Sodium dibutyldithiocarbamate

Endpoint summary

Description of key information

No data on acute toxicity of isolated (anhydrous) sodium dibutyldithiocarbamate are available. However, the substance is solely manufactured and marketed by the registrant as a saturated aqueous solution (ca. % 45.5%-47.5% w/w) and it is not expected that exposure to pure substance is possible. Therefore for the risk assessment it is considered to be acceptable and in fact more relevant to use acute toxicity data on the substance as manufactured.
The acute oral toxicity studies with sodium dibutyldithiocarbamate as a 46.20% solution in water (SDBC is manufactured as a 45.5-47.5% solution) showed LD50 values between 300 and 2000 mg/kg bw. Calculated for the isolated (anhydrous) substance, this corresponds to LD50 of 141-940 mg/kg bw. In the earlier acute oral toxicity study with rats using 47.5% aqueous solution of SDBC, LD50 of 1430 and 1330 mg/kg bw was established for males and females, respectively; recalculated for the isolated (anhydrous) substance, this corresponds to LD50 of 672 and 625 mg/kg bw for males and females, respectively.
In the acute dermal toxicity study in which 3 female rats were treated with 1000 mg/kg bw sodium dibutyldithiocarbamate as 46.20% solution in water one animals died and two animals were killed at day 8 in extremis, showing that the LD50 value is around or slightly below 1000 mg/kg bw.
No data on acute inhalation toxicity are available; however, in accordance with REACH Annex VIII, the study does not need to be conducted as data on two other routes of exposure are available.

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8-12 weeks old
- Weight at study initiation: +/- 20% of the sex mean
- Fasting period before study: overnight
- Housing: group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 – 21.5
- Humidity (%): 38 - 75
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 46.20%
- Amount of vehicle: 1.887 mL/kg bw (2000 mg/kg bw) and 0.283 mL/kg bw (300 mg/kg bw)
- Justification for choice of vehicle: substance as manufactured and marketed

Doses:

300 and 2000 mg/kw bw

No. of animals per sex per dose:

6 females/dose (in two groups of 3 females)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed twice daily for mortality. Body weights were determined at Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight. The value is determined for 46.2% solution of the substance; recalculated for pure substance it corresponds to LD50 of 141-940 mg/kg bw.

Mortality:

In the first group, treated with 2000 mg/kg bw test substance, 1 female died. In the second group administered the same dose all 3 animals died. Deaths occurred at days 1 or 2 post-treatment.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.

Gross pathology:

Upon macroscopic post mortem examination, several reddish or many dark red foci were found in the stomach glandular mucosa of all animals at 2000 mg/kg that were found dead during the study. Cannibalism and beginning autolysis were noted for one of these animals at necropsy. Macroscopic post mortem examination of the surviving animals at termination did not reveal any abnormalities.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

This is applicable for the 47% aqueous solution of SDMC.

Executive summary:

No data on acute toxicity of pure SDBC are available. The acute oral toxicity studies with SDBC as a 46% solution in water were used. In an OECD 423, GLP study in rats (Notox 2010), SDBC was given orally by gavage at 300 and 2000 mg/kg bw. In the first group, treated with 2000 mg/kg bw, 1 female died. In the second group administered the same dose all 3 animals died. Deaths occurred at days 1 or 2 post-treatment. Lethargy, tremor of the head, general muscle twitching, hunched posture, uncoordinated movements, piloerection and ptosis were observed. The surviving animals at 2000 mg/kg had fully recovered from the symptoms by Day 3. Hunched posture and/or piloerection were also noted among the animals at 300 mg/kg which had fully recovered from the symptoms by Day 3. Upon macroscopic post mortem examination, several reddish or many dark red foci were found in the stomach glandular mucosa of all animals at 2000 mg/kg that were found dead during the study. Cannibalism and beginning autolysis were noted for one of these animals at necropsy. Macroscopic post mortem examination of the surviving animals at termination did not reveal any abnormalities. The LD50 values were between 300 and 2000 mg/kg bw. The average of 2 dead animals per set of 3 treated animals at 2000 mg/kg was used for the assessment of the LD50 cut-off value. The LD50 cut-off value was considered to be 1000 mg/kg bw. Calculated for the isolated (anhydrous) substance, this corresponds to LD50 of 141-940 mg/kg bw. However, the lower limit of this range is meaningless for classification and labeling purposes for the pure substance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

300 mg/kg bw

Quality of whole database:

OECD TG 423 study performed under GLP

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 10-11 weeks old
- Weight at study initiation: +/- 20% of the sex mean
- Fasting period before study: overnight
- Housing: group housing of 3 animals per cage in labeled Macrolon cages (MIV type; height 18 cm) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.7 – 21.5
- Humidity (%): 38 - 73
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females.
- % coverage: 100
- Type of wrap if used: a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing: tap water for animals at 1000 mg/kg
- Time after start of exposure: 24 hr

TEST MATERIAL
- Amount applied: 2000 mg/kg (1.887 mL/kg) bw and 1000 mg/kg (0.943 mL/kg) bw.
- Constant concentration used: yes


VEHICLE
- Amount applied: 1.887 mL/kg (2000 mg/kg) bw and 0.943 mL/kg (1000 mg/kg) bw.

Duration of exposure:

24 hours for 1000 mg/kg bw dose groups; animals at 2000 mg/kg were found dead or were killed in extremis between 2 and 4 hours after application.

Doses:

1000 and 2000 mg/kg bw

No. of animals per sex per dose:

For 2000 mg/kg bw: 5/sex/dose; for 1000 mg/kg bw: 3 females/dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: for 2000 mg/kg bw, one male and four females died between 2 and 4 hours after application of the test substance, and, subsequently, the remaining female and four males at 2000 mg/kg were killed in extremis. At 1000 mg/kg one female was found dead on Day 1 and the remaining two females at 1000 mg/kg were killed in extremis on Day 8.
- Frequency of observations and weighing: Days 1 (pre-administration) and 8.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

< 1 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The treated skin of the two animals at 1000 mg/kg that were killed in extremis showed severe effects such as necrosis and a wound and these animals were hypersensitive to touch of the treated skin. The data correspond to 46.2% solution of SDBC.

Mortality:

Between 2 and 4 hours after application of the test substance, one male and four females at 2000 mg/kg were found dead and, subsequently, the remaining female and four males at 2000 mg/kg were killed in extremis. One female at 1000 mg/kg was found dead on Day 1 and the remaining two females at 1000 mg/kg were killed in extremis on Day 8.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

The two females at 1000 mg/kg that were killed in extremis on Day 8 showed changes in body weight gain over the first week post-treatment which were within the range expected for rats used in this type of study.

Gross pathology:

The two females at 1000 mg/kg that were killed in extremis on Day 8 showed isolated or several scab formations in the dorso-lumbar region of the skin at macroscopic post mortem examination. No abnormalities were found at macroscopic post mortem examination of the animals at 2000 mg/kg and 1000 mg/kg that were found dead or killed in extremis on Day 1.

Other findings:

The treated skin of the two animals at 1000 mg/kg that were killed in extremis showed severe effects such as necrosis and a wound and these animals were hypersensitive to touch of the treated skin. These signs suggest that treatment with the test substance caused marked pain and distress due to corrosive or irritating properties of the test substance. According to the test guidelines, further testing of the test substance need not be carried out based on these findings. A worst-case approach has been adopted by the study director for classification and labeling of the test substance for acute dermal toxicity.

A worst case Category 1 dermal toxicity classification as proposed by Notox for SDBC (fatal in contact with skin, category 1) seems to be inconsistent with the findings of the study and the results obtained for SDMC.

Based on the observations reported in the study report the systemic dermal LD50 is considered to be around 1.000 mg/kg. Therefore, an assumption that the LD50 for dermal exposure is in the range of 200-1000 mg/kg appears to be justified and in line with the precautionary principle. This leads to a classification Category 3 (toxic by the dermal route).

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on the observations reported in the study report the systemic dermal LD50 is considered to be around 1.000 mg/kg. Therefore, an assumption that the LD50 for dermal exposure is in the range of 200-1000 mg/kg appears to be justified and in line with the precautionary principle. This leads to a classification Category 3 (toxic by the dermal route).

Executive summary:

Acute dermal toxicity of SDBC as 46.20% solution was studied in an OECD 402, GLP study with rats. Initially, the test substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight (corresponding to 940 mg/kg bw pure substance) for 2-4 hours after which the animals were found dead or killed in extremis. Based on the mortality at 2000 mg/kg, an additional group of 3 females was treated at 1000 mg/kg bw (corresponding to 490 mg/kg bw pure substance) for 24 hours. One female at 1000 mg/kg was found dead on Day 1 and the remaining two females at 1000 mg/kg were killed in extremis on Day 8. Individual animals at 2000 mg/kg showed general muscle twitching or lethargy at two hours post-treatment. The animal at 1000 mg/kg that died on Day 1 showed lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea and ptosis prior to death. Similar clinical signs were observed between Days 1 and 8 for the two animals at 1000 mg/kg that were killed in extremis on Day 8. In addition, these two animals showed focal erythema, necrosis, scabs, a wound and/or a thickened area in the treated skin-area between Days 2 and 8. The two females at 1000 mg/kg that were killed in extremis on Day 8 showed isolated or several scab formations in the dorso-lumbar region of the skin at macroscopic post mortem examination. No abnormalities were found at macroscopic post mortem examination of the animals at 2000 mg/kg and 1000 mg/kg that were found dead or killed in extremis on Day 1. The dermal LD50 value of SDBC in Wistar rats is considered to be around or slightly below 1000 mg/kg bw for 46.2% aqueous solution of the substance (470 mg/kg bw for pure substance). The treated skin of the two animals at 1000 mg/kg that were killed in extremis showed severe effects such as necrosis and a wound and these animals were hypersensitive to touch of the treated skin. These signs suggest that treatment with the test substance caused marked pain and distress due to corrosive or irritating properties of the test substance. According to the test guidelines, further testing of the test substance need not be carried out based on these findings.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

< 1 000 mg/kg bw

Quality of whole database:

OECD TG 402 study performed under GLP

Additional information

No data on acute toxicity of isolated (anhydrous) sodium dibutyldithiocarbamate are available. However, the substance is solely manufactured and marketed as a saturated aqueous solution (ca.45.5%-47.5% w/w) by the registrant and it is not expected that exposure to pure substance is possible. Therefore for the risk assessment it is considered to be acceptable and in fact more relevant to use acute toxicity data on the substance as manufactured.

 

Acute oral toxicity

Acute oral toxicity of sodium dibutyldithiocarbamate (SDBC) as 46.20% solution was studied in a GLP-compliant guideline study with rats, using acute toxic class method (Notox, 2010a). Two groups of 3 female rats were administered the test substance as received by oral gavage at dose level 2000 mg/kg bw. 1 out of 3 animals of the first set and 3 out of 3 animals of the second set were found dead. Therefore the next dose level of 300 mg/kg bw was administered to the next two groups of 3 females each. All animals survived the treatment. All animals at 2000 mg/kg showed a combination of the following clinical signs on Day 1: lethargy, tremor of the head, general muscle twitching, hunched posture, uncoordinated movements, piloerection and ptosis. The surviving animals at 2000 mg/kg had fully recovered from the symptoms by Day 3. Hunched posture and/or piloerection were also noted among the animals at 300 mg/kg which had fully recovered from the symptoms by Day 3. The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. Upon macroscopic post mortem examination, several reddish or many dark red foci were found in the stomach glandular mucosa of all animals at 2000 mg/kg that were found dead during the study. Macroscopic post mortem examination of the surviving animals at termination did not reveal any abnormalities.

 

The oral LD50 value of SDBC in its manufactured form in Wistar rats was established to be within the range of 300-2000 mg/kg body weight (for 46.20% solution). The average of 2 dead animals per set of 3 treated animals at 2000 mg/kg was used for the assessment of the LD50 cut-off value. According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight. Calculated for the isolated (anhydrous) substance, this corresponds to LD50 of 141-940 mg/kg bw. However, the lower limit of this range is meaningless for classification and labelling purposes for the pure substance.

 

Acute oral toxicity of sodium dibutyldithiocarbamate (SDBC) as 47.5% aqueous solution was also investigated in the study with rats (Sumimoto Chemical Co., 1977), in which 10 male and 10 female rats per dose were administered the test substance at doses 100, 250, 500, 750, 1000, 1500, 2000 and 2500 mg/kg bw. At dose levels of 750 mg/kg bw and above, death occurred mostly 4-16 hours after treatment. No toxic signs were found at the lowest dose level, while at 250 and 500 mg/kg about 1 hour after administration decrease of spontaneous motor activity, piloerection and irregular respiration were developed, and disappeared in 1-2 days. At higher dose levels, also dyspnea, diarrhea and ataxia in hind limbs or whole body were observed. Toxic symptoms of surviving animals disappeared in 4-7 days. Necropsy findings did not reveal any remarkable findings in any test group. Based on the results of the studies LD50 for 47.5% solution of SDBC for males was calculated to be 1430 mg/kg bw (95% CI = 1100 -1860 mg/kg bw) and for females 1330 mg/kg bw (95% CI = 961 -1840 mg/kg bw). Calculated for the isolated (anhydrous) substance, this corresponds to LD50 of 672 and 625 mg/kg bw for males and females, respectively.

 

Acute dermal toxicity

Acute dermal toxicity of SDBC as 46.20% solution was studied in a GLP-compliant guideline study with rats (Notox, 2010b). Initially, the test substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight (corresponding to 940 mg/kg bw pure substance) for 2-4 hours after which the animals were found dead or killedin extremis. Based on the mortality at 2000 mg/kg, an additional group of 3 females was treated at 1000 mg/kg bw (corresponding to 490 mg/kg bw pure substance) for 24 hours. The animals at 1000 mg/kg were subjected to daily observations and weekly determination of body weight. Macroscopic examination of all animals was performed within 24 hours after death.

 

One female at 1000 mg/kg was found dead on Day 1 and the remaining two females at 1000 mg/kg were killed in extremis on Day 8. Individual animals at 2000 mg/kg showed general muscle twitching or lethargy at two hours post-treatment. The animal at 1000 mg/kg that died on Day 1 showed lethargy, hunched posture, uncoordinated movements, shallow respiration, piloerection, chromodacryorrhoea and ptosis prior to death. Similar clinical signs were observed between Days 1 and 8 for the two animals at 1000 mg/kg that were killed in extremis on Day 8. In addition, these two animals showed focal erythema, necrosis, scabs, a wound and/or a thickened area in the treated skin-area between Days 2 and 8.

The two females at 1000 mg/kg that were killed in extremis on Day 8 showed changes in body weight gain over the first week post-treatment which were within the range expected for rats used in this type of study.

 

The two females at 1000 mg/kg that were killed in extremis on Day 8 showed isolated or several scab formations in the dorso-lumbar region of the skin at macroscopic post mortem examination. No abnormalities were found at macroscopic post mortem examination of the animals at 2000 mg/kg and 1000 mg/kg that were found dead or killedin extremison Day 1. The dermal LD50 value of SDBC in Wistar rats is considered to be around or slightly below 1000 mg/kg body weight for 46.2% aqueous solution of the substance (470 mg/kg bw for pure substance).

The treated skin of the two animals at 1000 mg/kg that were killed in extremis showed severe effects such as necrosis and a wound and these animals were hypersensitive to touch of the treated skin. These signs suggest that treatment with the test substance caused marked pain and distress due to corrosive or irritating properties of the test substance. According to the test guidelines, further testing of the test substance need not be carried out based on these findings.

 

The toxic effects are separate from the corrosive effects: Toxic effects are central nervous system related and appear quite rapidly, whereas local effects show up in surviving animals later on. So there is a clear separation between 'systemic' and 'local' effects.

Based on the observations reported in the study report the systemic dermal LD50 is considered to be around 1.000 mg/kg. Therefore, an assumption that the LD50 for dermal exposure is in the range of 200-1000 mg/kg appears to be justified and in line with the precautionary principle.

 

The classification and labelling of the test substance for acute dermal toxicity is based on the weight of evidence applied to systemic vs. local effects at 1000 mg/kg bw.

Justification for classification or non-classification

Based on LD50 between 300 and 2000 mg/kg bw established in the acute oral toxicity study, according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, sodium dibutyldithiocarbamate (SDBC) in its manufactured and marketed form (as 45.5 -47.5% aqueous solution) should be classified as Category 4 and should be labelled as H302: Harmful if swallowed. 

The study of Sumimoto Chemical Co., 1977, in which the exact value of LD50 was determined for 47.5% solution of sodium dibutyldithiocarbamate rather than a range, allows calculation of the exact value of LD50 (672 and 625 mg/kg bw for males and females) for pure (anhydrous) sodium dibutyldithiocarbamate. Based on this value, according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, pure (anhydrous) sodium dibutyldithiocarbamate (SDBC) should also be classified as Category 4 and should be labelled as H302: Harmful if swallowed. 

Based on the results of acute dermal toxicity study and a careful separation of systemic and local effects and from a precautionary point of view, sodium dibuthyldithiocarbamate (SDBC) in its manufactured and marketed form should be classified according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures as Category 3 and should be labelled as H311: Toxic in contact with skin. Since the bioavailability of the pure substances is considered to be limited by the maximum aqueous concentration of 47% solution, it is considered to be acceptable to apply the same classification for the pure substance as for the 47% solution.