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

Endpoint summary

Description of key information

The key acute oral toxicity study for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane reports an LD50 of 161 mg/kg bw in a reliable study conducted according to current guideline and in accordance to GLP (WIL, 2000).

The key acute inhalation study for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane reports an LC50 of >26ppm (vapour) (equivalent to 377 mg/m³ or 0.38 mg/L) in a study conducted according to an OECD guideline but not in compliance with GLP (Dow Corning Corporation, 1993).

The key acute dermal toxicity study for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane reports an LD50 of 1972 mg/kg bw, in a study conducted according to OECD TG 402 and in compliance with GLP (Pharmakon, 1994). 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 16 April 1999 to 28 May 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Species:

rat

Strain:

other: Crl:CD (SD) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Labs, Raleigh, NC, USA
- Age at study initiation: 8-10 wk (m); 9-11 wk (f)
- Weight at study initiation, g: 246-313 (m); 193-216 (f)
- Fasting period before study: 18-20 h
- Housing: 1/suspended wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 71.5-72.2 deg F
- Humidity (%): 39-57.7
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: not given

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
None

MAXIMUM DOSE VOLUME APPLIED: 0.26 ml/kg bw (neat test substance)

Doses:

150, 200, 250 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21 days
- Frequency of observations and weighing: mortality hourly to 4 h, then twice daily for 21 days; clinical observations hourly to 4 h, then daily for 21 days; body weights at -1, 0, 7, 14 and 21 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

Statistics:

Litchfield & Wilcoxon

Sex:

male

Dose descriptor:

LD50

Effect level:

153 mg/kg bw

Based on:

test mat.

95% CL:

140 - 166

Remarks on result:

other: Adverse effects observed

Sex:

female

Dose descriptor:

LD50

Effect level:

170 mg/kg bw

Based on:

test mat.

95% CL:

134 - 215

Remarks on result:

other: Adverse effects observed

Sex:

male/female

Dose descriptor:

LD50

Effect level:

161 mg/kg bw

Based on:

test mat.

95% CL:

139 - 185

Remarks on result:

other: Adverse effects observed

Mortality:

3 out of 10 animals (2 male and 1 female rats) treated with 150 mg/kg bw died between days 5 and 9 of the study period. All animals treated with 200 mg/kg bw died within 9 days of the observation period. 9 out of 10 animals (5 male and 4 female rats) treated with 250 mg/kg bw died during the treatment period. 8 of these animals died within the first 9 days post-administration, while 1 animal died later (after day 9).

Clinical signs:

other: There were clinical findings in all dose groups, most (4/5 or 5/5) had decreased defaecation, over a third were hypoactive, had pale extremities, impaired muscle coordination or hypothermia. Many had discharge from the eyes, nose or anogenital area. At th

Gross pathology:

The target organ was identified as the liver, with hepatic findings in 24 of the 30 (80%) of the animals in the study (17/22) that died and 7/8 that survived). Other observations on gross necropsy of those that succumbed were: red fluid contents in the abdominal cavity, thoracic cavity and/or urinary bladder; dark red stomach and/or intestinal contents; lungs that were dark red or pale; discoloured thymus; pale pancreas; foamy contents in the trachea; reddened testes and/or reddened and enlarged mediastinal lymph nodes. The scheduled necropsy found (besides the hepatic effects) white areas or capsular scarring on the spleen; dark red areas on the lungs.

Table 1: Number of animals dead and time range within which mortality occurred

Dose (mg/kg bw)	Mortality (dead/total)			Time range of deaths (days)
	Male	Female	Combined	1-4	5-9	10-21
150	2/5	1/5	3/10	-	3	-
200	5/5	5/5	10/10	1	9	-
250	5/5	4/5	9/10	-	8	1

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

A reliable study conducted in compliance with the standard guideline and in accordance with GLP, identified LD50 values of 153 and 170 mg/kg bw for male and female rats for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane, respectively. The liver was found to be the target organ and there was clear evidence of toxicity at the lowest tested dose of 150 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

161 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

A detailed description of analytical verification of test concentration is missing, although nominal concentrations have been reported.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: 6-9 weeks
- Weight at study initiation: 155-205 g
- Fasting period before study: not reported
- Housing: standard stainless steel wire mesh bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: Stainless steel and glass exposure chambers, where chamber air was ambient air which had been filtered (hepa and charcoal filters). The test material was introduced in to the chamber through a specifically designed glass J tube, into which the material was metered with a syringe pump. Glass beads and heating tape were used to help vaporize the test material, which was passed into the inlet port at the top of the chamber.

- Exposure chamber volume: 450 litres

- Source and rate of air: Airflow was kept at approximately 12-15 air changes per hour.

- Treatment of exhaust air: Filtered by hepa and charcoal filters and passed through a water cyclone before exhausted through the roof of the building.

- Temperature, humidity, pressure in air chamber: Temperature and humidity were recorded every five minutes and kept in the range of 26-29C and 30-39% relative humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: not described
- Samples taken from breathing zone: not described

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not reported
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not reported

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Concentrations:

Target concentrations: 1, 4, 12 and 25 ppm
Nominal concentrations: 1, 4, 8 and 26 ppm
The saturated vapour concentration of the test material at room temperature is reported to be 40 ppm. The target concentration of 25ppm was considered the highest concentration that could be reasonably produced given the test generating equipment and exposure chamber.

No. of animals per sex per dose:

4 groups of five animals per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations, weights taken on days 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: respiratory, dermal, behavioural, nasal, ocular changes were all recorded.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 26 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Equivalent to >0.38 mg/l

Mortality:

No mortality occurred in any of the test animals during exposure.

Clinical signs:

other: No overt signs of toxicity were observed in any of the animals during exposure or observation period.

Body weight:

None reported.

Gross pathology:

Gross pathologic examination of the animals during terminal sacrifice revealed hemorrhagic foci of the lung in two male rats. No abnormalities were observed during microscopic examination of these lungs. The macroscopic finding of lung hemorrhages was interpreted as a terminal event at the time of sacrifice. Any other changes noted in the tissues of all other rats were considered to be typical of incidental findings of rats of this age and strain euthanized in this manner.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

An LC50 of >26ppm (vapour) (equivalent to 377 mg/m3 or 0.38 mg/l) is reported for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane in a study conducted according to an OECD guideline but not in compliance with GLP. This was the highest achievable concentration at which no mortality or effects of toxicity were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

377 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

minor deviation from recommended humidity.

GLP compliance:

yes

Test type:

other: Preliminary study, limit test and standard acute study (main study).

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no details
- Age at study initiation: no details
- Weight at study initiation g: male: 242-3 (pre-study); 250 (limit test); 265-283 (main test). female 220-223 (pre-study); 215 (limit test); 234-246 (main test).
- Fasting period before study: no details
- Housing: 1/cage; polycarbonate
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no details
- Humidity (%): no details except that humidity reached 73% (30-70% is recommended in the guideline)
- Air changes (per hr): no details
- Photoperiod (hrs dark / hrs light): no details

IN-LIFE DATES: no details

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: no details
- % coverage: 10%
- Type of wrap if used: no details

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no details
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): given in table 1
- Concentration: neat
- Constant volume or concentration used: no

Duration of exposure:

24h

Doses:

0, 1591, 1785, 2008, 2241, 2512 mg/kg bw

No. of animals per sex per dose:

5 in limit and main study, 2 in preliminary study.

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation daily, weighed on days 0, 7, 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,

Statistics:

Bliss method. Litchfield and Wilcoxon method.

Preliminary study:

See table 1.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 972 mg/kg bw

95% CL:

1 850 - 2 101

Remarks on result:

other: Bliss method

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 977 mg/kg bw

95% CL:

1 734 - 2 255

Remarks on result:

other: Litchfield & Wilcoxon method

Mortality:

Mortality occurred from day 6-13 with higher susceptibility in the females.

Clinical signs:

other: Subdued behaviour and prostration from day 8-10. One case of abdominal distension was noted from day 9-12.

Gross pathology:

The majority of animals which died during the study showed haemorrhagic ascites, cloudy pleural liquid and thickening of the hepatic capsule. Thickening of the hepatic capsule was noted in treated animals euthanised on study termination. No macroscopically detectable abnormality was noted in control group.

Other findings:

Some cases of paleness of the cutaneous surface were noted from day 6 to day 14.

Table 1: Number of animals dead and with evident toxicity

Dose (mg/kg bw)	Volume ml/kg bw (neat)	Mortality (dead/total)			Time range of deaths (days)	Number with overt toxicity (no./total)	Description of toxicity/body weight/necropsy findings
		Male	Female	Combined		Combined male/female	Combined male/female
Control^c	purified water	0/5	0/5	0/10	-	0/10	No findings.
1009^a	1.04	0/2	0/2	0/4	to day 8	-	-
2008^a	2.07	0/2	0/2	0/4	to day 8	-	-
2008^b	2.07	0/5	5/5	5/10	days 8-13	5/10	Transient: prostration (3/10); subdued behaviour (2/10); abdominal distension (1/10). Females that died had haemorrhagic ascites (excess fluid containing blood in the peritoneal cavity, commonly associated with liver damage), thickening of the hepatic capsule (the membrane surrounding the liver), and pale lungs or cloudy pleural fluid, No macroscopic abnormalities were detected in males.
1591^c	1.64	0/5	0/5	0/10	-	1/10	Transient pale skin surface (1/10). Liver effects (thickening of hepatic capsule or granulomatous liver) (4/5f).
1785^c	1.84	0/5	4/5	4/10	days 8-11	4/10	Transient: pale skin surface (3/10); subdued behaviour (3/10). Significantly reduced body weight gains in both sexes. Possible liver effects (haemorrhagic ascites, discoloured liver, thickening of hepatic capsule) (5/5f, 5/5m). Lung (cloudy pleural fluid) (4/5f).
2008^c	2.07	0/5	3/5	3/10	days 7-13	3/10	Transient: pale skin surface (3/10); subdued behaviour (3/10); abdominal distension (1/10). Significantly reduced body weight gains in both sexes. Possible liver effects (haemorrhagic ascites, white or discoloured liver, thickening of hepatic capsule) (5/5f, 2/5m). Lung (cloudy pleural fluid) (3/5f, 1/5m).
2241^c	2.31	4/5	5/5	9/10	days 6-12	9/10	Transient: pale skin surface (5/10); subdued behaviour (7/10); abdominal distension (3/10). Significantly reduced body weight gains in both sexes. Possible liver effects (haemorrhagic ascites, thickening of hepatic capsule) (5/5f, 5/5m). Lung (cloudy pleural fluid) (5/5f, 3/5m).
2512^c	2.59	5/5	5/5	10/10	days 7-13	10/10	Transient: pale skin surface (5/10); subdued behaviour (7/10); abdominal distension (3/10); prostration (1/10). Not possible to ascertain body weight effects due to excessive mortality. Possible liver effects (haemorrhagic ascites, white liver, thickening of hepatic capsule) (5/5m, 3/5f). Lung (cloudy pleural fluid) (4/5f, 4/5m). Kidney (enlarged or darkened) (1/5m). Intestine (blackish) (1/5f).

a preliminary study

b fixed dose study

c main study

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

A reliable study conducted in compliance with the standard guideline and in accordance with GLP, identified an LD50 of 1972 mg/kg bw, with some evidence of toxicity from the lowest dose tested in the main study, of 1591 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 972 mg/kg bw

Additional information

The selected key studies were the most recent studies available, conducted according to appropriate OECD test guidelines.

The key study for acute oral toxicity was conducted according to the now-deleted OECD TG 401 and in compliance with GLP (WIL 2000). An LD₅₀ of 161 mg/kg bw was reported. The deaths reported in the study were as follows: 9/10, 10/10 and 3/10 animals died at 250, 200 and 150 mg/kg bw respectively. There were clinical findings in all dose groups, most had decreased defaecation, over a third were hypoactive, and had pale extremities, impaired muscle coordination or hypothermia. Many had discharge from the eyes, nose or anogenital area. At the top dose (250 mg/kg bw) laboured breathing and prostration were noted. Surviving animals in the 150 and 250 mg/kg bw groups had transient weight loss during the first two weeks following dosing, but had passed their initial body weight by day 21. The target organ was identified as the liver, with hepatic findings in 80% of the animals in the study. In addition to the hepatic effects, white areas or capsular scarring on the spleen and dark red areas on the lungs were evident at necropsy.

A supporting study for acute oral toxicity was conducted according to a method equivalent to OECD TG 401 but not in compliance with GLP (Huntingdon Life Sciences, 1997). The clinical signs in the surviving animals ranged from lethargic and demonstrated decreased activity, hypothermia, emaciation and prostration, with survivors making a full recovery by day 13. The main finding of gross pathology was effects in the liver. The LD₅₀ values for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane were concluded to be 281 and 237 mg/kg bw for male and female rats respectively, with evidence of overt toxicity at the lowest treated dose of 175 mg/kg bw.

A second supporting study was also available for acute oral toxicity, conducted largely in compliance with a standard guideline and in accordance with GLP (Pharmakon, 1993). An LD₅₀ value of 215 mg/kg bw was reported in male and female rats for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane, with evidence of toxicity at the lowest tested dose of 165 mg/kg bw. The clinical signs included subdued behaviour, lethargy and paleness and the gross pathology revealed cloudy pleural fluid, haemorrhagic ascites (bloody peritoneal fluid) or thickening of the hepatic capsule frequently in all treated groups.

The key study for acute inhalation toxicity reported an LC₅₀ of >26 ppm (vapour) (equivalent to 377 mg/m³ or 0.38 mg/L) in a study conducted according to an OECD guideline but not in compliance with GLP (Dow Corning Corporation, 1993). The target concentration of 25 ppm was considered the highest concentration that could be reasonably produced given the test generating equipment and exposure chamber. No mortality occurred in any of the test animals during exposure. No overt signs of toxicity were observed in any of the animals during exposure or observation period. No changes in body weight were reported. Gross pathologic examination of the animals during terminal sacrifice revealed haemorrhagic foci of the lung in two male rats. No abnormalities were observed during microscopic examination of these lungs. The macroscopic finding of lung haemorrhages was interpreted as a terminal event at the time of sacrifice. Any other changes noted in the tissues of all other rats were considered to be typical of incidental findings of rats of this age and strain euthanized in this manner.

A reliability 4 supporting study was also available for inhalation toxicity. An LC₅₀ of >26ppm (vapour) (equivalent to 0.38 mg/L) is reported (Dow Corning Corporation, 1995), which supports the findings of the key study.

 

The key study for acute dermal toxicity was conducted in accordance with OECD TG 402 and in compliance with GLP (Pharmakon 1994). The study reported an LD₅₀ of 1972 mg/kg bw, with some evidence of toxicity from the lowest dose tested in the main study, of 1591 mg/kg bw. The clinical signs in the majority of animals which died included haemorrhagic ascites, cloudy pleural liquid and thickening of the hepatic capsule. Mortalities occurred between days 6 and 13 with higher susceptibility in the females. Subdued behaviour and prostration, and one case of abdominal distension was also noted.

Two supporting studies were also available for acute dermal toxicity with 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane.

The first supporting study was a semi-occlusive exposure conducted according to OECD TG 402 and in compliance with GLP (WIL, 1999). Desquamation was noted sporadically during the study for all animals. Clinical signs of toxicity were noted after day 4 of the study for female rats and included decreased defecation, decreased urination and hypo activity. These findings subsided by study termination. The test substance was not observed to be irritating to the skin. The study reported an LD₅₀of >2000 mg/kg bw.

The second supporting study for acute dermal toxicity was conducted according to OECD TG 402 and to GLP (Dow Corning Corporation, 1997). The LD50 reported for 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane was 1090 mg/kg in New Zealand white rabbits. Observed adverse effects were reduced body weight gain or body weight loss, and in animals that died red/brown discolouration and/or firmness of the liver, and fluid in the abdominal cavity.

Justification for classification or non-classification

Based on the available data, the registered substance, 4,4,7,7-tetraethoxy-3,8-dioxa-4,7-disiladecane, is classified as Acute Oral Toxicity Category 3, H301: Toxic if swallowed and Acute Dermal Toxicity Category 4, H312: Harmful in contact with skin, in accordance with Regulation (EC) No. 1272/2008. No classification is required for acute inhalation toxicity in the absence of mortalities at the highest achievable test concentration.