4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane

Endpoint summary

Description of key information

A LOAEC of 0.186 ppm air (equivalent to 2.7 mg/m³) was concluded from a study conducted according to OECD TG 412 and in accordance with GLP (Dow Corning Corporation, 1998). A NOAEC could not be determined due to the degeneration of olfactory epithelium at all dose levels in all rats from all the exposure groups. The observed effect had a dose related increase in severity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available (further information necessary)

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19/12/1996 - 17/08/1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: ca. 6 weeks
- Weight at study initiation: males 196 g, females 146 g (average)
- Fasting period before study: 16 hours before exposure and sacrifice
- Housing: stainless steel, wire mesh cages
- Diet: ad libitum, except during exposure
- Water: ad libitum, except during exposure
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 44-75
- Air changes (per hr): 10 - 10.4
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Particle size distribution measurements to detect aerosol formation were made using TSI Aerodynamic Particle Sizer.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber: 5 male and 5 female rats, individually, in suspended stainless steel inhalation caging units
- Source and rate of air: syringe pump equipped with a plastic syringe delivered the test material via tubing onto the glass helix of a counter current volatalization chamber.
- System of generating particulates/aerosols: Not applicable
- Temperature, humidity, pressure in air chamber: Were recorded every 30 minutes using a temperature/humidity gauge. The chambers were operated dynamically under slight negative pressure. The chamber size and airflow rates were considered adequate to maintain the animal loading factor below 5% and an oxygen content at least 19%.

- Air flow rate: 218-227 Lpm
- Air change rate: 4.4 - 4.6 min
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Coarse filter, HEPA filter, charcoal filter and in incinerator.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Exposure levels were determined by gas chromatography.

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

Once daily, 5 days per week, for 4 weeks.

Dose / conc.:

0.12 ppm

Remarks:

target

Dose / conc.:

0.36 ppm

Remarks:

target

Dose / conc.:

1.2 ppm

Remarks:

target

Dose / conc.:

0.186 ppm (analytical)

Dose / conc.:

0.567 ppm (analytical)

Dose / conc.:

1.4 ppm (analytical)

No. of animals per sex per dose:

Five

Control animals:

yes

Details on study design:

- Dose selection rationale: Not given
- Rationale for animal assignment (if not random): random

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once per exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice pre-test, and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: twice pre-test, weekly thereafter, pre- and post-fasting before sacrifice.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, once pre-test, weekly thereafter

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Anaesthetic used for blood collection: Yes (Co2/02)
- Animals fasted: Yes
- How many animals: total of 40 animals
- Parameters checked: hemoglobin concentration, hematocrit, erythrocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, total leukocyte counts, differential leukocyte count, absolut lymphocytes, absolute segmented neutrophils, reticulocyte count, erythrocyte morphology.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Animals fasted: Yes
- How many animals: total of 40 animals
- Parameters checked: aspartame amino transferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, fasting glucose, total protein, albumin, globulin, albumin, total bilirubin, sodium, potassium, chloride, calcium, inorganic phosphorus, gamma-glutamyl transferase.

URINALYSIS: Yes
- Time schedule for collection of urine: test day 30
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: appearance, specific gravity, protein, glucose, pH, ketones, occult blood (semi-quantitatively), bilirubin, urobilinogen. Protein results of 100 mg/dL or greater were verified using a three percent sulfosalicylic acid test. POsitiv bilirubin results were confirmed via lctotest reagent tablets. Microscopic examination of sediment was performed on urine samples via light microscopy.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 1)
HISTOPATHOLOGY: Yes (see table 1)

Clinical signs:

no effects observed

Mortality:

no mortality observed

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:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
All animals survived the duration of the study. No adverse effects were seen in clinical observations.

BODY WEIGHT AND WEIGHT GAIN
No effects.

FOOD CONSUMPTION
No effects.

HAEMATOLOGY
Increased haemoglobin values and/or erythrocyte counts at all exposure levels.

CLINICAL CHEMISTRY
Increased total serum protein in 1.40 ppm exposed male animals.

URINALYSIS
No treatment related effects.

ORGAN WEIGHTS
No effects.

GROSS PATHOLOGY
There were no exposure related macroscopic findings

HISTOPATHOLOGY: NON-NEOPLASTIC
Adverse effects were seen in microscopic histopathological examinations at all exposure levels, including degenerative changes in the nasoturbinal mucosa and metaplasia/hyperplasia of laryngeal tissues.

OLFACTORY MUCOSA
Degeneration/atrophy (moderate to severe) of olfactory epithelium was seen in all males and females from all the exposure groups. In both sexes, there was a dose dependent increase in severity. The degenerative changes were characterised by epithelial disorganization, cytoplasmic disruption and fragmentation and/or exfoliation. In the affected areas, the basement membrane appeared to remain intact. The following changes were associated with olfactory degeneration: edema, dilated glands, focal ulcers, subacute (chronic active)/chronic inflammation and fusion involving nasoturbinates and the nasal septum.

RESPIRATORY MUCOSA
Goblet cell hypertrophy/hyperplasia (minimal to moderately severe) in the anterior portion of the nose was seen in all rats from all groups. In both sexes there was a dose related increase in severity. Hyperplasia of the respiratory epithelium (minimal to moderate) was seen at the anterior part of the nose in both sexes at the higher doses. The following changes were also seen: focal ulcers, subacute (chronic active/chronic) inflammation, scattered foci of squamous metaplasia. The incidence and severity of the findings was greatest at high dose.

NASAL LUMEN
Inflammatory cell debris was seen in nasal lumen of all rats from the exposure groups, with little difference in severity between groups.

LARYNX
Squamous/squamoid metaplasia/hyperplasia (minimum to slight) of the pseudostratified columnar epithelium in the sections with the ventral seromucous gland was evident in rats from groups 0.36 and 1.2 ppm. Hyperplasia (minimal to slight) of the stratified squamous epithelium normally lining portions of the larynx was seen in a number of rats from high dose . Some evidence of hyperkeratosis also present.

NASOPHARYNX
Eosinophilic material (minimal to slight) was seen in a number of rats, mainly at high dose.

A NOAEL could not be determined due to histopathology effects in the nasoturbinal tissues, larynx, and nasopharynx.

Key result

Dose descriptor:

LOAEC

Effect level:

0.186 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Table 2. Findings in the olfactory nasal mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Epithelium –Degeneration/ Atrophy	Total	1	5	5	5	0	5	5	5
	Slight	1	0	0	0	0	0	0	0
	Moderate	0	3	0	0	0	5	0	0
	Moderately	0	2	3	0	0	0	4	3
	Severe
	severe	0	0	2	5	0	0	1	2
Re-epithelized with Cuboidal/Columnar Epithelium (non-ciliated and/or ciliated)	total	0	5	5	5	0	3	5	5
	Slight	0	1	0	0	0	0	0	1
	Moderate	0	4	4	3	0	3	3	2
	Moderately	0	0	1	2	0	0	2	2
	severe
Oedema	Total	0	5	5	5	0	5	5	5
	Minimal	0	1	0	0	0	1	0	0
	Slight	0	2	0	0	0	3	1	0
	Moderate	0	2	4	4	0	1	3	5
	Moderately	0	0	1	1	0	0	1	0
	Severe
Glands-dilated	Total	0	4	5	5	0	4	5	5
	Minimal	0	1	0	0	0	0	0	0
	Slight	0	3	0	0	0	4	0	0
	Moderate	0	0	5	5	0	0	4	4
	Moderately	0	0	0	0	0	0	1	1
	Severe

 

Table 3. Findings in the respiratory nasal mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Goblet Cell Hypertrophy/Hyperplasia	Total	5	5	5	5	5	5	5	5
	Minimal	4	0	0	0	5	4	0	0
	Slight	0	1	1	0	0	1	2	0
	Moderate	1	4	3	1	0	0	1	2
	Moderately	0	0	1	4	0	0	2	3
	severe
Epithelium - Hyperplasia	total	0	3	3	5	0	0	2	5
	Minimal	0	2	1	0	0	0	0	0
	Slight	0	1	2	1	0	0	1	2
	Moderate	0	0	0	4	0	0	1	3
Erosions/Ulcers	Total	0	1	0	1	0	0	0	3
	Minimal	0	1	0	0	0	0	0	0
	Slight	0	0	0	1	0	0	0	2
	Moderate	0	0	0	0	0	0	0	1
Subacute (chronic active/chronic inflammation	Total	1	2	1	5	0	0	2	3
	Minimal
	Slight	1	2	1	0	0	0	1	0
	Moderate	0	0	0	5	0	0	1	3
Squamous/Squamoid Metaplasia	Total	1	2	2	3	0	0	0	2
	slight	1	2	2	3	0	0	0	2

 

Table 4. Findings in the larynx mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Squamous/Squamoid Metaplasia/Hyperplasia	Total	0	0	4	5	0	0	3	4
	Minimal	0	0	0	1	0	0	3	2
	Slight	0	0	4	4	0	0	0	2
Stratified Squamous Epithelium (Normal) - Hyperplasia	Total	0	0	1	5	0	0	0	2
	Minimal	0	0	0	1	0	0	0	2
	Slight	0	0	1	4	0	0	0	0
Stratified Squamous Epithelium (Normal)- Hyperkeratosis	Total	0	0	0	2	0	0	0	0
	Minimal	0	0	0	2	0	0	0	0

 

Table 5. Findings in the nasopharynx

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Eosinophilic Material (lumen)	Total	0	1	2	3	0	1	1	2
	Minimal	0	1	2	1	0	1	1	2
	Slight	0	0	0	2	0	0	0	0
Goblet Cell Hypertrophy/Hyperplasia	Total	0	0	1	2	0	0	0	2
	Minimal	0	0	1	1	0	0	0	2
	Slight	0	0	0	1	0	0	0	0

 

Conclusions:

A NOAEC could not be determined for 4,4,7,7,-tetraethoxy-3,8-dioxa-4,7-disiladecane due to clinical pathology and histopathology effects in the respiratory tract seen at all exposure levels. The LOAEC for these local effects was therefore concluded to be 0.186 ppm (equivalent to 2.7 mg/m3). There were no adverse systemic effects reported, as the effects on serum protein and haematology parameters are considered to be a secondary consequence of the local effects (study summary author opinion).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19/12/1996 - 17/08/1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: ca. 6 weeks
- Weight at study initiation: males 196 g, females 146 g (average)
- Fasting period before study: 16 hours before exposure and sacrifice
- Housing: stainless steel, wire mesh cages
- Diet: ad libitum, except during exposure
- Water: ad libitum, except during exposure
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 44-75
- Air changes (per hr): 10 - 10.4
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Particle size distribution measurements to detect aerosol formation were made using TSI Aerodynamic Particle Sizer.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber: 5 male and 5 female rats, individually, in suspended stainless steel inhalation caging units
- Source and rate of air: syringe pump equipped with a plastic syringe delivered the test material via tubing onto the glass helix of a counter current volatalization chamber.
- System of generating particulates/aerosols: Not applicable
- Temperature, humidity, pressure in air chamber: Were recorded every 30 minutes using a temperature/humidity gauge. The chambers were operated dynamically under slight negative pressure. The chamber size and airflow rates were considered adequate to maintain the animal loading factor below 5% and an oxygen content at least 19%.

- Air flow rate: 218-227 Lpm
- Air change rate: 4.4 - 4.6 min
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Coarse filter, HEPA filter, charcoal filter and in incinerator.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Exposure levels were determined by gas chromatography.

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

Once daily, 5 days per week, for 4 weeks.

Dose / conc.:

0.12 ppm

Remarks:

target

Dose / conc.:

0.36 ppm

Remarks:

target

Dose / conc.:

1.2 ppm

Remarks:

target

Dose / conc.:

0.186 ppm (analytical)

Dose / conc.:

0.567 ppm (analytical)

Dose / conc.:

1.4 ppm (analytical)

No. of animals per sex per dose:

Five

Control animals:

yes

Details on study design:

- Dose selection rationale: Not given
- Rationale for animal assignment (if not random): random

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once per exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice pre-test, and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: twice pre-test, weekly thereafter, pre- and post-fasting before sacrifice.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, once pre-test, weekly thereafter

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Anaesthetic used for blood collection: Yes (Co2/02)
- Animals fasted: Yes
- How many animals: total of 40 animals
- Parameters checked: hemoglobin concentration, hematocrit, erythrocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, total leukocyte counts, differential leukocyte count, absolut lymphocytes, absolute segmented neutrophils, reticulocyte count, erythrocyte morphology.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Animals fasted: Yes
- How many animals: total of 40 animals
- Parameters checked: aspartame amino transferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, fasting glucose, total protein, albumin, globulin, albumin, total bilirubin, sodium, potassium, chloride, calcium, inorganic phosphorus, gamma-glutamyl transferase.

URINALYSIS: Yes
- Time schedule for collection of urine: test day 30
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: appearance, specific gravity, protein, glucose, pH, ketones, occult blood (semi-quantitatively), bilirubin, urobilinogen. Protein results of 100 mg/dL or greater were verified using a three percent sulfosalicylic acid test. POsitiv bilirubin results were confirmed via lctotest reagent tablets. Microscopic examination of sediment was performed on urine samples via light microscopy.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 1)
HISTOPATHOLOGY: Yes (see table 1)

Clinical signs:

no effects observed

Mortality:

no mortality observed

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:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
All animals survived the duration of the study. No adverse effects were seen in clinical observations.

BODY WEIGHT AND WEIGHT GAIN
No effects.

FOOD CONSUMPTION
No effects.

HAEMATOLOGY
Increased haemoglobin values and/or erythrocyte counts at all exposure levels.

CLINICAL CHEMISTRY
Increased total serum protein in 1.40 ppm exposed male animals.

URINALYSIS
No treatment related effects.

ORGAN WEIGHTS
No effects.

GROSS PATHOLOGY
There were no exposure related macroscopic findings

HISTOPATHOLOGY: NON-NEOPLASTIC
Adverse effects were seen in microscopic histopathological examinations at all exposure levels, including degenerative changes in the nasoturbinal mucosa and metaplasia/hyperplasia of laryngeal tissues.

OLFACTORY MUCOSA
Degeneration/atrophy (moderate to severe) of olfactory epithelium was seen in all males and females from all the exposure groups. In both sexes, there was a dose dependent increase in severity. The degenerative changes were characterised by epithelial disorganization, cytoplasmic disruption and fragmentation and/or exfoliation. In the affected areas, the basement membrane appeared to remain intact. The following changes were associated with olfactory degeneration: edema, dilated glands, focal ulcers, subacute (chronic active)/chronic inflammation and fusion involving nasoturbinates and the nasal septum.

RESPIRATORY MUCOSA
Goblet cell hypertrophy/hyperplasia (minimal to moderately severe) in the anterior portion of the nose was seen in all rats from all groups. In both sexes there was a dose related increase in severity. Hyperplasia of the respiratory epithelium (minimal to moderate) was seen at the anterior part of the nose in both sexes at the higher doses. The following changes were also seen: focal ulcers, subacute (chronic active/chronic) inflammation, scattered foci of squamous metaplasia. The incidence and severity of the findings was greatest at high dose.

NASAL LUMEN
Inflammatory cell debris was seen in nasal lumen of all rats from the exposure groups, with little difference in severity between groups.

LARYNX
Squamous/squamoid metaplasia/hyperplasia (minimum to slight) of the pseudostratified columnar epithelium in the sections with the ventral seromucous gland was evident in rats from groups 0.36 and 1.2 ppm. Hyperplasia (minimal to slight) of the stratified squamous epithelium normally lining portions of the larynx was seen in a number of rats from high dose . Some evidence of hyperkeratosis also present.

NASOPHARYNX
Eosinophilic material (minimal to slight) was seen in a number of rats, mainly at high dose.

A NOAEL could not be determined due to histopathology effects in the nasoturbinal tissues, larynx, and nasopharynx.

Key result

Dose descriptor:

LOAEC

Effect level:

0.186 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

Table 2. Findings in the olfactory nasal mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Epithelium –Degeneration/ Atrophy	Total	1	5	5	5	0	5	5	5
	Slight	1	0	0	0	0	0	0	0
	Moderate	0	3	0	0	0	5	0	0
	Moderately	0	2	3	0	0	0	4	3
	Severe
	severe	0	0	2	5	0	0	1	2
Re-epithelized with Cuboidal/Columnar Epithelium (non-ciliated and/or ciliated)	total	0	5	5	5	0	3	5	5
	Slight	0	1	0	0	0	0	0	1
	Moderate	0	4	4	3	0	3	3	2
	Moderately	0	0	1	2	0	0	2	2
	severe
Oedema	Total	0	5	5	5	0	5	5	5
	Minimal	0	1	0	0	0	1	0	0
	Slight	0	2	0	0	0	3	1	0
	Moderate	0	2	4	4	0	1	3	5
	Moderately	0	0	1	1	0	0	1	0
	Severe
Glands-dilated	Total	0	4	5	5	0	4	5	5
	Minimal	0	1	0	0	0	0	0	0
	Slight	0	3	0	0	0	4	0	0
	Moderate	0	0	5	5	0	0	4	4
	Moderately	0	0	0	0	0	0	1	1
	Severe

 

Table 3. Findings in the respiratory nasal mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Goblet Cell Hypertrophy/Hyperplasia	Total	5	5	5	5	5	5	5	5
	Minimal	4	0	0	0	5	4	0	0
	Slight	0	1	1	0	0	1	2	0
	Moderate	1	4	3	1	0	0	1	2
	Moderately	0	0	1	4	0	0	2	3
	severe
Epithelium - Hyperplasia	total	0	3	3	5	0	0	2	5
	Minimal	0	2	1	0	0	0	0	0
	Slight	0	1	2	1	0	0	1	2
	Moderate	0	0	0	4	0	0	1	3
Erosions/Ulcers	Total	0	1	0	1	0	0	0	3
	Minimal	0	1	0	0	0	0	0	0
	Slight	0	0	0	1	0	0	0	2
	Moderate	0	0	0	0	0	0	0	1
Subacute (chronic active/chronic inflammation	Total	1	2	1	5	0	0	2	3
	Minimal
	Slight	1	2	1	0	0	0	1	0
	Moderate	0	0	0	5	0	0	1	3
Squamous/Squamoid Metaplasia	Total	1	2	2	3	0	0	0	2
	slight	1	2	2	3	0	0	0	2

 

Table 4. Findings in the larynx mucosa

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Squamous/Squamoid Metaplasia/Hyperplasia	Total	0	0	4	5	0	0	3	4
	Minimal	0	0	0	1	0	0	3	2
	Slight	0	0	4	4	0	0	0	2
Stratified Squamous Epithelium (Normal) - Hyperplasia	Total	0	0	1	5	0	0	0	2
	Minimal	0	0	0	1	0	0	0	2
	Slight	0	0	1	4	0	0	0	0
Stratified Squamous Epithelium (Normal)- Hyperkeratosis	Total	0	0	0	2	0	0	0	0
	Minimal	0	0	0	2	0	0	0	0

 

Table 5. Findings in the nasopharynx

		MALE				FEMALE
Group		I	II	II	IV	I	II	III	IV
Target Exposure		0.0	0.12	0.36	1.2	0	0.12	0.36	1.2
Number Examined		5	5	5	5	5	5	5	5
Eosinophilic Material (lumen)	Total	0	1	2	3	0	1	1	2
	Minimal	0	1	2	1	0	1	1	2
	Slight	0	0	0	2	0	0	0	0
Goblet Cell Hypertrophy/Hyperplasia	Total	0	0	1	2	0	0	0	2
	Minimal	0	0	1	1	0	0	0	2
	Slight	0	0	0	1	0	0	0	0

 

Conclusions:

A NOAEC could not be determined for 4,4,7,7,-tetraethoxy-3,8-dioxa-4,7-disiladecane due to clinical pathology and histopathology effects in the respiratory tract seen at all exposure levels. The LOAEC for these local effects was therefore concluded to be 0.186 ppm (equivalent to 2.7 mg/m3). There were no adverse systemic effects reported, as the effects on serum protein and haematology parameters are considered to be a secondary consequence of the local effects (study summary author opinion).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

2.7 mg/m³

Study duration:

subacute

Species:

rat

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

The repeated dose toxicity inhalation study conducted according to OECD TG 412 and in accordance with GLP was not able to establish a NOAEC (Dow Corning Corporation, 1998). Rats were exposed to 0.12, 0.36, 1.2 ppm (vapour) for 28 days. There were no mortalities, or effects on body weight or body weight gain. Increased haemoglobin values and/or erythrocyte counts were present at all exposure levels. Increased total serum protein in 1.40 ppm exposed male animals. There were no exposure related macroscopic findings. However, adverse effects were seen in microscopic histopathological examinations at all exposure levels, including degenerative changes in the nasoturbinal mucosa and metaplasia/hyperplasia of laryngeal tissues. Degeneration/atrophy (moderate to severe) of olfactory epithelium was seen in all males and females from all the exposure groups. In both sexes, there was a dose dependent increase in severity. The degenerative changes were characterised by epithelial disorganization, cytoplasmic disruption and fragmentation and/or exfoliation. In the affected areas, the basement membrane appeared to remain intact. The following changes were associated with olfactory degeneration: edema, dilated glands, focal ulcers, subacute (chronic active)/chronic inflammation and fusion involving nasoturbinates and the nasal septum. Goblet cell hypertrophy/hyperplasia (minimal to moderately severe) in the anterior portion of the nose was seen in all rats from all groups. In both sexes there was a dose related increase in severity. Hyperplasia of the respiratory epithelium (minimal to moderate) was seen at the anterior part of the nose in both sexes at the higher doses. The following changes were also seen: focal ulcers, subacute (chronic active/chronic) inflammation, scattered foci of squamous metaplasia. The incidence and severity of the findings was greatest at high dose. Squamous/squamoid metaplasia/hyperplasia (minimum to slight) of the pseudostratified columnar epithelium in the sections with the ventral seromucous gland was evident in rats from groups 0.36 and 1.2 ppm. Hyperplasia (minimal to slight) of the stratified squamous epithelium normally lining portions of the larynx was seen in a number of rats from high dose . Some evidence of hyperkeratosis also present. LOAEC of 0.186 ppm air (equivalent to 2.7 mg/m³) was concluded. A NOAEC could not be determined due to the degeneration of olfactory epithelium at all dose levels in all rats from all the exposure groups. The observed effect had a dose related increase in severity. There were no adverse systemic effects reported, as the effects on serum protein and haematology parameters are considered to be a secondary consequence of the local effects (study summary author opinion).

Justification for classification or non-classification

Based on the available data for 4,4,7,7,-tetraethoxy-3,8-dioxa-4,7-disiladecane, classification STOT RE 1 " H372: Causes damage to organs (nasoturbinal tissues, larynx, and nasopharynx) through prolonged or repeated exposure" is applied according to Regulation (EC) No. 1272/2008.