Urea,N'-[3-[[[(dimethylamino)carbonyl]amino]methyl]-3,5,5-trimethylcyclohexyl]-N,N-dimethyl-

Endpoint summary

Description of key information

Due to structural similarities of TDI- and IPDI-Uron acute oral and dermal toxicity of IPDI-Urone (39992-90-0) was assessed by read-across with TDI-Urone (17526-94-2).

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

TDI-Uron is used as read across partner because it is structural analog to IPDI-Uron.
For detailed justification, please see attached report in section 13.2.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of IPDI-Urone was established to be > 2000 mg/kg body weight. As none of the animals died the corresponding LD50 is > 2000 mg/kg bw. Thus, IPDI-Urone is practically nontoxic.

Executive summary:

The LD50 of IPDI-Urone was established to be > 2000 mg/kg body weight. As none of the animals died the corresponding LD50 is > 2000 mg/kg bw. Thus, IPDI-Urone is practically nontoxic.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-04-09 to 2001-04-25

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)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

- Substance type: organic
- Physical state: colourless solid
- Analytical purity: 100%
- Purity test date: 01 March 2000
- Lot/batch No.: 0232 07
- Expiration date of the lot/batch: March 2003
- Storage condition of test material: store dry in closed containers
- Other: stable at dry storage conditions for at least 2 years

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen
- Age at study initiation: no data
- Weight at study initiation: Body weight at the commencement of the study: male 150- 168 g and female 142- 160 g. 3 male and 3 female animals were used.
- Fasting period before study: Prior to administration of the test item animals were fasted by withholding food overnight. Following the period of fasting the animals were weighed and the test item was administered. Then the food was withheld for a further 3-4hours.
- Housing: The animals were barrier maintained (semi-barrier) in air conditioned rooms
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: adequate

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3°C
- Humidity (%): 55+/-10%
- Air changes (per hr): 10x per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2000 mg TDI-Urone in 1 % Carboxymethylcellulose (CMC, Sigma, Lot-No. 36H0738) ad 10 ml
- Amount of vehicle (if gavage): 10 ml/kg body weight
- Justification for choice of vehicle:The vehicle was chosen due to its non-toxic characteristics.
- Lot/batch no. (if required): 36H0738
- Purity: no data

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 males and 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 for 14 days after dosing. The animals were weighed prior to first application and once a week thereafter. A careful clinical examination was made twice a day on the day of dosing and once a day thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

none

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

As none of the animals died the LD0 is >2000 mg/kg body weight.

Clinical signs:

other: No clinical signs of toxicity were observed throughout the observation period.

Gross pathology:

Necropsy revealed an acute injection of blood vessels in all animals in fue abdominal region. This finding is due to euthanasia with an overdose of pentobarbital injected intraperitoneally.

Other findings:

no other findings

Table1: Bodyweight gain

Animal No.		Day 0	Day 7	Day 14
male	1	150	188	229
	2	168	215	256
	3	160	210	240
female	1	142	158	170
	2	146	159	180
	3	160	169	184

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of TDI-Urone was established to be > 2000 mg/kg body weight. As none of the animals died the corresponding LD0 is > 2000 mg/kg bw. Thus, TDI-Urone is practically nontoxic.

Executive summary:

In an acute oral toxicity study according to OECD 423, groups of 3 male and 3 female rats (Wistar) were given a single oral dose of 2000 mg/kg body weight TDI-Urone in 1% Carboxymethylcellulose and were observed for 14 days.

Considering the reported data of this toxicity test it can be stated that the test item TDI-Urone has no acute toxic characteristics.

According to the results obtained the LD50 was determined to be > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Basic study is according OECD, therefore quality is good

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

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

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:

key study

Study period:

2011-12-28 to 2011-12-14

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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): TDI urone
- Substance type: organic
- Physical state: solid, white powder
- Analytical purity: 97.5 %
- Lot/batch No.: 126815
- Expiration date of the lot/batch: 2013-06-01
- Storage condition of test material: room temperature in the dark

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: at least 200 g +/-20 %
- Fasting period before study: no
- Housing: housed individually during the 24-Hour exposure period and in groups of five, by sex, for the remainder of the study
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): 15 changes per hours
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: approximately 10% of the total body surface
- % coverage: approximately 10% of the total body surface
- Type of wrap if used: surgical gauze; piece of self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): treated skin and surrounding hair was wiped with cotton wool moistened with distilled water to remove any residual test item
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): see below
- Dose applied: 2000 mg/kg bw.
- For solids, paste formed: For the purpose of the study the test item was weighed out according to each animal's individual bodyweight and moistened with distilled water prior to application.

VEHICLE
- Amount(s) applied (volume or weight with unit): not specified
- Concentration (if solution): n.a.
- Lot/batch no. (if required): not reported
- Purity: distilled water

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females and five males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,dermal reations

Statistics:

none

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: There were no signs of systemic toxicity.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

no other findings

Table 1: Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg	Animal number and sex	Body weight (g) at day			Body weight change (g) during week
2000		0	7	14	1	2
	1-0 male	390	402	419	12	17
	1-1 male	365	379	400	14	21
	1-2 male	329	351	390	22	39
	1-3 male	357	369	381	12	12
	1-4 male	330	357	383	27	26
	2-0 female	216	220	232	4	12
	2-1 female	209	215	217	6	2
	2-2 female	200	204	217	4	13
	2-3 female	208	213	219	5	6
	2-4 female	218	222	228	4	6

Interpretation of results:

GHS criteria not met

Conclusions:

TDI-Urone is considered to be practically nontoxic when dermally applied in a single dose. The LD50 was determined to be > 2000 mg/kg bw. As none of the animals died the LD0 is > 2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study groups of 8-12 week old Wistar rats (5 males and 5 females) were dermally exposed to TDI-Urone (97.5%) moistened with water for 24 hours to 10% of the body surface area at a dose of 2000 mg/kg bw. Animals then were observed for 14 days.

The dermal LD50 (combined) was determined to be > 2000 mg/kg bw. As none of the animals died the LD0 is > 2000 mg/kg bw.

Therefore, TDI-Urone is considered as practically non-toxic when applied dermally in a single dose of 2000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

TDI-Uron is used as read across partner because it is structural analog to IPDI-Uron.
For detailed justification, please see attached report in section 13.2.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Interpretation of results:

GHS criteria not met

Conclusions:

IPDI-Urone is considered to be practically nontoxic when dermally applied in a single dose. The LD50 was determined to be > 2000 mg/kg bw. As none of the animals died the LD0 is > 2000 mg/kg bw.

Executive summary:

IPDI-Urone is considered to be practically nontoxic when dermally applied in a single dose. The LD50 was determined to be > 2000 mg/kg bw. As none of the animals died the LD0 is > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Basic study is according OECD, therefore quality is good

Justification for classification or non-classification

The LD₅₀ (oral) > 2000 mg/kg BW for TDI-Urone can also be assumed for IPDI-Urone.

According to the CLP-regulation substances with an LD₅₀ (oral) > 2000 mg/kg BW are not classified as toxic if swallowed.

The LD₅₀(dermal) > 2000 mg/kg BW for TDI-Urone can also be assumed for IPDI-Urone.

According to the CLP-regulation substances with an LD₅₀(derml) > 2000 mg/kg BW are not classified as toxic if if contact with skin.