Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no measured data available to assess the reproductive toxicity potential of N-[3-(trimethoxysilyl)propyl]butylamine (CAS 31024 -56 -3), however, data are available on the closest structurally related substance N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3).

The following data are used as an interim approach for hazard and risk assessment of the registerd substance until reliable data has been generated on the registered substance itself.

Oral: Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422, CAS 1760 -24 -3), rat: NOAEL (parental)≥ 500 mg/kg bw; NOAEL (offspring)≥500 mg/kg bw

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
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
Frequency of treatment:
Daily (7 days/week)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
nasal sounds/squeaky vocalisation in every dose group, but not in controle animals
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:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
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.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS):
No adverse effects were detected throughout the study period.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
No adverse effects were detected 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 on parent animals.
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
VIABILITY (OFFSPRING):
No adverse findings were observed throughout the study.

CLINICAL SIGNS (OFFSPRING):
No adverse findings were observed throughout the study.

BODY WEIGHT (OFFSPRING):
No adverse findings were observed throughout the study.

GROSS PATHOLOGY (OFFSPRING):
No adverse findings were observed throughout the study.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects on offspring were observed.
Reproductive 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 relating to repeated dose (parental systemic) effects and to reproductive 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. Thus, the same effects are estimated for the target substance.
Effect on fertility: via oral route
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 according to an appropriate OECD test guideline, and in compliance with GLP.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

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

 

Discussion of results:

Oral exposure:

In the available key study (Dow Corning Corpporation, 2002) N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) was tested for toxicity to reproduction according to the OECD TG 422, and in compliance with GLP. Sprague-Dawley rats were daily administered the test material in corn oil via gavage, whereas males received the test item for 28 consecutive days, and the females 39-44 days (2 weeks prior to mating, throughout mating and pregnancy until day 3 postpartum). 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. During mating procedure the animals were cohoused in 1:1 (m/f) ratios until evidence of copulation occurred or up to 2 weeks. No further matings after unsuccessfull attempt was carried out, and the non-pregnant females were sacrificed 21 days post mating. The ovaries and uterine content examination after termination included the number of corpora lutea and the number of implantations. Litter observations included number and sex of pups, stillbirths, live births, runts, presence of gross anomalies, weight gain, and physical or behavioural abnormalities. Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. No histopathology was conducted. No significant adverse systemic effects in maternal animals were observed throughout the study period. Hence, the NOAEL for maternal toxicity was set at ≥ 500 mg/kg bw.

 

Effects on developmental toxicity

Description of key information

According to ECHA decision number TPE-D-2114428714 -48-01/F, there is an ongoing pre-natal developmental toxicity study with the registration substance, conducted according to OECD TG 414 and in compliance with GLP. The study will be submitted as soon as possible once the final report is available. In the meanwhile, 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.

Oral: Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD 422), rat: NOAEL (maternal)≥ 500 mg/kg bw; NOAEL (developmental)≥ 500 mg/kg bw.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No significant adverse systemic effects in maternal animals were observed throughout the study period.
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No abnormal behaviour or effects, including teratogenic, were observed in the offspring throught 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 effects observed
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No developmental toxicity properties are estimated for the source as well for the target substance.
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

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

In the available key study (Dow Corning Corpporation, 2002) N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) was tested for toxicity to reproduction according to the OECD TG 422, and in compliance with GLP. Sprague-Dawley rats were daily administered the test material in corn oil via gavage, whereas males received the test item for 28 consecutive days, and the females 39-44 days (2 weeks prior to mating, throughout mating and pregnancy until day 3 postpartum). 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. During mating procedure the animals were cohoused in 1:1 (m/f) ratios until evidence of copulation occurred or up to 2 weeks. No further matings after unsuccessfull attempt was carried out, and the non-pregnant females were sacrificed 21 days post mating. The ovaries and uterine content examination after termination included the number of corpora lutea and the number of implantations. Litter observations included number and sex of pups, stillbirths, live births, runts, presence of gross anomalies, weight gain, and physical or behavioural abnormalities. Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. No histopathology was conducted. No significant adverse systemic effects in maternal animals were observed throughout the study period. No abnormal behaviour or effects, including teratogenic, were observed in the offspring throught the study period. Hence, the NOAEL for both maternal and developmental toxicity was set at ≥ 500 mg/kg bw.

Justification for classification or non-classification

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