1,2,3-trichloropropane

Endpoint summary

Description of key information

- Oral:           LD50: 120 mg/kg bw for the male rat (OECD TG 401); study Shell Development Company (1980a))
- Dermal:        LD50: 390 mg/Kg bw for the male rabbit (OECD TG 402); study Shell Development Company (1980b)
- Inhalation: LC50(4 h): >= 4800 mg/kg bw for the rat (OECD TG 403); study Monsanto Company (1987)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: - followed recognized toxicology testing procedures - GLP compliant - study results copied without further assessment from the SIDS dossier

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Qualifier:

according to guideline

Guideline:

other: FIFRA Pesticide Assessment Guidelines, Subdivision F, 81-1 (1982) and TSCA, Health Effects Test Guidelines, Acute Oral Exposure

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

- Age at study initiation: 9 - 12 wks
- Weight at study initiation: males: 281 - 325 g, females: 225- 248 g
- Fasting period before study: yes, 18 h over night
- Housing: not reported in SIDS dossier
- Diet (e.g. ad libitum): not reported in SIDS dossier
- Water (e.g. ad libitum): not reported in SIDS dossier
- Acclimation period: not reported in SIDS dossier


ENVIRONMENTAL CONDITIONS
- not reported in SIDS dossier

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- no vehicle used


MAXIMUM DOSE VOLUME APPLIED: 350 mg/Kg bw

Doses:

Range-finding doses: 100, 180, 320, 560 and 1000 mg/kg.
LD50 study: 80, 120, 170, 250 and 350 mg/kg; administered as received.

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: day -1, day 1, day 7 and day 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Statistics:

LD50 calculated using the method of Miller, Lloyd C., and M. L. Tainter (1944).

Preliminary study:

not reported

Sex:

male

Dose descriptor:

LD50

Effect level:

205 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

170 mg/kg bw

Mortality:

not reported in SIDS dossier

Clinical signs:

other: The most prevalent in-life observations included: ataxia; decreased activity/prostration; hypopnea; wet rales; nasal/oral/ocular discharge; soft stool; fecal and urinary staining; decreased food consumption and unthrifty coat. Decreased food consumption

Gross pathology:

Significant gross necropsy findings in animals found dead included: changes in the stomach/intestines suggested of irritation or corrosive effect (red or black foci in stomach walls, presence of red or black material and discoloration of walls); some red or brown fluid in the urinary bladder; and red foci and discoloration of the lungs in all dosed animals

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute oral toxicity of 1,2,3-trichloropropane was tested using a recognized scientific procedure and followed recognized GLP procedures.
The following threshold values were determined:
LD50 (oral, rat, male) = 205 mg/Kg bw
LD50 (oral, rat, female) = 170 mg/Kg bw

Executive summary:

In the present study (Monsanto Company,1985) male and female Sprague-Dawley rats were treated once orally with undiluted 1,2,3 -trichloropropane via gavage and analysed for mortality, body weight development and clinical signs following generally the OECD TG 401 in compliance with GLP.

The following threshold values were determined:

LD50 (oral, rat, male) = 205 mg/Kg bw

LD50 (oral, rat, female) = 170 mg/Kg bw

Based on this results 1,2,3 -trichloropropane is classified as Category III (Toxic if swallowed (oral)) according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

Twenty-five male and 25 female Sprague-Dawley rats were divided equally into 5 dosage groups and administered a single dose of the test material via gavage. Animals were fasted overnight for 18 hours (except for water). Animals were observed at least twice daily for 14 days for mortality, pharmacologic and/or toxicologic effects. Individual body weights were recorded prior to fasting, at time of dosing and on days 7 and 14, or at time of discovery of death. All animals were subjected to gross necropsy, either at termination or time of discovery of death.

The most prevalent in-life observations included: ataxia; decreased activity/prostration; hypopnea; wet rales; nasal/oral/ocular discharge; soft stool; fecal and urinary staining; decreased food consumption and unthrifty coat. Decreased food consumption was observed in some animals through day 7. Significant gross necropsy findings in animals found dead included: changes in the stomach/intestines suggested of irritation or corrosive effect (red or black foci in stomach walls, presence of red or black material and discoloration of walls); some red or brown fluid in the urinary bladder; and red foci and discoloration of the lungs in all dosed animals.

Reference 2

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: - followed recognized toxicology testing procedures - GLP compliant - study results copied without further assessment from the SIDS dossier

Qualifier:

according to guideline

Guideline:

other: NAS Publication 1138 dtd 1977); Thompson-Weil Moving Average Method (1947)

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: not reported
- Age at study initiation: not reported
- Weight at study initiation: males weighing 205-275 grams; females weighing 180-240 grams when tested
- Fasting period before study: 16 - 24 h
- Housing: 1 per cage
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- no vehicle used


MAXIMUM DOSE VOLUME APPLIED: 1.8 ml/kg


DOSAGE PREPARATION (if unusual): no dosage preparation, treatment with undiluted test item via gavage

Doses:

Seven dose levels: 0.056, 0.1, 0.18, 0.32, 0.56, 1.0, and 1.8 ml/kg (equivalent to: 78.8, 140, 253, 450, 788, 1400 and 2530 mg/kg);

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: pre and post dosing and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: not reported

Statistics:

Values determined by method of Thompson and Weil, where appropriate, or by Litchield and Wilcoxon and 95% confidence limits provided.

Sex:

male

Dose descriptor:

LD50

Effect level:

120 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

188 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

152 mg/kg bw

Mortality:

males are generally more susceptible to 1,2,3-trichloropropane toxicity than females, see table 1 for details

Clinical signs:

other: The most prevalent in-life observations included: piloerection, polyuria, diarrhea, lacrimation, salivation, decreased activity, constricted pupils, corneal opacity, ptosis, nasal discharge, ataxia, lethargy, and difficult and labored breathing.

Gross pathology:

Significant gross necropsy findings included: discoloration of the stomach/intestines/urinary bladder/ liver and kidneys; testes drawn into abdominal cavity; distended cecum, prolapsed penis, black patches on liver, red patches on cardiac region and pyloric regions of stomach

- Table 1: Number of animals dead

 

Dose (mL/kg bw)	Mortality (# dead/total)			Time range of deaths (hours)
	Male	Female	Combined
Control	-	-	-
0.056	0/5	0/5	0/10
0.100	4/5	1/5	5/10	d 1 to d 10
0.180	5/5	-	-	d 1 to d 2
0.320	5/5	-	-	d 1 to d 2
0.560	5/5	5/5	10/10	d 1 to d 2
1.00	5/5	5/5	10/10	d 1
1.80	5/5	-	-	d 1

- Table 2: Average body weights and body weight gains before and after single oral treatment

Dose rate (ppm)	Body Weights (g)				Total Weight Gain
	day ‑1	day 1	day7	Day 14	g	% of lowest dose
Male
0.056	280 ± 16.6	257 ± 16.0	302 ± 25.4	328 ± 32.7	48 ± 21.7	100
0.100	261 ± 18.5	240 ± 20.9	200 ± 77.8	295	n/a	-
0.180	254 ± 17.1	231 ± 13.9	-	-	-	-
0.320	255 ± 15.0	237 ± 14.4	-	-	-	-
0.560	253 ± 14.8	229 ± 13.4	-	-	-	-
1.00	249 ± 9.6	228 ± 7.6	-	-	-	-
1.80	252 ± 21.7	249 ± 45.7	-	-	-	-
Female
0.056	226 ± 12.4	209 ± 13.9	231 ± 201	247 ± 18.2	21 ± 7.4	100
0.100	215 ± 11.7	193 ± 9.1	211 ± 9.5	230 ± 16.6	15 ± 22.6	71.4
0.560	215 ± 25	196 ± 24.3	-	-	-	-
1.00	216 ± 8.2	200 ± 7.1	-	-	-	-

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute oral toxicity of 1,2,3-trichloropropane was tested using a recognized scientific procedure and followed recognized GLP procedures.
The following threshold values were determined:
LD50 (oral, rat, male) = 120 mg/Kg bw
LD50 (oral, rat, female) = 188 mg/Kg bw
LD50 (oral, rat, combined) = 152 mg/Kg bw

Executive summary:

In the present study (Shell Development Company,1980) male and female Sprague-Dawley rats were treated once orally with undiluted 1,2,3 -trichloropropane via gavage and analysed for mortality, body weight development and clinical signs following generally the OECD TG 401 in compliance with GLP.

The following threshold values were determined:

LD50 (oral, rat, male) = 120 mg/Kg bw

LD50 (oral, rat, female) = 188 mg/Kg bw

LD50 (oral, rat, combined) = 152 mg/Kg bw

Based on this results 1,2,3 -trichloropropane is classified as Category III (Toxic if swallowed (oral)) according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

Thirty-five male and 35 female Sprague-Dawley rats were divided equally into 7 dosage groups (0.056, 0.1, 0.18, 0.32, 0.56, 1.0, and 1.8 ml/kg,equivalent to: 78.8, 140, 253, 450, 788, 1400 and 2530 mg/kg) and administered a single dose of the test material via gavage. Animals were fasted overnight for 16-24 hours (except for water). Animals observed for 14 days for mortality, pharmacologic and/or toxicologic effects hourly for the first 6 hours and at least twice daily for 14 days. Individual body weights were recorded prior to fasting, at time of dosing and on day 7 and 14, or at time of discovery of death. All animals were subjected to gross necropsy, either at termination or time of discovery of death.

The most prevalent in-life observations included: piloerection, polyuria, diarrhea, lacrimation, salivation, decreased activity, constricted pupils, corneal opacity, ptosis, nasal discharge, ataxia, lethargy, and difficult and labored breathing. Significant gross necropsy findings included: discoloration of the stomach/intestines/urinary bladder/ liver and kidneys; testes drawn into abdominal cavity; distended cecum, prolapsed penis, black patches on liver, red patches on cardiac region and pyloric regions of stomach.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

120 mg/kg bw

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:

other: - followed recognized toxicology testing procedures - GLP compliant - study results copied without further assessment from the SIDS dossier

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Qualifier:

according to guideline

Guideline:

other: FIFRA Pesticide Assessment Guidelines, Subdivision F, 81-3 (1982) and TSCA, Health Effects Test Guidelines, Acute inhalation Exposure.

GLP compliance:

yes

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: not reported in SIDS dossier study summary
- Age at study initiation: not reported in SIDS dossier study summary
- Weight at study initiation:males: 289 - 310 g; females: 167 - 176 g
- Fasting period before study: not reported in SIDS dossier study summary
- Housing: not reported in SIDS dossier study summary
- Diet (e.g. ad libitum): not reported in SIDS dossier study summary
- Water (e.g. ad libitum): not reported in SIDS dossier study summary
- Acclimation period: not reported in SIDS dossier study summary

ENVIRONMENTAL CONDITIONS
- not reported in SIDS dossier study summary

Route of administration:

inhalation: vapour

Type of inhalation exposure:

other: not clearly reported in SIDS dossier study summary, expected to be whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: New York University-style stainless steel chamber (300 L) with a pyramidal top and bottom.
- Exposure chamber volume: 300 L
- Method of holding animals in test chamber: not reported in SIDS dossier study summary
- Source and rate of air: Airflow rate was 63.9 L/min
- Method of conditioning air: not reported in SIDS dossier study summary
- System of generating vapor: liquid was metered to a Laskin-style nebulizer (sonic jet orifice) which generated the test atmosphere
- Method of particle size determination:
- Treatment of exhaust air:
- Temperature, humidity, pressure in air chamber: 26 °C; relative humidity: 35%; oxygen level: 21%.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: not reported in SIDS dossier study summary

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gas chromatography

Duration of exposure:

4 h

Concentrations:

4800 mg/m³

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: pre exposure and at selected intervals post exposure
- Necropsy of survivors performed: yes

Statistics:

not reported in SIDS dossier study summary

Preliminary study:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4 800 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: limit test

Mortality:

- no mortality at the limit dose

Clinical signs:

other: - during exposure: hypoactivity, lacrimation and slow labored breathing; - post exposure: periocular wetness, clear nasal discharge, hypoactivity, labored respiration, gasping, rattling sounds in lungs, red/brown perinasal encrustation and ataxia.

Body weight:

- a slight body weight decrease was seen for the first 2 days post exposure.

Gross pathology:

- no adverse findings at necropsy

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute respiratory toxicity of 1,2,3-trichloropropane was tested in compliance with OECD TG 403 in Sprague-Dawley rats of both sexes at a limit dose of 4800 mg/m³ (exposure duration = 4 h). No fatalities occurred. Based on this result 1,2,3-trichloropropane should not be classified according to CLP.

Executive summary:

In the present study (Monsanto 1987) the acute respiratory toxicity of 1,2,3-trichloropropane was tested in compliance with OECD TG 403 in Sprague-Dawley rats of both sexes at a limit dose of 4800 mg/m³ (exposure duration = 4 h). No fatalities occurred. Based on this result 1,2,3-trichloropropane should not be classified according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

Animals were probably whole body exposed in a New York University-style stainless steel chamber (temp.: 26 °C; relative humidity: 35%; oxygen level: 21%). Test item concentrations were analysed by gas chromatography. Animals were subsequently observed for clinical signs and body weight effects and sacrificed and necropsied 14 days after the exposure.

No fatalities occured at this limit dose, while during exposure hypoactivity, lacrimation and slow labored breathing was reported. Post exposure periocular wetness, clear nasal discharge, hypoactivity, labored respiration, gasping, rattling sounds in lungs, red/brown perinasal encrustation and ataxia were seen.At necropsy nevertheless no adverse effects were reported.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4 800 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: - followed recognized toxicology testing procedures - GLP compliant - study results copied without further assessment from the SIDS dossier

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

other: FIFRA Pesticide Assessment Guidelines, Subdivision F, 81-2 (1982) and TSCA, Health Effects Test Guidelines, Acute Dermal Exposure. Appears to follow OECD 402 for Acute Dermal Toxicity (although not specified).

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

- Age at study initiation: 8 wks
- Weight at study initiation: males: 2.2-3.2 Kg, females: 2.4-3.2 Kg.
- Fasting period before study: no
- Housing: 1 per cage
- Diet (e.g. ad libitum): not reported in SIDS dossier
- Water (e.g. ad libitum): not reported in SIDS dossier
- Acclimation period: not reported in SIDS dossier

ENVIRONMENTAL CONDITIONS
- not reported in SIDS dossier

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Five male and 5 female New Zealand White rabbits were placed into three dosage groups and had their backs shaved. The area was wrapped with gauze and occluded with an impervious plastic sleeve for 24 hours. After 24 hours, the bandages were removed and the backs were gently wiped with a moist towel. Animals were observed at 1, 2, and 4 hours post-dosing, and daily thereafter for 14 days. Body weights were measured at days 0, 7 and 14, or at the time of discovery of death. A gross necropsy was performed on each animal.
TEST SITE
- Area of exposure: backs
- % coverage: not reported in SIDS dossier
- Type of wrap if used: The area was wrapped with gauze and occluded with an impervious plastic sleeve for 24 hours


REMOVAL OF TEST SUBSTANCE
- Washing (if done): backs were gently wiped with a moist towel
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500, 1000 and 2000 mg/Kg
- Concentration (if solution): undiluted
- Constant volume or concentration used: no



VEHICLE
- no vehicle used

Duration of exposure:

24

Doses:

500, 1000 and 2000 mg/Kg

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: observation: 1, 2, and 4 hours post-dosing, and daily thereafter for 14 days; weighting: at days 0, 7 and 14, or at the time of discovery of death
- Necropsy of survivors performed: yes

Statistics:

LD50 was calculated using the method of Miller, Lloyd C., and M. L. Tainter (1944).

Preliminary study:

no

Sex:

male

Dose descriptor:

LD50

Effect level:

900 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

850 mg/kg bw

Sex:

male/female

Dose descriptor:

LD50

Effect level:

880 mg/kg bw

Mortality:

500 mg/kg 0/10; 1000 mg/kg (4/5 males and 5/5 females); 2000 mg/kg (10/10).

Clinical signs:

other: Rabbits at 1000 and 2000 mg/kg displayed decreased activity and food consumption; oral/nasal/ and ocular discharge; staining of the ano-genital area (red in color). Two of 5 rabbits in the low dose displayed hypoactivity, decreased food consumption, and

Gross pathology:

Gross necropsy of animals that died was primarily postmortem autolytic changes. Several rabbits had red fluid in the urinary bladder, and some had red and/or yellow fluid in the abdominal or thoracic cavities. Necropsies of animals at day 14 were comparable to historical controls.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute dermal toxicity of 1,2,3-trichloropropane was tested using a recognized scientific procedure and followed recognized GLP procedures.
The following threshold values were determined:
LD50 (dermal, rabbit, male) = 900 mg/Kg bw
LD50 (dermal, rabbit, female) = 850 mg/Kg bw
LD50 (dermal, rabbit, combined) = 880 mg/Kg bw

Executive summary:

In the present study (Monsanto Company,1985) male and female New Zealand White Rabbits were treated once orally with undiluted 1,2,3 -trichloropropane dermaly under occlusive conditions for 24 h and analysed for mortality, body weight development and clinical signs following generally the OECD TG 403 in compliance with GLP.

The following threshold values were determined:

LD50 (dermal, rabbit, male) = 900 mg/Kg bw

LD50 (dermal, rabbit, female) = 850 mg/Kg bw

LD50 (dermal, rabbit, combined) = 880 mg/Kg bw

Based on this results 1,2,3 -trichloropropane is classified as Category III (Toxic in contact with skin (dermal)) according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

Five male and 5 female New Zealand White rabbits were placed into three dosage groups (500, 1000 and 2000 mg/Kg) and had their backs shaved. The area was wrapped with gauze and occluded with an impervious plastic sleeve for 24 hours. After 24 hours, the bandages were removed and the backs were gently wiped with a moist towel. Animals were observed at 1, 2, and 4 hours post-dosing, and daily thereafter for 14 days. Body weights were measured at days 0, 7 and 14, or at the time of discovery of death. A gross necropsy was performed on each animal.

Mortality was as follows: 500 mg/kg 0/10; 1000 mg/kg (4/5 males and 5/5 females); 2000 mg/kg (10/10). Most surviving rabbits exhibited slight body weight loss at day 7, but gained weight from days 7-14. Rabbits at 1000 and 2000 mg/kg displayed decreased activity and food consumption; oral/nasal/ and ocular discharge; staining of the ano-genital area (red in color). Two of 5 rabbits in the low dose displayed hypoactivity, decreased food consumption, and nasal or ocular discharge up to day 7, but were normal thereafter. Gross necropsy of animals that died was primarily postmortem autolytic changes. Several rabbits had red fluid in the urinary bladder, and some had red and/or yellow fluid in the abdominal or thoracic cavities. Necropsies of animals at day 14 were comparable to historical controls.

Reference 2

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: - followed recognized toxicology testing procedures - GLP compliant - study results copied without further assessment from the SIDS dossier

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

other: Consistent with NAS Publication 1138 dtd 1977); Thompson-Weil Moving Average Method (1947) and Litchfield/Wilcoxon

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: not reported
- Age at study initiation: not reported in SIDS dossier
- Weight at study initiation: 2 - 3 Kg
- Fasting period before study: not reported in SIDS dossier
- Housing: 1 per cage
- Diet (e.g. ad libitum): not reported in SIDS dossier
- Water (e.g. ad libitum): not reported in SIDS dossier
- Acclimation period: not reported in SIDS dossier


ENVIRONMENTAL CONDITIONS
- not reported in SIDS dossier

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: backs were shaved and one half of the test animals were further prepared by abrading their backs (deep enough to penetrate the stratum corneum but not to the derma).
- % coverage: not reported in SIDS dossier
- Type of wrap if used: The area was wrapped with gauze and occluded with clear polyethylene film.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): backs were gently wiped with a moist towel
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.18, 0.32, 0.56, 0.78, 1.00, 1.80, and 3.20 mL/Kg bw (equivalent to: 253, 450, 788, 1097, 1406, 2530 and 4500 mg/Kg bw)
- Concentration (if solution): undiluted
- Constant volume or concentration used: no



VEHICLE
- no vehicle used

Duration of exposure:

24 h

Doses:

males: 0.18, 0.32, 0.56, 0.78, 1.00, 1.80, and 3.20 mL/Kg bw (equivalent to: 253, 450, 788, 1097, 1406, 2530 and 4500 mg/Kg bw)
females: 0.32, 0.56, 0.78, 1.00, 1.80, and 3.20 mL/Kg bw (equivalent to: 450, 788, 1097, 1406, 2530 and 4500 mg/Kg bw)

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation: at 24 hours, and twice daily for 14 days; weighing: at day 0, 7 and 14, or at the time of discovery of death
- Necropsy of survivors performed: yes

Statistics:

Thompson-Weil Moving Average Method (1947) and Litchfield/Wilcoxon

Sex:

male/female

Dose descriptor:

LD50

Effect level:

523 mg/kg bw

Sex:

male

Dose descriptor:

LD50

Effect level:

390 mg/kg bw

Sex:

female

Dose descriptor:

LD50

Effect level:

765 mg/kg bw

Mortality:

Mortality was observed at all dose levels; all males died at 0.56 ml/kg or higher, and all females at 1.0 ml/kg.

Clinical signs:

other: The most prevalent cageside in-life observations included: activity decrease, ataxia and nasal discharge. As dose increased the following additional signs were observed: few feces, no urination, hematuria, swollen testes/urethra, iritis, cyanosis and dea

Gross pathology:

Gross necropsy observations included: discolored internal organs (kidney, lungs, urinary bladder, liver, intestines); organs distended with blood; mottled organs (kidney, liver); swollen testes; fluid in abdominal cavity and pronounced serosal blood vessels on intestines.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute dermal toxicity of 1,2,3-trichloropropane was tested using a recognized scientific procedure and followed recognized GLP procedures.
The following threshold values were determined:
LD50 (dermal, rabbit, male) = 390 mg/Kg bw
LD50 (dermal, rabbit, female) = 765 mg/Kg bw
LD50 (dermal, rabbit, combined) = 523 mg/Kg bw

Executive summary:

In the present study (Shell Development Company, 1980) male and female New Zealand White rabbits were treated once with undiluted 1,2,3 -trichloropropane dermaly under occlusive conditions for 24 h and analysed for mortality, body weight development and clinical signs following generally the OECD TG 403 in compliance with GLP.

The following threshold values were determined:

LD50 (dermal, rabbit, male) = 390 mg/Kg bw

LD50 (dermal, rabbit, female) = 765 mg/Kg bw

LD50 (dermal, rabbit, combined) = 523 mg/Kg bw

Based on this results 1,2,3 -trichloropropane is classified as Category III (Toxic in contact with skin (dermal)) according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

Six male and 6 female New Zealand White rabbits were divided equally into 7 dosage groups (except the lowest dose which had no females; 0.18, 0.32, 0.56, 0.78, 1.00, 1.80, and 3.20 mL/Kg bw (equivalent to: 253, 450, 788, 1097, 1406, 2530 and 4500 mg/Kg bw)). Their backs were shaved and one half of the test animals were further prepared by abrading their backs (deep enough to penetrate the stratum corneum but not to the derma). The area was wrapped with gauze and occluded with clear polyethylene film for 24 hours. After 24 hours the bandages were removed, and the backs were gently wiped with a moist towel. Animals were observed at 24 hours, and twice daily for 14 days. Body weights measured at day 0, 7 and 14, or at the time of discovery of death. A gross necropsy was performed on each animal.

The authors reported that severe dermal lesions were not present on any animal at any time during the study. The most prevalent cageside in-life observations included: activity decrease, ataxia and nasal discharge. As dose increased the following additional signs were observed: few feces, no urination, hematuria, swollen testes/urethra, iritis, cyanosis and death. Gross necropsy observations included: discolored internal organs (kidney, lungs, urinary bladder, liver, intestines); organs distended with blood; mottled organs (kidney, liver); swollen testes; fluid in abdominal cavity and pronounced serosal blood vessels on intestines. Mortality was observed at all dose levels; all males died at 0.56 ml/kg or higher, and all females at 1.0 ml/kg. The dermal LD50 in male rabbits was 0.277 ml/kg (390 mg/kg); the dermal LD50 in females was 0.544 ml/kg (765 mg/kg), slope of 2.52; and combined it was 0.372 ml/kg (523 mg/kg), slope of 1.61

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

390 mg/kg bw

Additional information

- oral toxicity:

A LD50(oral, Sprague-Dawley rat, male) of 120 mg/kg bw is reported in the key study Shell Development Company (1980a) / key (rat acute oral toxicity, reliability Klimisch 2). The LD50(oral, rat, female) is 180 mg/Kg bw and the LD50 (oral, rat, combined) for both sexes is 152 mg/Kg bw. In the second available study that is also reliable (Monsanto Company (1985) / (rat, acute oral toxicity); Klimisch 2) comparable LD50 values are reported (Sprague-Dawley rats, males: 205 mg/Kg bw; females 170 mg/Kg bw). So both studies suggest a slight difference in the susceptibility of the two sexes to acute toxicity of 1,2,3-trichloropropane. Both studies report comparable clinical signs: (ataxia; decreased activity/prostration; hypopnea; wet rales; nasal/oral/ocular discharge; soft stool; fecal and urinary staining; decreased food consumption and unthrifty coat) and comparable necropsy findings(changes in the stomach/intestines suggested of irritation or corrosive effect (red or black foci in stomach walls, presence of red or black material and discoloration of walls); some red or brown fluid in the urinary bladder; and red foci and discoloration of the lungs and other organs of the central cavities and testes drawn into abdominal cavity ).

No additional data for other species is available. As the rat is the standard model organism for acute toxicity testing, these results are deemed sufficient for classification & labelling purposes and hazard assessment.

- dermal toxicity:

A LD50(NewWhite, rabbit, male) LD50 (dermal, rabbit, male) = 390 mg/Kg bw is reported in the key study of Shell Development Company (1980b) / key (rabbit acute dermal toxicity, reliability Klimisch 2). The LD50 (dermal, rabbit, female) is 765 mg/Kg bw and the combined LD50 (dermal, rabbit, combined) for both sexes is 523 mg/Kg bw In the second available study that is also reliable Monsanto Company (1985) / (rabbit, acute dermal toxicity; Klimisch 2) slightly higher values are reported (New Zealand White rabbits, LD50 (dermal, rabbit, male) = 900 mg/Kg bw , LD50 (dermal, rabbit, female) = 850 mg/Kg bw LD50 (dermal, rabbit, combined) = 880 mg/Kg bw). So in the Shell study a notably sex difference was seen as in rats in acute oral toxicity, while in the Monsanto study no such difference was obvious. Both studies report comparable clinical signs that are also comparable to the clinical signs in rats in the acute oral studies (activity decrease, ataxia and nasal discharge, few feces, no urination, hematuria, swollen testes/urethra, iritis, cyanosis and death). At gross necropsy comparable effects were found in both dermal studies that are in-line with findings in the acute studies in rats (discolored internal organs (kidney, lungs, urinary bladder, liver, intestines); organs distended with blood; mottled organs (kidney, liver); swollen testes; fluid in abdominal cavity and pronounced serosal blood vessels on intestines).

- inhalation toxicity:

Diverging data is available for inhalation toxicity. In a study that was deemed reliable in SIDS dossier on 1,2,3-trichloropropane (Monsanto Company (1987) / (rat, acute respiratory toxicity)) toxicity was apparent but did not lead to mortality at the used limit dose of 4800 mg/m³. The reported clinical signs were hypoactivity, lacrimation and slow labored breathing during exposure and periocular wetness, clear nasal discharge, hypoactivity, labored respiration, gasping, rattling sounds in lungs, red/brown perinasal encrustation and ataxia after exposure.

The other available studies give different results, but are all deemed unreliable for several reasons. At least they all lack information on substance purity.

Study name	LC50(4h) in mg/m³
Monsanto Company (1987) / (rat, acute respiratory toxicity)	≥ 4800
DOW K-002524-005 / (F344 rat and B6C3F1 mouse, acute inhalation toxicity)	No numerical data presented Mice: < 740 Rats: 740 < LC50(4h) < 2000
Hazelton 776-137 / (F344 rat, 1h inhalation exposure)	Females, 1 h exposure: 8560 Females, calculated 4 h exposure: 2140 Males, 1 h exposure: 13980 Males, calculated 4 h: 3495
NIOSH RTECSfor 1,2,3-trichloropropane	Union Carbide datasheet, rat, 2h exposure 3400 Union Carbide datasheet, rat, 4 h calculated: 1700 Citation Bandman A.L. et al. 1990: lowest lethal concentration = 3050

 In addition to the lack on substance purity data, DOW K-002524-005 does not present any precise numerical data on mortalities. It is only verbally described, that all mice died at 740 mg/m³ and fatalities occurred in rats at 740 and 2000 mg/m³ while all animals survived at higher doses. Of Hazelton 776-137 pages on animal source and husbandry was missing and during the 4 h trials no mortality occurred at any of the used doses, rendering the correct functioning of the test system questionable also for the measurements at 1 h of exposure. NIOSH RTECS for 1,2,3-trichloropropane cites two sources: a Union Carbide datasheet and Bandman A.L. et al. 1990 both of which are not available. Therefore the reliability of the stated results remains unclear. Monsanto Company (1987) remains the only reliable study that nevertheless does not deliver a clear LC50 value but only an estimation for a lower limit of this threshold value.

Justification for classification or non-classification

- oral toxicity: 1,2,3-trichloropropane is moderately toxic via the oral route based on systemic effects that lead to corrosive effects in the stomach and distended organs and possibly cyanosis as final cause for death. Classification as Category III (H301: toxic if swallowed) is considered to be required according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

- dermal toxicity: 1,2,3-trichloropropane is moderately toxic via the dermal route based on systemic effects that lead to discolorated and distended organs and possibly cyanosis as final cause for death. Classification as Category III (H311: Toxic in contact with skin) is considered to be required according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.

- inhalation toxicity: The results for inhalation toxicity of 1,2,3-trichloropropane are ambiguous. Based on the results of the only study deemed reliable in the SIDS report on 1,2,3-trichloropropane and following a conservative approach the substance is deem moderately toxic, Classification as Category III (Danger: H331: Toxic if inhaled) according to CLP (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL) as implementation of UN-GHS in the EU.