3,3,6,6-tetramethoxy-2,7-dioxa-3,6-disilaoctane

Endpoint summary

Description of key information

Several acute inhalation toxicity studies performed with the test material were available:

An acute vapor inhalation limit test was conducted with Dow Corning® X1 -6145A Additive in the Sprague Dawley rat (Kolesar and Sibert, 1990). Male and female rats were exposed to 0 and 0.92 mg/L (83 ppm) of the test material for four hours. No mortality or apparent abnormalities were observed in the control or test group animals during the exposure or first day. however, within 24 hours, test animals exhibited labored breathing and exhaustion. All test group animals were sacrificed in a moribund condition approximately 24 hours after exposure. Gross pathological examination revealed treatment-related lung changes and gas distention of the digestive tract in both male and female animals. Additionally, several female animals exhibited lung mottling. These results suggest that Dow Corning® X1 -6145A Additive does pose a significant acute inhalation hazard (LC₅₀< 0.92 mg/L corresponding to 83 ppm) under the conditions of this study.

An acute and 14 -day repeated dose inhalation study was initiated to assess the inhalation toxicity and to determine the NOAEL of DOW CORNING® X1-6154A Additive in rats (Crofoot et al., 1993). The study consisted of both an acute and repeated dose phase. Eight groups of five rats/sex were exposed acutely for six hours to target concentrations of 0, 0.5, 1.0 and 2.0 ppm of the test material. Four groups, one from each concentration level, were sacrificed immediately following exposure. The remaining groups were scheduled to be sacrificed following a 14 -day recovery period.

All rats in the acute phase, which were scheduled for immediate sacrifice, survived the exposure. Three rats, two male and one female, from the acute recovery phase died in the 2.0 ppm group. The remaining animals in this group were sacrificed in moribund state two days post-exposure. All other rats in the acute recovery phase survived to the scheduled sacrifice.

Clinical signs of toxicity which were considered treatment-related included ocular and nasal discharge, facial soiling, rough coats, soft feces, lethargy and labored breathing.

A statistically significant decrease in body weights was seen in male rats in the 0.5 and 1.0 ppm groups of the acute recovery phase.

Gross pathologic examination indicated that there were no test article-related lesions at necropsy in any of the rats from the acute phase which were sacrificed immediately after exposure. Histopathologic examination of tissues, however, indicated necrosis of respiratory epithelium of the nasal cavity in rats in the 1.0 and 2.0 ppm groups. Test article-related necrosis of the tracheal epithelium was also noted in these groups. No test article-related microscopic changes were observed in the respiratory tract or other organs examined in the 0.5 ppm group.

In the acute recovery phase, corneal opacity and a decrease in thymus size was noted in some animals in the 0.5 and 1.0 ppm groups. Several organs had test article-related effects, these included the eye and various levels of the respiratory tract. As in the acute immediate sacrifice phase of this study, necrosis of the respiratory epithelium of the nasal cavity was evident.

An acute vapor inhalation toxicity study (key study) was conducted to determine the four hour LC50 for DOW CORNING® X1-6154A Additive in Fischer 344/H rats (Siddiqui and Kolesar, 1993). Four groups of ten animals (5/sex/group) were exposed for four hours to target concentrations of 0.5, 2.0, 4.0 and 6.0 ppm. The animals were observed for 23 days following the exposures.

The actual exposure concentrations, as determined by the Analect Diamond 20 FT-IR analyzer, were 0.4, 2.0, 2.6 and 5.7 ppm. All animals died at the highest exposure concentration. One female rat died at 2.0 ppm and seven rats (5 males and 2 females) died at 2.6 ppm. Test article-related clinical signs of toxicity were observed in all exposure groups. The primary clinical signs observed included nasal discharge, mouth breathing, rales and labored breathing. The severity of effects was the function of the exposure concentration.

None of the animals exposed to 0.4 ppm had any gross lesions. Gross necropsy observations of animals that died during the study consisted of severe upper respiratory tract irritation and corneal opacity. Corneal opacity was the only gross lesion that occurred to animals in the other exposure groups that survived the observation period.

The LC50 was determined to be 2.4 ppm.

The study by Siddiqui and Kolesar, 1993, is considered the key study for the endpoint of acute toxicity because it allowed for determination of a LC50. The results of the two other available studies (Kolesar and Sibert, 1990; Crofoot et al., 1993) do not contradict the LC50 of 2.4 ppm from the Siddiqui and Kolesar (1993) study and deliver supplementary information for exposure at higher and lower concentrations and, in part, different exposure durations.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted May 12, 1981

GLP compliance:

yes

Test type:

traditional method

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

EXPERIMENTAL ANIMALS:
Male and female Fischer 344 rats (weighing approximately 125-150 g and 7-8 weeks of age) were purchased from Charles River Breeding Laboratories, Kingston, New York. Upon arrival at the Toxicology Department, all rats were quarantined for 1 week. Approved rats were weighed and randomized into test groups (5/sex/group) using the Xylon ASLECT program. After randomization, animals were ear-tagged and color coded.

ANIMAL MAINTENANCE:
THe rats were housed individually in stainless steel wire mesh cages. Before the exposure, the rats were transferred into cages that were designed to be placed within the exposure chambers. After the exposure, the rats were returned to their oiriginal housing. The rats were fed Purina® rodent chow and water at libitum except during the exposure. Relative humidity ca. 40%, light/dark cycle 12/12 hours.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

EXPOSURE METHODS AND GENERATION EQUIPMENT:
Exposures were conducted in 2 m3 liter stainless steel whole body exposure chambers. The chambers were operated under dynamic conditions where the chamber air was room air, which had been filtered (hepa and charcoal filters). Airflow through the chambers were kept at approximately 12-15 air changes per hour. Chamber temperature, humidity, and airflow were monitored continuously and were recorded every five minutes by the Camile(R) Data Acquisition System during the exposure period. The test material was introduced into the chambers through special designed glass J-tubes. The test material was metered into the J-tubes with Harvard Apparatus syringe pumps. Instrument air which was filtered flowed through the J-tubes at a controlled rate. The air/vapor mixture passed into the inlet port at the top of the chambers. During the exposure period, attempts were made to keep the actual concentrations of the test material in the chambers as constant as possible.
The duration of the exposure period was four hours after equilibration of the chamber concentration. The equilibration time, which is a function of chamber airflow, was approximately 25 minutes. The amount of test material used during the exposure period was determined by pre- and post-measuring the weight of the test material in each syringe. The exposure duration (exposure period and equilibration time), test material uses and airflow through the chambers were then used to calculate nominal concentration values.
Actual chamber concentrations were measured a minimum of once an hour with an Analect(R) Diamond 20 FT-IR analyzer. The analyzer was calibrated before the start of the study.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

by means of FT-IR

Duration of exposure:

4 h

Concentrations:

0.5, 2.0, 4.0 and 6.0 ppm (target concentrations); 0.4, 2.0, 2.6 and 5.7 ppm (actual concentrations)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

OBSERVATIONS:
All surviving rats were observed daily during the post-exposure period for treatment-related signs of toxicity, in particular, any evidence of respiratory, dermal, behavioral, nasal and/or ocular changes. The observation period was prolonged to further evaluate potential delayed toxicity.

BODY WEIGHT MEAUREMENTS:
Individual body weights were collected prior to exposure for animals in all groups. Also, body weights were collected on days 8, 15 and 23.

GROSS PATHOLOGY:
Necropsies were conducted on all animals which died spontaneously or at the termination of the study. Animals found dead after the working hours were refrigerated and necropsied on the next working day.

Statistics:

Statistical analysis was conducted on mortality data. The Health and Environmental Science Probit Program was used to calculate the LC50 value.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

2.4 ppm

Exp. duration:

4 h

Mortality:

All animals died at the highest exposure concentration. One female rat died at 2.0 ppm and seven rats (5 males and 2 females) died at 2.6 ppm.

Clinical signs:

other: Test article-related additional clinical signs were observed at all exposure levels. Rales and nasal discharge were observed in animals exposed to 0.4 ppm. Additional clinical signs observed in the other exposure groups included labored breathing, corneal

Body weight:

Body weights were intially depressed in a dose-dependent manner after one week. Surviving animals were gaining weight by the end of the observation period.

Gross pathology:

None of the animals exposed to 0.4 ppm had any gross lesions. Gross necropsy observations of animals that died during the study consisted of severe upper respiratory tract irritation and corneal opacity. Corneal opacity was the only gross lesion that occurred to animals in the other exposure gorups that survived the observation period.

Summary of mortality data:

	Number dead/number treated
Target exposure concentration (ppm)	Male	Female	Male/female combined
0.5	0/5	0/5	0/10
2.0	0/5	1/5	1/10
4.0	5/5	2/5	7/10
6.0	5/5	5/5	10/10

Summary of mean body weight data (g) - males:

Target exposure concentration (ppm)	Day of study
	1	8	15	22
0.5	184.0 (N=5)	177.0 (N=5)	202.0 (N=5)	225.0 (N=5)
2.0	184.0 (N=5)	121.0 (N=5)	151.0 (N=5)	186.0 (N=5)
4.0	184.0 (N=5)	129.0 (N=5)	NA	NA
6.0	185.0 (N=5)	120.0 (N=1)	NA	NA

Summary of mean body weight data (g) - females:

Target exposure concentration (ppm)	Day of study
	1	8	15	22
0.5	148.0 (N=5)	141.0 (N=5)	151.0 (N=5)	156.0 (N=5)
2.0	149.0 (N=5)	103.0 (N=5)	127.0 (N=4)	146.0 (N=4)
4.0	148.0 (N=5)	101.0 (N=5)	112.0 (N=4)	133.0 (N=3)
6.0	149.0 (N=5)	98.0 (N=3)	NA	NA

Necropsy findings:

	Male	Female
Disposition
·        Terminal sacrifice	10/20	12/20
·        Moribund sacrifice	0	0
·        Spontaneous death	10/20	8/20
Animals within all groups having grossly normal tissues
·        Group I (0.5 ppm)	3/5	5/5
·        Group II (2.0 ppm)	3/5	0
·        Group III (4.0 ppm)	0	1/5
·        Group IV (6.0 ppm)	0	0
Group II gross tissue changes
·        Eye: corneal opacity	2/5	3/5
·        Muzzle, vibrisses: porphyrin pigment	0	1/5
·        Hair, perineum: urine stained	0	1/5
·        Adipose tissue: atrophy, generalized	0	2/5
·        Stomach, mucosa: ulceration	0	1/5
·        Lung: congestion	0	1/5
·        Liver: congestion, mild	0	1/5
·        Liver: small	0	1/5
·        Thymus: small	0	1/5
·        Intestines: empty & gas distention	0	1/5
Group III gross tissue changes
·        Eye: corneal opacity	2/5	3/5
·        Hair, muzzle, vibrisses: porphyrin pigment	2/5	1/5
·        Skin, perineum: feces stained	1/5	0
·        Skin, nose: reddened, bilateral	2/5	0
·        Nose: blood present	0	1/5
·        Dehydration	3/5	2/5
·        Adipose tissue: atrophy, generalized	5/5	2/5
·        Stomach: blood, intraluminal	1/5	0
·        Stomach: ulceration	1/5	0
·        Lungs: congestion	5/5	2/5
·        Lungs: atelectasis, minimal	1/5	0
·        Liver: congestion, mild	2/5	2/5
·        Liver: small	2/5	2/5
·        Intestines: small amount digested & gaseous distention	5/5	2/5
Group IV gross tissue changes
·        Eye: corneal opacity	1/5	3/5
·        Hair, muzzle/forelegs: porphyrin pigment	4/5	3/5
·        Skin, perineum: feces stained	2/5	0
·        Skin, nose: reddened, bilateral	2/5	1/5
·        Nose: blood present	2/5	0
·        Adipose tissue: atrophy, generalized	0	4/5
·        Stomach: blood, intraluminal	0	0
·        Stomach: ulceration	0	0
·        Dehydration	5/5	4/5
·        Lungs: congestion	5/5	2/5
·        Lungs: atelectasis, minimal	0	0
·        Lungs: edema, minimal to mild	4/5	3/5
·        Intestines: small amount digested / gaseous distention	5/5	2/5
·        Adrenal gland, medulla: congestion	3/5	0
·        Liver: congestion, mild	2/5	1/5
·        Liver: small	0	1/5

Interpretation of results:

Category 1 based on GHS criteria

Executive summary:

An acute vapor inhalation toxicity study was conducted to determine the four hour LC50 for DOW CORNING® X1-6154A Additive in Fischer 344/H rats. Four groups of ten animals (5/sex/group) were exposed for four hours to target concentrations of 0.5, 2.0, 4.0 and 6.0 ppm. The animals were observed for 23 days following the exposures.

The actual exposure concentrations, as determined by the Analect Diamond 20 FT-IR analyzer, were 0.4, 2.0, 2.6 and 5.7 ppm. All animals died at the highest exposure concentration. One female rat died at 2.0 ppm and seven rats (5 males and 2 females) died at 2.6 ppm. Test article-related clinical signs of toxicity were observed in all exposure groups. The primary clinical signs observed included nasal discharge, mouth breathing, rales and labored breathing. The severity of effects was the function of the exposure concentration.

None of the animals exposed to 0.4 ppm had any gross lesions. Gross necropsy observations of animals that died during the study consisted of severe upper respiratory tract irritation and corneal opacity. Corneal opacity was the only gross lesion that occurred to animals in the other exposure groups that survived the observation period.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the 4 -h-LC50 of 2.4 ppm (corresponding to 0.027 mg/L) as a vapor, the test material is classified into Cat. 1 for acute inhalation toxicity according to CLP. The observed effects indicate that the dominant toxic effect is local damage to the respiratory tract and that the observed clinical signs and mortality are secondary to that. Therefore, the substance is additionally labelled with EUH71 (corrosive to the respiratory tract).