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Administrative data

Description of key information

Methyl isothiocyanate is acutely toxic by the oral, dermal and inhalation routes. In guideline studies, the oral LD50 in rats was 77 or between 50 and 300 mg/kg bw, the 1-hour LC50 in rats was 1.9 mg/l (4-h LC50 estimated at 0.85 mg/l) and the dermal LD50 was 174 mg/kg bw in rabbits and 198 mg/kg bw in rats.

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:
other: GLP Guidelines Study (OECD 401)
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Qualifier:
according to guideline
Guideline:
other: Pesticide assessment guidelines
Deviations:
not specified
GLP compliance:
yes
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: Kleintierfarm madoerin AG (CH 4414 Fuellinsdorf, Switzerland)
- Age at study initiation: 8-10 weeks old
- Weight at study initiation: males = 181-215g, females = 160-196g
- Fasting period before study: yes, 12/18 hours
- Housing: in Makrolon type-3 cages with standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard kliba 343, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2°C
- Humidity (%): 50+/-10%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: polyethylene glycol
Details on oral exposure:
Application volume = 10 ml
Doses:
25, 60, 100 and 300 mg/kg bw
No. of animals per sex per dose:
5 animals/sexe/dose (after randomization)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations :4 times during test day 1, and daily during days 2-15.
- Frequency of weighing: test day 1, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology
Statistics:
Yes. The LOGIT-model was applied to estimate the LD50 value. Additionally, the 90, 95 and 99% confidence intervals for the LD50 for each sex and the slope of the concentration response line was estimated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
67 mg/kg bw
95% CL:
> 45 - < 93
Sex:
male
Dose descriptor:
LD50
Effect level:
82 mg/kg bw
95% CL:
> 43 - < 155
Sex:
female
Dose descriptor:
LD50
Effect level:
55 mg/kg bw
95% CL:
> 12 - < 99
Mortality:
At 25 mg/kg : 0% of mortality, 60 mg/kg (40%), 100 mg/kg (90%), 300 mg/kg (100%).
Clinical signs:
other: -At 25 mg/kg : sedation, dyspnea, curved body position, ruffled fur. -At 60 mg/kg : sedation, dyspnea, curved body position, ruffled fur + spams -At 100 mg/kg : sedation, dyspnea, curved body position, ruffled fur + spams + cryins, ventral body position,
Gross pathology:
-At 25 mg/kg (killed animals, 10) : no pathologic changes.
-At 60 mg/kg (dead animals, 4): intestines= reddened, slight.
-At 60 mg/kg (killed animals, 6) : no pathologic changes.
-At 100 mg/kg (dead animals, 9): lung = mottled, intestines = reddened and slight.
-At 100 mg/kg (killed animals, 1): no pathologic changes.
-At 300 mg/kg (dead animals, 10) : lung = mottled and slight.
Other findings:
no
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC no.1272/2008 (CLP)
Conclusions:
In this study, the acute oral LD50 of MITC in rats observed for a period of 14 days is 67 mg/kg.
Executive summary:

MITC was administered to rats (5 animals/sexe/dose) of both sexes by oral gavage, at 25, 60, 100 and 300 mg/kg bw of MITC. Rats were observed during 14 days after administration. At the lower dose, no mortality was observed. At 60 mg/kg bw, 40% of rats died; 90% at 100 mg/kg bw and 100% at 300 mg/kg bw. Based on observations, the acute oral LD50 of MITC in rats observed for a period of 14 days is 67 mg/kg.

Clinical signs, as sedation, dyspnea, curved body position, ruffled fur were observed at 25 mg/kg bw and higher.

According this result, MITC is classified in the Category 3 on the Regulation EC 1272/2008 as "toxic if swallowed".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
67 mg/kg bw
Quality of whole database:
Both studies are reliable, and performed in accordance with the OECD guidelines.

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study [OECD 403]
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Anglia Laboratory animals (Alconbury, Cambridgeshire).
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: in polyprolylene wire bottomed cages which were suspended on movable racks. Each cage held 5 rats of the same sex.
- Diet (e.g. ad libitum): Spratt's laboratory Diet 1, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 55-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Details on inhalation exposure:
A stainless steel chamber with infernal dimensions 0.37 x 0.37 x 0.37 m and a nominal capacity of 50 L was used for the exposures. The chamber was divided horizontally into two sections by stainless steel mesh. The male and female animals were held in separate sections of the chamber during the exposure and the position of the sexes was changed for each exposure.
The total sample of methylisothiocyanate (1 kg) was melted by heating the container in a water bath at 400C and about 60 g of the Iiquid sample was transferred to the generator flask. The vapour from the generator flask passed through a distillation column packed loosely with glass wool into a second flask where it was diluted with air before entering the exposure chamber. The glass wool packing prevented the particulate rnaterial, formed as the vapour cooled, from reaching the dilution flask.
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
1 h
Concentrations:
0.6, 1.5, 2.2, 2.5 and 3.1 g per cubic metre of chamber air
No. of animals per sex per dose:
5 rats/ sexe / dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations : twice daily
- Frequency of weighing : on days 1, 3, 7, 10, 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
no
Preliminary study:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
1.9 mg/L air
Exp. duration:
1 h
Mortality:
yes see table.
Clinical signs:
other: A period of hyperactivity lasting for approximately 5 minutes was observed in all test groups on first contact with MITC vapour. Eye irritation, laboured breathing, hypoactivity convulsion and death were observed subsequently during the exposures. The rap
Body weight:
Groups exposed to concentrations of MITC between 1.5 and 2.5 g/m3 showed a temporary decrease in group mean bodyweight. The surviving animals had resumed a normal rate of body weight gain after 1-3 days.
Gross pathology:
Abnormalities seen in animals that died as a result of exposure were limited to slight to moderate lung congestion, areas of lung haemorrhage and hepatisation and distended gas filled stomachs and small intestine. Macroscopic pathology was considered to be within normal limits for animals that survived the 14 day observation period.
Other findings:
Organ weight : Lung to bodyweight ratios of animals that died following exposure to concentration of MITC between 1.5 and 2.5 g/m3 were considered to be high.

Table : Results of mortality

Concentration of MITC (g/m3)

No. dead/ No. exposed

3.1

10/10

2.5

5/10

2.2

4/10

1.5

3/10

0.6

0/10

0

0/10

Interpretation of results:
other: Fatal if inhaled
Remarks:
Criteria used for interpretation of results: other: REGULATION (EC) No 1272/2008
Conclusions:
The LC50 (1h) for MITC is estimated at 1.9 g/m3 of air. Generic concentration limits for classification for inhalation toxicity are based on 4 hour testing exposures. According to the guidance to Regulation (EC) No 1272-2008 on classification, labelling and packaging (CLP) of substances and mixtures, conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours. Accordingly the equivalent 4-hour LC50 for MITC is 0.85 mg/l for labelling purpose.
Executive summary:

Five groups (5 male + 5 female rats) were exposed continuously for 1 hour to the vapour generated from the sample of MITC. Rats were exposed at 0, 0.6, 1.5, 2.2, 2.5 or 3.1 g MITC/m3. Animals were observed during 14 days. Mortality, clinical signs, bodyweight, gross pathology were recorded.

No mortalities were observed at 0 and 0.6 g/m3. Respectively, 3, 4, 5 and 10 rats died at 1.5, 2.2, 2.5 and 3.1 g/m3 air.

A period of hyperactivity lasting for approximately 5 minutes was observed in all test groups on first contact with MITC vapour. Eye irritation, laboured breathing, hypoactivity convulsion and death were observed subsequently during the exposures. The rapidity of onset and the severity of these effects appeared to be dose related. The behaviour of animals in the control group was normal throughout the exposure period.

The LC50 (1h) for MITC is estimated at 1.9 g/m3 of air.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
1 900 mg/m³ air
Quality of whole database:
The key study is reliable with a klimisch score of 2.

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: GLP Guidelines study (OECD 402)
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
other: EPA - Pesticide assessment guidelines.
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: Kleintierfarm Madoerin AG (CH4414 Fuellinsdorf/ Switzerland)
- Age at study initiation: 15-16 weeks old
- Weight at study initiation: males = 1.8/3.2 kg, females = 2.6-3.4 kg
- Fasting period before study: no data
- Housing: individually in stainless steel cages equipped with an automatic cleaning and drinking system.
- Diet (e.g. ad libitum): pelleted standard kliba 341, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 55+/-10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12 (music/light period)
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: backs of the animals
- % coverage: 40 square centimeters
- Type of wrap if used: after application, area was covered with an occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with lukewarm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.05 ml (50 mg/kg), 0.15 ml (150 mg/kg), 0.30 ml (300 mg/kg)

Duration of exposure:
24 hours
Doses:
50, 150 and 300 mg/kg bw
No. of animals per sex per dose:
5 rabbits/ sexe/ dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: four times during test day 1, and daily during days 2-15.
- Frequency of weighing: test day 1, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology.
Statistics:
The LOGIT-Model was applied to estimate the LD50 value. Additionally, the 90, 95 and 99% confidence intervals for the LD50 for each sex and the slope of the concentration response line was estimated.
Preliminary study:
no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
174 mg/kg bw
95% CL:
> 123 - < 272
Sex:
male
Dose descriptor:
LD50
Effect level:
145 mg/kg bw
95% CL:
> 81 - < 293
Sex:
female
Dose descriptor:
LD50
Effect level:
202 mg/kg bw
95% CL:
> 106 - < 140
Mortality:
At 50 mg/kg : 0% of mortality. At 150 mg/kg = 30%, and at 300 mg/kg : 90 % of mortality.
Clinical signs:
other: -At 50 mg/kg : sedation, dyspnea, myosis, erythema, edema, necrosis, curved body position. -At 150 mg/kg : sedation, dyspnea, myosis, erythema, edema, necrosis + atawia (males), latero-abdominal position (males), salivation -At 300 mg/kg : sedation, dyspn
Gross pathology:
-At 50 mg/kg (killed animals, 10) : lung (mottled, slight) = 1, no pathologic changes = 9.
-At 150 mg/kg (dead animals, 3) : lung (mottled, slight) =1, liver (mottled, slight) =1, no pathologic changes =1.
-At 150 mg/kg (killed animals, 7) : lung (mottled, severe) = 3, dark-red = 2, no pathologic changes =4.
-At 300 mg/kg (dead animals,9) : lung (mottled, slight) =1, lung (mottled, severe) = 1, dark-red seveve = 4, liver pale = 4, mottled = 2; stomach (marginal area, spotted, dark-red)=1, mammary glands (discolored, dark-red) =1, no pathologic changes =1.
-At 300 mg/kg (killed animals, 1) : lung (mottled, slight) = 1.
Other findings:
no
Interpretation of results:
Toxicity Category II
Remarks:
Migrated information Criteria used for interpretation of results: other: Guidance on the application of regulation(EC) No 1272/2008
Conclusions:
Based on the observations, the LOGIT-Estimation for the acute dermal LD50 of MITC in rabbits of both sexes over a period of 15 days is 174 mg/kg.
Executive summary:

MITC was applied to the skin of rabbits (5/dose/sex) of both sexes for 24 hours at 50, 150 and 300 mg/kg bw.

Animals were observed during 15 days, mortality, clinical signs and bodyweight were recorded.

No mortality were observed at 50 mg/kg bw. 30% of rabbits died at 150 mg/kg bw, and 90% at 300 mg/kg bw.

Clinical signs as sedation, dyspnea, miosis, erythema, edema, necrosis, curved body position were observed at 50 mg/kg bw and higher.

Based on the observations, the acute dermal LD50 of MITC in rabbits of both sexes over a period of 15 days is 174 mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
174 mg/kg bw
Quality of whole database:
Both studies are reliable, and performed in accordance with the OECD guidelines.

Additional information

Oral route

A guideline study (OECD 401) was initiated by Ullman (1985a). Methyl isothiocyanate was administered to rats (5 animals/sexe/dose) of both sexes by oral gavage, at 25, 60, 100 and 300 mg/kg bw of methyl isothiocyanate. Rats were observed during 14 days after administration. At the lower dose, no mortality was observed. At 60 mg/kg bw, 40% of rats died; 90% at 100 mg/kg bw and 100% at 300 mg/kg bw. Based on observations, the acute oral LD50 of methyl isothiocyanate in rats observed for a period of 14 days was 67 mg/kg. Clinical signs, as sedation, dyspnea, curved body position, ruffled fur were observed at 25 mg/kg bw and higher.

An acute oral toxicity study (OECD 423) of methyl isothiocyanate was conducted using Sprague-Dawley rats (Takashima et al., 2004). Using an administration dose of 300 mg/kg at the start of administration (stage 1), administration was gradually conducted according to stages 2 and 3 based on the number of mortalities in the animals subject to administration. Stages 2 and 3 were subject to administration of 50 mg/kg, and 3 females were subject to each stage. Observations were conducted for 14 days following the administration date (day 1 of observation), the weights were measured during the period of observation, and the animals were subject to euthanasia on day 15 of observation and necropsy performed. The results indicated that all animals (3/3) in the 300 mg/kg administration group in stage 1 died on the day of administration. In this same group, lying prone, pale skin (ears, limbs, nose, tail), salivation, restlessness and transient clonic convulsions were observed, and the animals died 1~3 hours after administration. Necropsy on the mortalities noted wet skin in the vicinity of the mouth and nose, reddening and some dark red areas of the lungs. Furthermore, obvious edema was noted in the proventriculus of only one animal. On the other hand, no mortalities were noted in the 50 mg/kg administration group (stages 2 or 3). In this same group, there was a steady gain of weight and there were no abnormalities in the general conditions noted but during the necropsy, a whitish thickening and hardened area was noted in the proventriculus of one animal. The acute oral LD50 was between 50 and 300 mg/kg.

Inhalation route

In the study of Clark (1977), five groups (5 male + 5 female rats) were exposed continuously for 1 hour to the vapour generated from the sample of methyl isothiocyanate. Rats were exposed at 0, 0.6, 1.5, 2.2, 2.5 or 3.1 g methyl isothiocyanate/m3. Animals were observed during 14 days. Mortality, clinical signs, bodyweight, gross pathology were recorded. No mortalities were observed at 0 and 0.6 g/m3. Respectively, 3, 4, 5 and 10 rats died at 1.5, 2.2, 2.5 and 3.1 g/m3 air. A period of hyperactivity lasting for approximately 5 minutes was observed in all test groups on first contact with methyl isothiocyanate vapour. Eye irritation, laboured breathing, hypoactivity convulsion and death were observed subsequently during the exposures. The rapidity of onset and the severity of these effects appeared to be dose related. The behaviour of animals in the control group was normal throughout the exposure period. The LC50 (1h) for methyl isothiocyanate is estimated at 1.9 g/m3 (1.9 mg/L) of air.

Generic concentration limits for classification for inhalation toxicity are based on 4 hour testing exposures. According to the guidance to Regulation (EC) No 1272-2008 on classification, labelling and packaging (CLP) of substances and mixtures, conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours. Accordingly the equivalent 4-hour LC50 of methyl isothiocyanate is 0.85 mg/l for labelling purpose. This calculation is supported by the a 4-hour LC50 of 0.54 mg/l in rats reported in the Draft Assessment Report (DAR) of metham sodium (Anonymous, 2007).

Dermal route

The studies of Ullmann (1985b & c) on dermal toxicity in rats and rabbits were GLP Guideline studies (OECD 402).

Methyl isothiocyanate was applied to the skin of rats (5 animals/dose/sex) of both sexes for 24 hours at 60, 120, 250 and 600 mg/kg bw of methylisothiocyanate (Ullmann, 1985b). Animals were observed during 14 days, mortality, clinical signs and bodyweight were recorded. No mortality were observed at 60 and 120 mg/kg bw, 80% of rats died at 250 mg/kg bw and 100% at 600 mg/kg bw. Clinical signs as dyspnea, erythema, ruffled fur were observed at 60 mg/kg bw and higher. Based on the observations, the acute dermal LD50 of methyl isothiocyanate in rats of both sexes over a period of 14 days was 198 mg/kg.

Methyl isothiocyanate was applied to the skin of rabbits (5/dose/sex) of both sexes for 24 hours at 50, 150 and 300 mg/kg bw (Ullman, 1985c). Animals were observed during 15 days, mortality, clinical signs and bodyweight were recorded. No mortality were observed at 50 mg/kg bw. 30% of rabbits died at 150 mg/kg bw, and 90% at 300 mg/kg bw. Clinical signs as sedation, dyspnea, myosis, erythema, edema, necrosis, curved body position were observed at 50 mg/kg bw and higher. Based on the observations, the acute dermal LD50 of methyl isothiocyanate in rabbits of both sexes over a period of 15 days was 174 mg/kg.


Justification for selection of acute toxicity – oral endpoint
Sereval studies are available to evaluate the acute toxicity of MITC after a single oral administration. Two studies are reliable: Ullman study showed a LD50 of 67 mg/kg/d and Takashima's study a LD50 comprised between 50 and 300 mg/kg/d in rats.

Justification for selection of acute toxicity – inhalation endpoint
Only one reliable study is available to evaluate the acute toxicity of MITC after a single administration by inhalation.

Justification for selection of acute toxicity – dermal endpoint
Two reliable studies are available to evaluate the acute toxicity of MITC after a single dermal administration. The study on rabbits showed a lower LD50 (174 mg/kg/d) than the study performed on rats (198 mg/kg/d).

Justification for classification or non-classification

Mandatory classification:

- Regulation (EC) No 1272/2008 Annex VI Table 3.1

Acute Tox 3: H331, Toxic par inhalation.

Acute Tox 3: H301, Toxic if swallowed

- Regulation (EC) No 1272/2008 Annex VI Table 3.2

T, R23/25: Toxic by inhalation and if swallowed

Self classification:

- Regulation (EC) No 1272/2008

Acute Tox 2: H330, Fatal if inhaled

Acute Tox 3: H301, Toxic if swallowed

Acute Tox 2: H310, Fatal in contact with skin

- Directive 67/548/EEC

T, R23/24/25: Toxic by inhalation, in contact with skin and if swallowed