Registration Dossier

Administrative data

Description of key information

No studies were available to assess the toxicity after repeated oral exposure of N-[3 -(trimethoxysilyl)propyl]butylamine. Therefore, an OECD 408 study is progress in order to evaluate the toxicity after repeated oral exposure. In the meanwhile, repeated dose toxicity data from the closest structurally related substance N-(3(trimethoxysilyl) propyl)ethylenediamine (CAS 1760-24-3) has been used as an interim measure to conduct hazard and risk assessment for the registered substance.

A screening study (oral, similar to OECD TG 422) is available with the closest structurally related substance N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3).

Oral (similar to OECD TG 422, CAS 1760 -24 -3), rat: NOAEL ≥ 500 mg/kg bw

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached justification. This is an imterim justification until data on registered substance itself is available.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
nasal sounds/squeaky vocalisation in every dose group, but not in control animals
Mortality:
mortality observed, treatment-related
Description (incidence):
nasal sounds/squeaky vocalisation in every dose group, but not in control animals
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY:
One male in the 125 mg/kg bw/day dose group was found dead on study day 17 due to renal disease unrelated to treatment. There were two females in the reproductive groups that died due to dosing errors. All other animals survived to scheduled sacrifice. Clear perioral soiling was slightly more common in the high dose group. In the high dose groups there were increased nasal sounds, laboured breathing and/or soft squeaky vocalisation for one male and four toxicity and five reproductive group females. At 125 mg/kg bw/day, one toxicity group and one reproductive group female had increased nasal sounds. At 25 mg/kg bw/day, one toxicity group female exhibited soft squeaky vocalisation for three days of the study. The incidence of nasal sounds/squeaky vocalisation was noted in some animals and several times in others to a maximum of 18 days during the study. These findings were not observed in control rats.

BODY WEIGHT AND WEIGHT GAIN:
Mean body weights in males and females in the 25, 125 and 500 mg/kg bw/day groups were comparable to the control group values throughout the study; no statistically significant differences were noted. Reductions (not statistically significant) in weekly body weight gain were observed in the 25 and 125 mg/kg bw/day group males during week 4. These reductions were not considered to be test substance-related since the difference did not occur in a dose-dependent manner and no reductions were noted in female body weight gains during this time period.

FOOD CONSUMPTION:
There were no statistically significant differences in food consumption in any group throughout the study period.

HAEMATOLOGY:
There were no treatment-related effects on haematology parameters. However, in the toxicity group females there was a statistically-significant increase in platelet counts compared to controls. The counts for the treated groups were within published historical control ranges, whereas controls in the present study were somewhat below those ranges. No biological/toxicological significance is attributed to treatment.

CLINICAL CHEMISTRY: There were no treatment-related effects on clinical chemistry. However, in females, there was a statistically significant decrease in the chloride value (1.9%) in the high dose group, and a slight decrease (1.4%) in sodium in the middle and high dose groups. There was no dose-response. Sodium values for all female groups, including controls, were within or slightly below published historical control ranges. Chloride values for all groups were slightly above published control ranges. There were no associated clinical or morphological findings, so the findings were not thought to be biologically or toxicologically significant.

FOB:
Cage side observations: There were no treatment-related changes noted in unusual body movements, abnormal behaviour, posture or resistance to removal.
Handling observations: Palpebral closure, lacrimation, pupil size and reactivity, salivation, muscle tone, extensor thrust response and reactivity to handling were not affected by the treatment.
Open Field Observations: No differences were apparent between the control and treated groups in the open field observations.
Categorical Observations: No differences between control and treated groups when skin or hair coat, behaviour, respiration, muscle movements, eyes, urine or faeces, soiling, posture or general abnormalities were evaluated.
Measurements/counts: There was no effect on rectal temperature, hindlimb grip strength or landing foot splay assessments.
Motor activity: There were no effects on motor activity.

ORGAN WEIGHTS:
There were no treatment-related effects on organ weights. There was no dose-response associated with a statistically-significant small increase in relative prostate weight in the 25 mg/kg bw/day group.

GROSS PATHOLOGY:
There were no findings attributable to the test substance throughout the study period.

HISTOPATHOLOGY:
There were no treatment-related findings throughout the study period.
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant adverse effects were observed throughout the study period.
Critical effects observed:
not specified
Conclusions:
In an oral gavage study conducted similar to OECD 422 and to GLP the NOAEL for N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) relating to repeated dose (systemic) effects and to developmental toxicity was at least 500 mg/kg bw/day, as no significant adverse effects were observed up to the highest dose of 500 mg/kg bw/day tested in rats. The same effects are estimated for the target substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was conducted similar to an appropriate OECD test guideline, and in compliance with GLP.

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

No adequate repeated-dose toxicity data are available for N-[3 -(trimethoxysilyl)propyl]butylamine, therefore good quality oral data on the closest structrually related substance N-(3(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) has been used as an interim measure to conduct hazard and risk assessment for the registered substance.

According to ECHA decision number TPE-D-2114428714 -48-01/F, there is an ongoing sub-chronic repeated dose toxicity study with the registration substance.

 

Discussion of results:

Repeated dose toxicity: oral

In the available key study (Dow Corning Corpporation, 2002) N-(3-(trimethoxysilyl)propyl) ethylenediamine (CAS 1760-24-3) was tested for specific organ toxicity after subacute repeated exposure according to the OECD TG 422, and in compliance with GLP. 10 male and 10 female Sprague-Dawley rats per dose were daily administered the test material in corn oil via gavage for 28 and 29 consecutive days, respectively. The doses applied (25, 125, and 500 mg/kg bw/day) were based on a previous 7-day range-finding study, and concurrent control animals received the vehicle only. The animals were observed twice daily for morbidity, moribundity and mortality, and general clinical observations were made at least once per day, approximately one hour after dosing. Detailed clinical observations were recorded once before the first dosing and weekly thereafter. Moreover, body weights and food consumption were noted, and the functional obeservational battery was carried out prior to the start of dosing and during the fourth week of the treatment. Haematology analysis included haematocrit, haemoglobin, erythrocyte count, total and differential leucocyte count, platelet count and prothrombin time, mean cell volume (MCV), mean cell haemoglobin (MCH), and mean cell haemoglobin concentration (MCHC), and during clinical chemistry analysis total protein, albumin, glucose, cholesterol, total bilirubin, urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, phosphorous, sodium, potassium, and chloride were checked. Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera, and histopathology was carried out on adrenal glands, liver, stomach, aorta, lung, testes, lymph nodes, thymus, brain, thyroid, bone marrow, caecum, trachea, colon, peripheral nerve (sciatic n.), urinary bladder, duodenum, ovaries, uterus, epididymides, prostate, heart, seminal vesicles, ileum, jejunum, spinal cord, kidneys, spleen, and sternum. In addition, organ weights were determined. Except for nasal sounds and squeaky vocalisation, which was observed in every dose group, but not in control animals, no treatment related effects were observed in neither of the dosed animals. Hence, the NOAEL was set at ≥500 mg/kg bw for both male and female rats.

Justification for classification or non-classification

The available data is reliable and suitable for classification. Based on this data, classification for specific target organ toxicity according to EC/1272/2008 is not warranted.