benzylamine once daily over a period of 14 days. A standard dose volume of 4 mL/kg bw with a daily adjustment to the actual body weight was used. Four male and four female control animals were dosed with the vehicle alone (corn oil).

The following dose levels were applied:

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

Group 2: 30 mg/kg bw/day

Group 3: 100 mg/kg bw/day

Group 4: 300 mg/kg bw/day

The third dose group with a dose level of 300 mg/kg bw/day was subsequently added, since no adverse effects were observed up to and including of a dose level of 100 mg/kg bw/day. As a consequence of test item-related mortality, severe clinical signs and effects on body weights, dosing of 300 mg/kg bw/day was stopped after two days of treatment.

 

The following results were obtained:

 

Mortality and General Tolerability

One male at 300 mg/kg bw/day was found dead on the third day of the treatment phase. Clinical signs consisted of decreased activity, salivation, ruffled fur, hunched posture, prostrate appearance and labored breathing after one day of application onwards. Males were more severely affected than females.

In males at 100 mg/kg bw/day, salivation was noted for maximally two consecutive days during the first five days of treatment.

 

Food Consumption and Body Weights

No test item-related effects on mean food consumption and mean body weight were noted in animals treated up to 100 mg/kg bw/day when compared with controls.

At 300 mg/kg bw/day, a statistically significant reduction in body weight/body weight gain was noted. No food consumption was measured due to the short dosing period of this dose group.

 

Clinical Laboratory Investigations

The assessment of hematology and clinical biochemistry data did not reveal any test item-related effects in males and females.

 

Organ Weights

Up to 100 mg/kg bw/day there were no effects on organ weights when compared to controls. Organs of animals treated at 300 mg/kg bw/day were not weighed.

 

Macroscopic Findings

There were no test item-related macroscopically visible findings.

 

Conclusion

Based on these observations, dose levels of 30, 75 and 150 mg/kg bw/day were selected for the subsequent Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat.

 

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP and guideline compliant study.

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). No target organ of systemic toxicity was identified.