N,N’-di[3-(p-toluene sulfonyl)oxy]phenyl urea

Endpoint summary

Description of key information

The substance has been tested for acute toxicity via the oral and inhalation routes.

In an acute oral toxicity study conducted in accordance with OECD Guideline 420, the LD50 was reported as >2000 mg/kg (nominal).  No mortality or treatment-related effects were observed during the study.

In an inhalation toxicity study conducted in accordance with OECD Guideline 403, the 4h LC50 was reported as >1.819 mg/L air (Maximum Achievable Breathing Zone Concentration) equivalent to 34.052 mg/L air (nominal). No mortality or adverse toxic effects were observed during the study.

 

 

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 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

December 17, 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Remarks:

Crl:CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CRL, Japan
- Females: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 200.1g (sighting study); 194.8 - 210.7g (main study)
- Fasting period before study: 17 - 19 hours
- Housing: hanging stainless steel cages with mesh floors; barrier-system animal rooms
- Historical data:
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week
- Method of randomisation in assigning animals to test and control groups: not stated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 25°C 
- Humidity (%): 40 - 70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12hrs dark / 12hrs light

Route of administration:

oral: gavage

Vehicle:

olive oil

Remarks:

The substance was suspended in olive oil at a concentration of 20% (w/v)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20% (w/v)
- Amount of vehicle (if gavage): 20mL
- Justification for choice of vehicle: the test substance would not dissolve in purified water. Vehicle is commonly used in general toxicity studies

DOSAGE VOLUME: 10 mL/kg

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

sighting study: 1 female/dose
main study: 4 female/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed continuously for 10 minutes after administration, then 30 minutes, then 3 hours. From Day 1 to Day 14 the animals were observed once each morning.
- Necropsy of survivors performed: yes
- Clinical signs including body weight: yes
- Other examinations performed: gross necropsy. External surfaces of the body, all orifices, subcutis, cranial, thoracic, abdominal and pelvic cavities with their contents were observed.

Statistics:

None

Preliminary study:

No evidence of toxicity or mortality was observed in the sighting study.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other:

Body weight:

lower than 10% body weight loss

Remarks:

No body weight loss was observed. See Table 4 below

Gross pathology:

No treatment-related effects observed.

Table 3: Clinical signs

Study	Dose (mg/kg)	Animal no.	Day after administration
			0				1	2	3	4	5	6	7	8	9	10	11	12	13	14
			(min)			(hr)
			^0a)-5	5-10	30	3
Sighting	2000	1	-	-	-	MS	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Main		2	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
		3	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
		4	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
		5	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-

^{a) immediately after dose administration} 

^{- no abnormalities detected}

^{MS: mucous stool}

Table 4: Body weight

Study	Dose (mg/kg)	Animal No.	Body weight (g)
			Day after administration
			initial	1^a)	7^a)	14^a)
Sighting	2000	1	200.1	226.8 (26.7)	251.2 (24.4)	265.1 (13.9)
Main		2	195.1	213.5 (18.4)	239.7 (26.2)	253.0 (13.3)
		3	194.8	213.8 (19.0)	239.7 (25.9)	258.0 (18.3)
		4	199.7	218.5 (18.8)	221.3 (2.8)	250.5 (29.2)
		5	210.7	234.8 (24.1)	254.9 (20.1)	280.4 (25.5)

a) figues in parentheses indicate difference from previous body weight

Table 5: Historical data: Frequency of mucous stool after administration of olive oil to starved Crl:CD (SD)

Sign	Sex	No. of occurances/no. of dosed animals
Mucous stool	Female	38/135

Interpretation of results:

GHS criteria not met

Conclusions:

No mortality or treatment-related effects were observed during the study. The LD50 value was determined to be >2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

The study was part of a testing package where all the studies have been conducted under GLP and in accordance with OECD guidelines or national methods, where applicable. The quality of data has been assessed to be reliable.

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

September 07, 2009

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

RccHan

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: In-house Laboratory
- Females nulliparous and non-pregnant: yes
- Rationale for use of males (if applicable): not specified
- Age at study initiation: 9 to 10 weeks
- Weight at study initiation: Male (min. 262.7g, max. 269.3g); Female (min. 181.3g, max. 191.2g)
- Fasting period before study: not applicable
- Housing: 3 rats/cage (polypropylene cages covered with stainless steel grip tops
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23
- Humidity (%): 56 60 66
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

3.17 µm

Geometric standard deviation (GSD):

2.61

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose-only inhalation equipment
- Exposure chamber volume: 2.062 Litres
- Method of holding animals in test chamber:
- Source and rate of air (airflow): dynamic air flow rate of 523 to 524 air changes per hour, ensuring adequate oxygen content of at least 19%. Co2 level was less than 1%.
- System of generating particulates/aerosols: The test item was loaded in a cylindrical powder reservoir which was loaded onto the dust generation system positioned below the cylindrical brush. The transportation piston pushes the compacted mass at a given speed out of the reservoir and onto the rotating brush which carries it into the upper part of the dispersion head. The mass is blown out of the brush by a high velocity air stream and is carried off via the dust exit nozzle to the chamber. The air flow rate through the dust generator was maintained at approx. 18 litres per minute.
- Method of particle size determination: gravimetric analysis
- Temperature, humidity in air chamber: 21.2 to 22.4°C, 52.0 to 53.7%,

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: gravimetric samples were collected and analysed to determine the chamber aerosol concentration. The concentration of the aerosol present in the chamber was determined gravimetrically twice during the 4 hour exposure period. Each sample was taken by drawing chamber atmosphere from the animal breathing zone at a set rate using a constant flow air sampling pump (0.8 LPM)
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gravimetric analysis

Duration of exposure:

4 h

Remarks on duration:

As stated in the test guideline

Concentrations:

1.819 mg/L air (Maximum Achievable Breathing Zone Concentration) equivalent to 34.052 mg/L air (nominal)

No. of animals per sex per dose:

3 male/3 female per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats observed twice per day for morbidity and mortality, once per day for clinical signs. Body weights recorded at Day 0 and post-exposure Day 1, 3, 7 and 14
- Necropsy of survivors performed: yes
- Clinical signs including body weight
- Other examinations performed: gross pathology, external examination and the opening of the nasal passage, abdominal and thoracic cavities

Statistics:

Not applicable.

Preliminary study:

Conducted without animals to determine the maximum concentration of the test item which could be generated in the test system. Breathing zone concentration ca. 1.8 mg/L air. Same experimental conditions used for main study.

Sex:

male/female

Dose descriptor:

LC50 cut-off

Effect level:

> 1.819 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

No mortality was recorded at the highest concentration tested.

Mortality:

None.

Clinical signs:

other: None

Body weight:

A decrease in the mean body weight was observed on Day 1 whereas an increase in the mean body weight was observed on Day 3, 7 and 14 in both sexes when compared with the Day 0 mean body weight. See Table 1 below.

Gross pathology:

External: no abnormalities
Internal: no lesions
No treatment related effects.

Table 1: Individual and mean body weights (g) and body weight changes (%)

 

Maximum Achievable Breathing Zone Concentration (mg/L air)	Sex	Rat no.	Body weights (g) on Day					Percent body weight change on Day
			0	1	3	7	14	1	3	7	14
1.819	Male	1	265.8	263.1	279.1	302.9	330.0	-1.0	5.0	14.0	24.2
		2	262.7	260.4	275.2	294.3	320.2	-0.9	4.8	12.0	21.9
		3	269.3	267.8	280.8	300.2	330.4	-0.6	4.3	11.5	22.7
		Mean	265.9	263.8	278.4	299.1	326.9	-0.8	4.7	12.5	22.9
		Standard Deviation	3.3	3.7	2.9	4.4	5.8	0.2	0.4	1.3	1.2
	Female	4	181.5	180.1	190.7	198.0	211.3	-0.8	5.1	9.1	16.4
		5	181.3	180.2	184.5	195.5	213.1	-0.6	1.8	7.8	17.5
		6	191.2	189.2	200.8	208.8	219.9	-1.0	5.0	9.2	15.0
		Mean	184.7	183.2	192.0	200.8	214.8	-0.8	4.0	8.7	16.3
		Standard Deviation	5.7	5.2	8.2	7.1	4.5	0.2	1.9	0.8	1.3

Key: 0 = before exposure

Interpretation of results:

GHS criteria not met

Remarks:

The test item concentration was tested at the maximum achievable breathing zone concentration and no mortality was observed and hence no LC50 could be calculated.

Conclusions:

The 4 hour acute median lethal concentration (LC50) of the test item in male and female Wistar was found to be greater than the maximum achievable breathing zone concentration of 1.819 mg/L air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 1.819 mg/L air

Physical form:

inhalation: dust

Quality of whole database:

The study was part of a testing package where all the studies have been conducted under GLP and in accordance with OECD guidelines or national methods, where applicable. The quality of data has been assessed to be reliable.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation)

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The concentration used in the acute inhalation toxicity study was the maximum achieveable for the test substance (dust) and no mortality was observed and judged to be sufficient for classification purposes. The LD50/LC50 values in the acute oral and inhalation toxicity studies do not meet the criteria outline in the CLP regulation (1272/2008EC, as amended) to warrant classification as acutely toxic or Specific Target Organ Toxicity - Single Exposure.