N-[3-(trimethoxysilyl)propylcyclohexylamine]

Endpoint summary

Description of key information

RDT oral (OECD 422), rat: NOAEL ≥500 mg/kg bw/day (RA from CAS 1760-24-3)

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

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

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.

Remarks on result:

other: CAS 1760-24-3

Remarks:

Dow Corning Corporation (2002)

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: non-adverse effects on clinical signs, food consumption, haematology and clinical chemistry parameters in animals of the 1000 mg/kg bw/day dose group

Remarks on result:

other: CAS 227085-51-0

Remarks:

RCC (2001)

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Remarks on result:

other: CAS 227085-51-0

Remarks:

RCC (2001)

Key result

Critical effects observed:

no

Conclusions:

In an oral gavage study conducted similar to OECD 422 and to GLP the NOAEL for the structural analogue 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.
Oral administration of the structural analgoue CAS 227085-51-0 to rats for a period of twenty-eight consecutive days, at dose levels of 50, 200 and 1000 mg/kg bw/day did not produce any toxicologically relevant treatment-related changes and on this basis under the conditions of this study the NOAEL was considered to be ≥1000 mg/kg bw/day.
As explained in the analogue justification, the differences between the target and the source substance are unlikely to lead to differences in the oral NOAEL after repeated exposure.

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 available information comprises adequate, reliable (Klimisch score 1) and consistent studies, from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties> (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

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 data on repeated dose toxicity of N-[3 -(trimethoxysilyl)propylcyclohexylamine] (CAS 3068 -78-8) are available. However, an OECD 422 study with the registered substance is on-going, but the results will not be available before the REACh deadline in May. Therefore, as an interim measure, the hazard assessment was performed based on available data from the structural analogues N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) and N-ethyl-3-trimethoxysilyl-2-methylpropanamine (CAS 227085-51-0). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and in accordance with the Read across assessment framework (RAAF, ECHA 2017) read across from analogue substances has been applied to support the human health hazard assessment of N-[3 -(trimethoxysilyl)propylcyclohexylamine] (CAS 3068 -78-8). Details on read across justifications can be found in the attached justification in the respective target entry and in the overall justification for grouping of substances attached in IUCLID Section 13.

A reliable key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) is available and was performed according to OECD 422 and in compliance with GLP (Health and Environmental Sciences, 2002). Groups of 10 Sprague-Dawley rats of each sex were administered the test material at doses of 25, 125 and 500 mg/kg bw/day or vehicle alone (corn oil) via oral gavage for 28 days on 7 consecutive days per week. Based on mortality (1 male and 1 female) and further effects on clinical signs, slight effects on body weight and food consumption observed in a range-finding study in the high dose group and no further effects observed in all other dose groups a dose level of 500 mg/kg bw/day was chosen as the high dose in the main study. The animals were monitored for clinical signs, body weight, food consumption, haematology and clinical biochemistry parameters, organ weights and neurobehavioural examination. All animals were submitted to necropsy and histopathological examination. 1/10 males of the 125 mg/kg bw/day dose group died due to renal disease unrelated to treatment and 2/10 females of the reproductive group died due to dosing errors. Clinical signs such as increased nasal sounds, laboured breathing and/or soft squeaky vocalisation were recorded in animals of all dose groups. Body weight changes, food consumption, haematology, clinical chemistry, neurobehavioural examination, organ weights as well as gross pathology and histopathological examination revealed no treatment-related abnormalities or adverse effects. Based on the results of the study and due to the absence of any toxicological relevant adverse effect a subacute NOAEL of ≥500 mg/kg bw/day was derived for N-(3-(trimethoxysilyl)propyl)ethylenediamine.

A further reliable repeated dose toxicity study (28-day) with N-ethyl-3-trimethoxysilyl-2-methylpropanamine (CAS 227085-51-0) is available and was performed according to OECD 407 (RCC, 2001) and in compliance with GLP. Groups of 5 HanBrl: WIST rats of each sex were administered the test material at doses of 50, 200 and 1000 mg/kg bw/day or vehicle alone (peanut oil) via oral gavage for 28 days on 7 consecutive days per week. Dose selection was based on a 7-day range finding study where 3 Sprague-Dawley rats of each sex were dosed with the test material at concentrations of 125, 250, 500 or 1000 mg/kg bw/day via oral gavage. One male (1/5) of the 1000 mg/kg bw/day dose group was found dead on test day 4. No pre-mortem clinical signs of toxicity were evident in this rat. Findings noted during histopathological evaluation were commensurate with a dosing error. One female rat (1/5) treated with 1000 mg/kg bw/day had audible breathing noise, piloerection, hardened abdomen and labored respiration and emaciation. No further clinical signs were reported during the course of the study. Body weight changes, haematology, clinical chemistry and organ weight measurements as well as gross and histopathological examinations revealed no treatment-related abnormalities or adverse effects. Male rats treated with 1000 mg/kg bw/day were less active (except during the last measurement interval of 45 - 60 min) than the control males. A similar, but less overt difference was noted in females treated with 1000 mg/kg bw/day during the first measurement interval (0 - 15 min). This difference was considered to be a test item-related effect. Based on the results of the study and due to the absence of any toxicological relevant adverse effect a subacute NOAEL of ≥1000 mg/kg bw/day was derived for N-ethyl-3-trimethoxysilyl-2-methylpropanamine, respectively.

Overall, the NOAEL of 500 mg/kg bw/day derived from the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) will be used for risk assessment based on adverse effects in the range-finding study following the worst case approach. 

Justification for classification or non-classification

Reliable data from structural analogues on repeated dose toxicity indicate that N-[3 -(trimethoxysilyl)propylcyclohexylamine] do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and the available data are therefore conclusive but not sufficient for classification.