2-ethylhexyl 10-ethyl-4,4-dimethyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate

Endpoint summary

Description of key information

Acute oral LD50 1150 mg/kg bw in rats (OECD 401)

Acute dermal LD50 >1050 mg/kg bw in rabbits (OECD 402)

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Preferred study for this SIDS endpoint. Composition/purity of the test substance not reported.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

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: Harlan Sprague Dawley, Inc, Indianapolis, IN, USA
- Age at study initiation: Naïve young adult male and female rats
- Weight at study initiation: 204-321 grams
- Fasting period before study: Overnight prior to dosing
- Housing: All animals were acclimated to the laboratory for at least five days before being used. Animals were housed in groups of five in wire mesh suspension cages and were supplied Teklad 4% Mouse/Rat Diet and tap water ad libitum during both acclimation and test periods except for withholding food over night prior to dosing. The animal room was maintained on a 12-hour light12-hour dark cycle and at a temperature of 64-79◦F and a relative humidity of 30-70%. There were no contaminants in either the feed or the water that were expected to affect the outcome of this study.
- Diet: ad libitum, Tekland 4% Mouse/Rat diet
- Water: ad libitum
- Acclimation period: At least five days


ENVIRONMENTAL CONDITIONS
- Temperature: 64-79◦F
- Humidity (%): 30-70 %
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle


IN-LIFE DATES: From: July 30, 1996 To: August 22 1996

Route of administration:

oral: gavage

Vehicle:

other: none

Details on oral exposure:

VEHICLE: not applicable

MAXIMUM DOSE VOLUME APPLIED: 2.50 g/kg


DOSAGE PREPARATION (if unusual): The test material was administered undiluted using bulk density to determine the dose volume.

Doses:

625, 880, 1250, and 2500 mg/kg

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed frequently for gross signs of systemic toxicity and mortality on the day of test material administration, and at least twice daily thereafter for a total of 14 days. Body weights were measured for each animal on the day of dosing, on Day 7 of the observation period, and at the time of necropsy either at the end of the fourteen day observation period or following the death of any animal.
- Necropsy of survivors performed: yes

Statistics:

The LD50 and 95% confidence intervals were calculated by the method of Litchfield and Wilcoxon (1949).

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 150 mg/kg bw

95% CL:

850 - 1 550

Mortality:

Animals in the 880 and 1250 mg/kg bw groups died within 48 hours of dosing and all animals in the 2500 mg/kg bw group died within 24 hours of dosing.

Males:
2.50 g/kg- all animals dead at day 1
1.25 g/kg- one animal dead
0.88 g/kg- no animals died
0.625 g/kg- no animals died

Females:
2.50 g/kg- all animals dead at day 1
1.25 g/kg- 4 animals died on day1
0.88 g/kg- two animals died on day 1 and a total of 4 died by day 2.
0.625 g/kg- no animals died

Based on the cumulative mortality observed during the 14 day observation period following a single oral dose of undiluted Dimethyltin bis (2-ethylhexylthioglycolate) the acute oral LD50 value was calculated to be 1.15 g/kg with 95% Confidence Intervals of 0.85 g/kg and 1.55 g/kg.

Clinical signs:

other: Clinical signs noted during the observation period included varying degrees of depression, comatose, piloerection, eye squinting, hunched posture, labored breathing, ataxia, fecal stains, urine stains, and an unkempt fur coat.

Gross pathology:

The gross necropsy findings in the animals that died during the observation period included lungs, liver, and spleen mottled, lungs hemorrhagic, lungs reddened, liver pale and mottled, liver exhibits area of pale blanching, spleen darkened, kidneys pale and/or congested, left kidney enlarged, stomach distended with gas, intestines reddened, intestines contain paste-like material, urinary bladder contains red or yellowish-red fluid and external staining. The only necropsy findings noted in animals which survived the 14 day observation period was tip of spleen darkened in one animal

Interpretation of results:

other: Classified as Category 3 according to EU criteria.

Conclusions:

Based on the cumulative mortality observed during the 14-day observation period following a single oral gavage dose of undiluted test substance the acute oral LD50 value was calculated to be 1150 mg/kg.

Executive summary:

The acute oral toxicity of undiluted test substance was evaluated in the OECD test guideline 401. The test material was administered undiluted to groups of five male and five female Sprague-Dawley rats at a dose level of 625, 880, 1250, and 2500 mg/kg. Following a single oral administration, the animals were observed for 14 days.

Based on the mortality observed, the acute oral LD50 value was calculated to be 1150 mg/kg with the 95% Confidence Limits of 850 and 1550 mg/kg. Clinical signs noted during the observation period included varying degrees of depression, comatose, piloerection, eye squinting, hunched posture, labored breathing, ataxia, fecal stains, urine stains, and an unkempt fur coat. With exception of one animal, all surviving animals exhibited body weight gain at day 14. Gross necropsy findings for animals that died during the observation period included lungs, liver, and spleen mottled, lungs hemorrhagic, lungs reddened, liver pale and mottled, liver exhibits area of pale blanching, spleen darkened, kidneys pale and/or congested, left kidney enlarged, stomach distended with gas, intestines reddened, intestines contain paste-like material, urinary bladder contains red or yellowish-red fluid and external staining. The only necropsy findings noted in animals which survived the 14 day observation period was tip of spleen darkened in one animal. The test substance was classified according to 40 CFR 156 as Toxicity Category III based on the response observed following oral administration.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 150 mg/kg bw

Quality of whole database:

Two studies are available to address this endpoint; both were conducted in accordance with standardised guidelines. The quality of the database is therefore considered to be good.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline-type study, conducted under GLP.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Remarks:

none that affected the results of the study

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Western Oregon Rabbit Company (Philomath, OR).
- Age at study initiation: 11 to 12 weeks
- Weight at study initiation: 2.25 to 2.78 kg for males and 2.32 to 2.81 kg for females.
- Fasting period before study: Recorded in raw data.
- Housing: The animals were housed individually in stainless steel cages suspended above noncontact bedding pans containing Sani-Chips hardwood bedding (P.J. Murphy Forest Products, Montville, NJ).
- Diet (e.g. ad libitum): Rabbits received a daily ration of Purina Certified High-Fiber Rabbit Chow Type 5325 (Richmond, IN)
- Water: ad libitum. All rabbits had free access to purified (filtered, deionized, and UV-treated) tap water via automatic watering:
- Acclimation period: 7 day quarantine period


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19- 21
- Humidity (%): 36 – 67%
- Air changes (per hr): 10 air changes per hour with no recirculation
- Photoperiod (hrs dark / hrs light): 12 – hour on and 12 hour off


IN-LIFE DATES: From: March 25, 1993 To: April 8, 1993

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Two days before treatment, 10 male and 10 female rabbits were randomly selected from a healthy stock population and tentatively assigned to the study. The fur was clipped free from the dorsal area of the trunk of the selected rabbits by the use of electric clippers (Oster, Milwaukee, WI) with a size 40 blade. One day before treatment, the clipping was repeated. Care was taken to avoid abrading the skin, and only animals with healthy, intact skin were selected. Extra animals from the same shipment were available as substitutes for any animal assigned to the study that had unacceptable skin.
- % coverage: The test substance was applied uniformly within a 12 X 14 cm (168-cm-2) area of clipped intact skin.
- Type of wrap if used: Elastikon tape (Johnson & Johnson Products, Inc. New Brunswick, NJ).


REMOVAL OF TEST SUBSTANCE
- Washing (if done): The application sites were washed with a few milliliters (exact amount was not measured) of 1% (v/v) aqueous solution of Ivory® Liquid Hand Soap (Lot No. 2202 K 103; Proctor & Gamble, Inc., Cincinnati, OH). The soap was removed from the application sites by rinsing under a stream of running lukewarm tap water. The animals were then blotted dry with paper towels and returned to their respective cages.
- Time after start of exposure: 24-hour exposure period.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.89 ml/kg
- Concentration (if solution): Dose level of 1.05 g/kg
- Constant volume or concentration used: No, Use of the density measured by SRI, the volume dose was calculated.
- For solids, paste formed: NA, test material was liquid


VEHICLE
- Amount(s) applied (volume or weight with unit): 0.89 ml/kg of saline (0.9% Sodium Chloride
- Concentration (if solution): 0.9%
- Lot/batch no.: Lot No. G869024, Baxter Health Care Corp., Deerfield, IL).
- Purity: 0.9% Sodium Chloride

Duration of exposure:

24 hours

Doses:

1050 mg/kg

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations done at 0.00 hr to 1:11 hr; 1:45 to 2:56 hr; 2:25 to 3:36 hr; and 3:55 to 5:06 hr. Body weights were recorded on Day 0 (before dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: No deaths, or test substance-related systemic effects were observed over the 14-day observation period. After removal of the screen and patches, the applications sites of 9 of the ten rabbits had a slight oily film; after washing and rinsing, one of 10 rabbits had no visible residue, and 9 of 10 had “no appreciable film” visible. Of those nine animals, three required a second rinse. The only observation of an effect other than skin irritation was a single observation of “hyperactivity’ in one treated female on Day 9. Because this effect was observed in only one animal, and the effect occurred relatively late in the study, the effect is judged to be incidental and not related to treatment with the test substance. All male and female rabbits had varying degrees of skin irritation. Males and females in both the treated and control groups showed transient irritation for the “non-irritating” tape at the perimeter of the application site. Males and females in the treated group showed additional irritation responses, such as thickened skin and chapped and flaky skin within the application site beginning as early as Day 2; all animals had recovered by Day 12. Because the contact period was 24 hr (compared to 4 hr for a dermal irritation assessment; e.g. 40 CFR 798.4470), these observations should not be used to evaluate the primary irritation potential of the test substance.

Statistics:

Other than the calculation of the mean and standard deviations for the body weights, no statistical evaluations were conducted.

Preliminary study:

Before animal studies were initiated, preliminary work was conducted to verify that the test substance coudl be washed from the surface with a 1% aqueous solution of Ivory (R) Lilquid Hand Soap. Samples of polypropylene screen were placed in aliquots of the test substance for 25 hr at room temperature, and were found to increase their weight by less than 3%. These preliminary data indicated that the screen would be compatible with the test substance and that the proposed method of washing the apploication sites after the 24-hr contact period would be effective.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 050 mg/kg bw

Mortality:

No deaths were observed over the 14-day observation period.

Clinical signs:

other: There were no treatment-related systemic clinical signs. The only observation of an effect other than skin irritation was a single observation of “hyperactivity” in one treated female on Day 9. Because this effect was observed in only one animal, and th

Gross pathology:

Necropsy revealed a slightly rough outer surface of the spleen of one treated male. The observation is judged to be incidental and to have no obvious relationship to treatment with the test substance.

Other findings:

Skin effects in the rabbits included the following observations: Irritation around the perimeter of the application site, redness, thickened skin, chapped, flaky skin, and edema.

Interpretation of results:

other: coudl not be determined as the result is an inequality

Conclusions:

Based on the lack of observed mortality, the 14-day acute dermal LD50 of the test substance was reported as >1050 mg/kg for both sexes.

Executive summary:

The acute dermal toxicity of the test substance was assessed by applying the liquid test substance within a 12 x 14 cm are of clipped intact skin of five male and five female New Zealand White rabbits at 1050 mg/kg body weight. The application site was covered with a 4 -ply 15 x 15 cm gauze patch held in place by nonirritating tape and polypropylene screen for 24 hours, after which the patch and the screen were removed. The application sites were washed with a dilute soap solution, rinsed with water, then blotted dry. A control group of five males and five females was treated with 0.89 mL/kg of saline and were handled in the same way as the animals that received the test substance. No deaths, or test substance related systemic effects were observed over the 14 -day observation period. The only systemic clinical sign was a single observation of hyperactivity in one treated female on Day 9. Because this effect was observed in only one animal, and the effect occurred relatively late in the study, the effect is judged to be incidental and not related to treatment with the test substance. All male and female rabbits had varying degrees of skin irritation. Males and females in both the treated group showed additional irritation responses such as thickened skin, edema, and chapped and flaky skin beginning as early as Day 2; all animals had recovered by Day 12. Because the contact period was 24 hr (compared to 4 hr for a dermal irritation assessment), these observations should not be used to evaluate the primary irritation potential of the test substance. There were no apparent body weight effects. Necropsy revealed no treatment related effects. Under the conditions of this study, the acute dermal LD50 in male and female rabbits was greater than 1050 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 050 mg/kg bw

Quality of whole database:

The study was conducted in accordance with standardised guideline under GLP conditions. The quality of the database is therefore considered to be good.

Additional information

Acute oral LD50 of DMT(2-EHMA) is 1150 mg/kg bw in rats. The study of DMT(2-EHMA) was considered reliable - the key study was conducted under GLP conditions in accordance with a standardised guideline. The LD50 for rats administered DMT(2-EHMA) was 1150 (850-1550) mg/kg bw. The mortality rate for both sexes was 0/10, 4/10, 5/10, and 10/10 for dose levels of 625, 880, 1250, and 2500 mg/kg bw, respectively. Clinical signs of toxicity included comatose, diarrhoea, hunched posture, eye squinting, laboured breathing, hyperactivity, depression, piloerection, ataxia, and emaciation. Gross necropsy results of animals that died during the study included mottled lungs, liver, and spleen; haemorrhagic lungs; pale and/or congested liver; intestines containing paste-like material; red or yellow-red fluid in the urinary bladder; and external staining. No gross abnormalities in animals that survived to the end of the study.

 

The acute dermal LD50 of DMT(2-EHMA) is > 1050 mg/kg for male and female rabbits. Undiluted test substance was applied to the shaved, intact skin of rabbits and covered with an occlusive patch. No deaths or test substance-related systemic effects were observed, and varying degrees of skin irritation, including thickened, chapped, and flaky skin, were noted within 48 hours. All signs of irritation disappeared by day 12, and no gross abnormalities were observed. 

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance requires classification with respect to acute toxicity via both the oral and dermal routes as Category 4 (H302: Harmful if swallowed; H312: Harmful in contact with skin).

In accordance with Annex VI, Regulation (EC) No 1272/2008, the substance has a harmonised classification with respect to acute oral toxicity as Category 4 (H302: Harmful if swallowed).