N-[3-(triethoxysilyl)propyl]ethylenediamine

Endpoint summary

Description of key information

RDT (oral): OECD 422 (including FOB), 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

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 September 2001 to 06 September 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

(1996)

Deviations:

yes

Remarks:

(additionally 10 females per dose group were added to the study to determine the repeated dose toxicity to females)

Qualifier:

according to guideline

Guideline:

other: USEPA Health Effects test guideline OPPTS 870.3650 (2000)

Deviations:

yes

Remarks:

(additionally 10 females per dose group were added to the study to determine the repeated dose toxicity to females)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crl:CD (SD)IGBS VAF/Plus
- Source: Charles River Laboratories, Inc., Portage, MI, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: males 253-301 g, females 181-229 g
- Fasting period before study: None
- Housing: individually in suspended wire-mesh cages elevated over Bed-O'Cobs bedding; during cohabitation the females were pared 1 to 1 with a male in a suspended wire-mesh cage; pregnant females were moved into shoebox cages containing Enviro-dri and Bed-O'Cobs combination bedding (no later than three days prior to their expected delivery date until remainder of the study)
- Diet: PMI Certified Rodent Chow #5002 (PMI Nutritional International, St. Louis, MO, USA), ad libitum
- Watert: Municipal water, further purified by reverse osmosis, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 01 October 2001 to: 11 April 2002

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The dosing formulations were prepared daily by adding an appropriate amount of test substance to a measured amount of vehicle (dried and de-acidified) under nitrogen atmosphere. The dosing formulations were maintained under nitrogen atmosphere until the time of dosing.

VEHICLE
- Justification for use and choice of vehicle: Corn oil was dried and de-acidified to remove residual water before use as test substance hydrolyses in contact with moisture.
- Lot/batch no.: 070K0127
- Purity: 100%

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration, homogeneity and stability of the test substance in the vehicle were verified by gas chromatopgraphy with a flame ionisation detection (FID). Concentration verification was conducted on a weekly basis.

Duration of treatment / exposure:

Males: 28 days (beginning 2 weeks prior to mating)
Toxicity phase female: 29 days (beginning 2 week prior to mating)
Reproductive phase females: 39-44 days (2 weeks prior to mating, throughout mating and pregnancy until day 3 postpartum)

Frequency of treatment:

Daily (7 days/week)

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

10 males and 20 females (10 females in reproductive group and 10 females in toxicity group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose selection was based on a 7-day range finding study where 3 Sprague-Dawlex rats per sex were dosed per gavage with 125, 250, 500 or 1000 mg/kg bw/day. As a result one high dose female was found dead on study day 4. One high dose male was found moribund on study day 6 and was humanely sacrificed. All other animals survived until scheduled necropsy. Slight effects on body weight and food consumption have been observed in the treatment groups. Increased breathing sounds recorded as rales and soiling and wetness around the muzzle were the most common clinical findings related to treatment. Both findings were most common and most persistent in the 1000 mg/kg bw/day group. Some animals in the lower dose groups exhibited rales or wetness around the nose and/or mouth or soiling of the muzzle. However, these clinical findings were detectable for only one or two days of the study. At the highest dose, the majority of the clinical signs were associated with the two mortalities. However, one of the surviving females from the high dose group exhibited rales, hunched posture and muzzle soiling. Both of the animals that died before scheduled sacrifice had gaseous distension of the gastrointestinal tract and small dark livers. There were no adverse findings in the necropsy examination of the surviving animals.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for morbidity, moribundity and mortality. General clinical observations were made at least once per day, approximately one hour after dosing.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first dosing and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded weekly beginning approximately one week prior to test substance administration, on the first day of dosing and just prior to scheduled necropsy.

FOOD CONSUMPTION:
Individual food consumption was recorded weekly for female animals in the toxicity group for four weeks. Individual food consumption for the male animals and the reproductive group females were recorded during the first two weeks of treatment. Food consumption was not measured during the cohabitation period. Food consumption was measured for the reproductive group females throughout gestation until terminal sacrifice.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On the day of scheduled sacrifice
- Anaesthetic used for blood collection: Yes, ketamine HCl/Xylazine
- Animals fasted: Yes, overnight
- How many animals: All male and toxicity group females
- Parameters checked: haematocrit, haemoglobin, erythrocyte count, total and differential leucocyte count, platelet count and prothrombin time, mean cell volume (MCV), mean cell hamoglobin (MCH), and mean cell haemoglobin concentration (MCHC).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On the day of scheduled sacrifice
- Animals fasted: Yes
- How many animals: All male and toxicity group females
- Parameters checked: total protein, albumin, glucose, cholesterol, total bilirubin, urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, phosphorous, sodium, potassium, and chloride.

FUNCTIONAL OBSERVATIONAL BATTERY (FOB): Yes
- Time schedule for examinations: Prior to the start of dosing and during the fourth week of the treatment. The assessments were conducted following the daily dose administration.
- Dose groups that were examined: All male and toxicity group females.
- Battery of functions tested: cageside observations, hand-held observations, open field observations, categorical observations, measurements/counts, motor activity.

Sacrifice and pathology:

SACRIFICE
- Male animals: All surviving animals after 28 days of dosing.
- Maternal animals: All surviving animals on day 3 postpartum.
- Toxicity group females: All surviving animals after 29 days of dosing.

GROSS PATHOLOGY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.

Statistics:

All data analysis was carried out using SAS. In all comparisons, the family wise error rate was held at 5% (alpha=0.05). Prior to this analysis, an exploratory analysis was carried out on all variables tested. Bartlett's test was used to check for heterogeneity of variances and a Kolmogorov-smirnov test was used to test normality of the data. Parametric data was then tested using one-way Analysis of Variance (ANOVA) followed by Dunnett's Test (if significant). Non-parametric data were tested by Kruskal Wallis Test followed by Wilcoxon (if significant). For variables that had multiple measurements across time Repeated Measurement ANOVA was used to analyse the data. Categorical data were tested for equal proportions using the Fisher's Exact Test.

Statistically significant probabilities are reported at either the p≤0.05 or p≤0.01 levels.

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 500 mg/kg bw/d reproductive group 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 25, 125 and 500 mg/kg bw/day groups 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 the test material 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.

Reference 2

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:

Please refer to the Additional Information field in the endpoint study summary.

Reason / purpose for cross-reference:

read-across source

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: DCC, 2002

Critical effects observed:

not specified

Conclusions:

In an oral gavage study conducted similar to OECD 422 and to GLP the NOAEL for the test material 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.

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 an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group and similarities in physico-chemical and toxicological properties (refer to endpoint discussion for further details). The selected study is 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-(triethoxysilyl)propyl)ethylenediamine (CAS 5089-72-5) are available. Therefore risk assessment was performed based on available data from the structural analogue N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3).

READ-ACROSS JUSTIFICATION

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for N-[3-(triethoxysilyl)propyl]ethylenediamine (CAS 5089-72-5) is evaluated point by point.

Read-across hypothesis

After oral application, both N-[3-(triethoxysilyl)propyl]ethylenediamine (CAS 5089-72-5) and N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) hydrolyse to a common silicon-containing hydrolysis product, N-(3-(trihydroxysilyl)propyl)ethylenediamine. The other hydrolysis products are ethanol and methanol, respectively and will be discussed further below.

The half-lives of N-[3-(triethoxysilyl)propyl]ethylenediamine and N-(3-(trimethoxysilyl)propyl)ethylenediamine at at 20-25°C and pH 7 are 165 min and 1.5 min, respectively. As the hydrolysis reaction may be acid or base catalysed, the rate of reaction is expected to be slowest at pH 7 and increases as the pH is raised or lowered.

Reaction rate increases with temperature, therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Under ideal conditions, hydrolysis rate can be recalculated according to the equation:

DT50(XºC) = DT50(T) x e(0.08(T-X))

Where T = temperature for which data are available and X = target temperature.

For both the hydrolysis half-life at 37.5°C and pH 2 (relevant for oral exposure) is 5 s.

Analogue approach justification

(a) Structural similarity

Both N-[3-(triethoxysilyl)propyl]ethylenediamine and N-(3-(trimethoxysilyl)propyl)ethylenediamine are secondary amines with the identical silicon based substituent. The further substituents are propyl and ethylamine, respectively. The two substances hydrolyse very rapidly in the gut to produce a common silicon-containing hydrolysis product, N-(3-(trihydroxysilyl)propyl)ethylenediamine. The read-across substance was selected as the most appropriate based on chemical structure. Further information regarding the toxicity of the substances is attached in Section 13 of the IUCLID 5 dossier (PFA, 2013v).

(b) Similar physicochemical characteristics

A data matrix is attached in Section 13 of the IUCLID dossier, and the key physico-chemical parameters are summarised below.

Table 5.6.2 Data matrix of key physico-chemical properties of the submission substance and the analogue substance.

	Target (registration substance)	Source (read-across substance)
CAS Number	5089-72-5	1760-24-3
Chemical Name	N-[3-(triethoxysilyl)propyl]ethylenediamine	N-(3-(trimethoxysilyl)propyl) ethylenediamine
Si hydrolysis products	N-(3-(trihydroxysilyl)propyl)ethylenediamine	N-(3-(trihydroxysilyl)propyl)ethylenediamine
Molecular weight	264.4 g/mol	222.4 g/mol
Molecular weight (hydrolysis products)	180 g/mol	180 g/mol
log Kow(parent)	1.2	-1.67
log Kow (silicon containing hydrolysis products)	-3.4	-3.4
Water sol (parent)	2.4E+04 mg/l	1E+06 mg/l
Water sol (silicon containing hydrolysis products)	1E+06 mg/l	1E+06 mg/l
Vapour pressure (parent)	0.03 Pa	0.3-0.4 Pa
Hydrolysis t1/2at pH 7 and 20-25°C	165 min	1.5 min
Hydrolysis t1/2at pH 2 and 37.5°C	5 s	5 s

(c) Similar toxicokinetics

After oral exposure both substances hydrolyse rapidly in the gut. Therefore systemic exposure is supposed to be mainly to the hydrolysis products. Based on the phys. -chem. data oral absorption is possible for N-[3-(triethoxysilyl)propyl]ethylenediamine and its hydrolysis product by passive diffusion. Based on the low molecular weight of the hydrolysis products both have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Both may be well distributed within the body and will be excreted mainly via urine. No accumulation is supposed for both hydrolysis products.

In view of the rapid hydrolysis following oral dosing, it is therefore appropriate to read-across the available oral data for the read-across substance which produces a common silicon-containing hydrolysis product with similar toxicokinetic properties to address the potential for systemic toxicity after oral exposure.

(d) Similar acute toxicity

Acute oral toxicity studies are available for both the registered substance and the read-across substance. The acute oral LD50in rats was >2000 mg/kg bw for N-[3-(triethoxysilyl)propyl]ethylenediamine (CAS 5089-72-5) and 2295 mg/kg bw for N-[3-(trimethoxysilyl)propyl]ethylenediamine (CAS 1760-24-3), respectively. There was evidence of systemic toxicity and mortality observed in both studies with the registered and the read-across substance, indicating absorption and systemic availability at a dose of ≥ 2000 mg/kg bw. It is therefore considered appropriate to read-across the toxicity data after oral administration from N-[3-(trimethoxysilyl)propyl]ethylenediamine (CAS 1760-24-3) to N-[3-(triethoxysilyl)propyl]ethylenediamine (CAS 5089-72-5).

(e) Discussion of repeated systemic toxicity of the non-silicon containg hydrolysis products

The repeated dose toxicity of the non-silicon hydrolysis products, methanol and ethanol has been extensively studied. It is beyond the scope of this assessment to review all of the available data in detail. However, the key findings from the disseminated REACH dossiers and OECD SIAR report (OECD, 2004a) are reported here to support read-across arguments.

Methanol

The majority of repeated dose toxicity information for methanol comes from inhalation studies in rats and monkeys.

Generally effects noted include nasal irritation in rats (but not monkeys), CNS depression, effects on body and organ weight and in some cases effects on clinical chemistry parameters. Studies were conducted up to significant doses and generally effects when noted, are considered adverse only at upper end of the dose ranges studied e. g. 650 mg/m³ in monkeys, 13 000 mg/m³ in rats.

Methanol is not classified for repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.

Ethanol 

Generally in repeat dose studies in animals with ethanol very large doses are used, and often specific endpoints relating to known effects in humans are the primary focus of such studies. However, adverse effects on the liver have been noted in animals but only at very high doses >8 g/kg/day. Ethanol is not classified for repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.

Conclusion

In conclusion, the oral NOAEL in rats for methanol is greater than the dose that is expected to be generated from hydrolysis of N-[3-(trimethoxysilyl)propyl]ethylenediamine.

Discussion

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test accoring to OECD 422 and in compliance with GLP was performed with N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3) in Sprague-Dawley rats (Dow Corning Corporation, 2002). Ten male and 20 female rats (10 per reproductive and toxicity group each) were administered 25, 125 and 500 mg/kg bw/day of the test substance in corn oil by gavage, for up to 29 (males and toxicity group females) or 39-44 (reproductive group females) consecutive days. Control animals received the concurrent vehicle.The dose selection was based on a 7-day range finding study where 3 Sprague-Dawley rats per sex were dosed per gavage with 125, 250, 500 or 1000 mg/kg bw/day.As a result one high dose female was found dead on study day 4. One high dose male was found moribund on study day 6 and was humanely sacrificed. All other animals survived until scheduled necropsy. Slight effects on body weight and food consumption have been observed in the treatment groups. Increased breathing sounds recorded as rales and soiling and wetness around the muzzle were the most common clinical findings related to treatment. Both findings were most common and most persistent in the 1000 mg/kg bw/day group. Some animals in the lower dose groups exhibited rales or wetness around the nose and/or mouth or soiling of the muzzle. However, these clinical findings were detectable for only one or two days of the study. At the highest dose, the majority of the clinical signs were associated with the two mortalities. However, one of the surviving females from the high dose group exhibited rales, hunched posture and muzzle soiling. Both of the animals that died before scheduled sacrifice had gaseous distension of the gastrointestinal tract and small dark livers. There were no adverse findings in the necropsy examination of the surviving animals.In the main study no treatment-related deaths were observed. Clinical signs as clear perioral soiling were 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. 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. There were no statistically significant differences in food consumption in any group throughout the study period. There were no treatment-related effects on haematology parameters. However, in all 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. 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. Functional observational battery revealed no treatment-related effects. There were no pathology or histopathology findings attributable to the test substance throughout the study period and no treatment-related effects on organ weights were observed.

In conclusion, a NOAEL of ≥500 mg/kg bw/day was derived for the analogue substance N-(3-(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3).

Justification for classification or non-classification

Based on reliable data from the analogue substance N-(3 -(trimethoxysilyl)propyl)ethylenediamine (CAS 1760-24-3), the registered substance N-(3 -(triethoxysilyl)propyl)ethylenediamine (CAS 5089-72-5) does not meet the criteria to be classified for specific target organ toxicity - repeated exposure (STOT RE) according to Regulation (EC) No. 1272/2008.