long chain alkyl thio carbamide metal complex

Endpoint summary

Description of key information

The acute oral LD50 is >2,000 mg/kg bw.
The acute dermal LD50 is >2,000 mg/kg bw.

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:

15-May-2002 to 14-Jun-2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

yes

Species:

rat

Strain:

other: Crl: CD (SD) IGSBR

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, NY
- Age at study initiation: 10-13 weeks
- Weight at study initiation: 217-257 g
- Fasting period before study: yes, overnight
- Housing: singly housed in suspended stainless steel and wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7-22 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 15-May-2002 To: 14-Jun-2002

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.5 g/ml (50% w/v)
- Amount of vehicle (if gavage): 4 ml/kg bw
- Justification for choice of vehicle: standard vehicle in toxicology studies; test substance is mixed with lubricant base oil in the final product
- Lot/batch no. (if required): Sigma, product number C8267, lot number 70K0 127
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 4 ml/kg bw

DOSAGE PREPARATION (if unusual): "The test substance was mixed with the carrier to form a dosable mixture"

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females tested

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- viability: twice daily Monday through Friday and once daily on weekends and holidays
- clinical observations: at 30 minutes, 1, 2, 4 and 6 hours after dosing and once per day thereafter for a total of 14 days
- body weight: on the day prior to dosing (pretest), on the day of dosing (day 0), on day 7 and on day 14
- Necropsy of survivors performed: yes
- Other examinations performed:
- clinical signs: the nature, onset, severity, and duration of toxicological signs
- body weights
- gross necropsy: performed on all animals; included an examination of the external surface of the body, all orifices, the cranial, thoracic and abdominal cavities and their contents

Statistics:

Means and standard deviations of body weight and body weight change calculated by group and sex

Preliminary study:

Not applicable

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

0/5

Clinical signs:

other: Present in 2/5: wet rales were evident in one animal from the 1 hour observation through to day 2, and alopecia of the trunk was seen in a rat on day 4 until study termination. Clinical signs were not reported at the other observation periods for these

Gross pathology:

Effects on organs: all animals were free of gross postmortem abnormalities with the exception of the one animal that displayed alopecia of the trunk

Other findings:

None

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to OECD guideline 425, the acute oral LD50 of EC# 457-320-2 was >2000 mg/kg bw (the limit dose) in female rats.

Executive summary:

In a GLP study conducted according to OECD guideline 425, EC# 457-320-2 was administered by oral gavage to five female rats at 2000 mg/kg bw, the limit dose. The animals were observed for clinical signs of toxicity and body weights were recorded over a 14-day observation period. A gross necropsy examination was performed at study termination.

There were no deaths reported. Two animals exhibited clinical signs of: wet rales were evident in one animal from the 1-hour observation through to Day 2, and alopecia of the trunk was seen in a rat on Day 4 until study termination. There were no clinical signs in the remaining three animals and all rats displayed increased body weights over their initial values. All animals were free of gross postmortem abnormalities with the exception of the one rat that displayed alopecia of the trunk.

In conclusion, the acute oral LD50 of EC# 457-320-2 is >2000 mg/kg bw in female rats. In accordance with EU CLP regulations, the substance would not need to be classified as acutely toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

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

Study period:

In-life period: 2002-05-16 to 2002-05-30

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CD (SD) IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Stone Ridge, New York
- Age at study initiation: males - 8 to 9 weeks; females - 10 to 11 weeks
- Weight at study initiation: males - 263 to 284 g; females - 216 to 239 g
- Fasting period before study: none
- Housing: singly housed in suspended stainless steel with wire mesh cages
- Diet (e.g. ad libitum): PMI certified rodent diet meal 5002, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 to 22.2
- Humidity (%): 30 to 70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2002-05-16 to: 2002-05-30

Type of coverage:

occlusive

Vehicle:

other: The substance was applied as supplied.

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 x 10 cm
- % coverage: at least 10%
- Type of wrap if used: 6-ply gauze dressing secured with an occlusive covering held in place by Elastikon

REMOVAL OF TEST SUBSTANCE
- Washing (if done): peanut oil/paper towel
- Time after start of exposure: approx. 24 hr

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): not applicable
- Constant volume or concentration used: yes
- For solids, paste formed: not applicable

VEHICLE
- Amount(s) applied (volume or weight with unit): none

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations: 1, 2, 4 and 6 h after dosing, then daily for 14 days; weighed on days -1, 0, 7 and 14; dermal observations days 1, 4, 7, 11 and 14.
- Necropsy of survivors performed: yes, gross necropsy on day 14
- Other examinations performed: no

Statistics:

Mean and standard deviation of body weights and body weight changes

Preliminary study:

none

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred

Clinical signs:

other: All animals were free from clinical signs of toxicity throughout the study All animal displayed increases in bodyweight during the stud y.

Gross pathology:

There were no gross abnormalities observed at postmortem.

Other findings:

Dermal irritation was noted for all animals during the study and scored according to the Draize method of scoring.
The Day 1 dermal responses could not be evaluated due to staining of the dose site by the test substance.
Erythema: day 4 - 3 animals grade 4; 1 animal grade 3; 1 animal grade 2 and 4 animals grade 1
day 7 - 9 animals grade 4
day 11 - 8 animals grade 4
day 14 - 5 animals grade 4

Oedema: day 4 - 6 animals grade 2; 3 animals grade 1
day 7 - 2 animals grade 2; 6 animals grade 1
day 11 - 6 animals grade 1
day 14 - 3 animals grade 1

Desquamation was noted for eight animals during the study (5 males; 3 females) and eschar was noted for nine (4 males; 5 females). Skin cracking was noted in 2 females on day 4 only.

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to OECD guideline 402, the acute dermal LD50 of EC# 457-320-2 in the rat was >2000 mg/kg bw, the limit dose. The substantial irritation produced had not been completely resolved in all animals by day 14.

Executive summary:

In a GLP study conducted according to OECD guideline 402, five male and five female rats were administered EC# 457-320-2 at 2000 mg/kg bw, the limit dose. The undiluted test material was applied to clipped skin, covering at least 10% of the body surface, under an occlusive dressing and removed after approximately 24 hours using peanut oil/paper towels. Animals were observed for up to 14 days post application. Clinical observations were made at frequent intervals during the day of application and on all subsequent days until post-mortem. Body weights were recorded pretest and on days 0, 7 and 14 and dermal observations made on days 1, 4, 7, 11 and 14.

 

All animals survived to day 14 and gained in body weight. No clinical signs of toxicity were seen in any animals. Dermal irritation was seen in all animals during the study, being first noted on Day 4 (not evaluated on Day 1 due to staining of the skin by the test material). By Day 14, the lesions had resolved in four of five males and one of five females. Irritation was scored according to the Draize method.

Erythema (grade 4) was seen in one male on Day 4, and in four, three and one male(s) on Days 7, 11 and 14 respectively. In females, grade 4 erythema was seen in two animals on Day 4 and in five, five and four animals on Days 7, 11 and 14 respectively. The highest oedema score seen, grade 2, was noted in two males on Day 4 only, whereas in females, four animals had a grade 2 lesion on Day 4 and two rats on Day 7. Other signs of local effects were eschar and desquamation, seen in animals at all time points and skin cracking, seen in two females only on Day 4.

In conclusion, the acute dermal LD50 for EC# 457-320-2 was >2000 mg/kg bw. According to EU CLP regulations, the test material would not be classified as acutely toxic by the dermal route. The local dermal toxicity had resolved completely in four males and one female by day 14, although severe erythema was still present in one male and four females at this time.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1

Additional information

In the acute dermal toxicity study, dermal irritation was seen in all animals. Erythema (grade 4) was seen in one male on Day 4, and in four, three and one male(s) on Days 7, 11 and 14 respectively. In females, grade 4 erythema was seen in two animals on Day 4 and in five, five and four animals on Days 7, 11 and 14 respectively. The highest oedema score seen, grade 2, was noted in two males on Day 4 only, whereas in females, four animals had a grade 2 lesion on Day 4 and two rats on Day 7. Other signs of local effects were eschar and desquamation, seen in animals at all time points and skin cracking, seen in two females only on Day 4. By Day 14, the lesions had resolved in four of five males and one of five females. Irritation was scored according to the Draize method. All animals survived to day 14 and gained in body weight, and no clinical signs of toxicity were seen in any animals.

Therefore, according to EU CLP regulations, the test material would not be classified as acutely toxic by the dermal route. The LD50 > 2000 mg/kg bw and the local dermal toxicity had resolved completely in four males and one female by day 14, although severe erythema was still present in one male and four females at this time.

In accordance with the Specific Rules for Adaptation laid down in Annex VIII of REACH, a study of the acute inhalation toxicity of the substance is not required, since the potential for inhalation exposure to occur is considered negligible and studies of acute toxicity via oral exposure and via dermal exposure have been provided.

Justification for classification or non-classification

The acute oral LD50 is >2,000 mg/kg; the only clinical signs were wet rales in one animal from the one-hour observation to the Day 2 observation, and alopecia of the trunk in one animal from Day 4 to study termination. As there were no remarkable body weight effects or gross pathology findings, no classification for acute oral toxicity is required according to both DSD and CLP.

The acute dermal LD50 is >2,000 mg/kg bw; adverse effects were limited to local irritation effects of the skin at the site of application,

therefore, no classification for acute dermal toxicity is required according to both DSD and CLP.

No acute inhalation toxicity data are available. Based on the low acute systemic toxicity via both the oral and dermal routes of exposure, no classification for acute inhalation toxicity is proposed.

In the acute oral toxicity study, the only clinical signs were wet rales in one animal from the one-hour observation to the Day 2 observation, and alopecia of the trunk in one animal from Day 4 to study termination. There were no remarkable body weight effects or gross pathology findings. In the acute dermal toxicity study, adverse effects were limited to local irritation effects of the skin at the site of application. Consequently, no classification for Single Exposure Specific Target Organ Toxicity is required under CLP.