Registration Dossier

Administrative data

Description of key information

The test item was a mixture of the reaction products (1-(3-(Dimethylamino)propyl)urea (CAS 31506-43-1, EC 401-950-2, monoDMAPAU) )and 1,3-bis[3-(dimethylamino)propyl]urea (CAS  52338-87-1, EC 257-861-2, bisDMAPAU)

The test substance was evaluated with the Corrositex test method to determine its corrosive potential and to designate its Packing Group classification. The results of this study indicated that the sample was compatible with the Corrositex system. The pH of the test material placed it in Category 1. The results obtained from the evaluation of four replicate samples were reproducible, demonstrating that a mean time of 40.44 minutes was required to destroy the synthetic biobarriers.

In an in vivo skin irritation study irritation study, the test substance, after 3 minute exposure showed no erythema or edema. After 1 hour exposure there was no erythema or edema. After 4 hour exposure there was no erythema or edema.

Generally, results of in vivo studies have a higher relevance than those from in vitro studies.
Therefore the substance has not to be classified for skin irritation, based on the result of the in vivo study.

In an eye irritation study, corneal opacity, iritis and conjunctival irritation persisted through day 7. One instance of soiling of the anogenital area was noted during the observation period. monoDMAPAU is corrosive to a rabbit eye.

Based on the presence of approximately 15% of 1,3-bis[3-(dimethylamino)propyl]urea.(bisDMAPAU) in the test item, and according to the attached read-across justification this result is also deemed valid for 1,3-bis[3-(dimethylamino)propyl]urea (bisDMAPU).

bisDMAPAU is classified as causing serious Eye Damage Eye Category 1.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
This study was designed to comply with the standards set forth in 49 CFR 173.137 which directs that this study be conducted according to the July 1992 OECD Guideline for Testing of Chemicals, Number 404, "Acute Dermal InitationlCorrosionn.
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
Identity : NE 1060
Supplied By : Air Products and Chemicals, Inc.
Date Received : 12/17/99
Storage : Room temperature and humidity.
Description : Clear liquid
Sample Preparation : The test article was used as received.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
New Zealand White rabbits were received from Ace Animals, Boyertown, PA on 12/21/99. Following a quarantine period of at least one week, three healthy New Zealand White rabbits were selected for this test from a larger group.
The animals were born the weeks of 10110 through 10/24/99. The pretest body weight was 2.0 kg. The animals were identified by cage notation and a uniquely numbered metal eartag. The animals were housed llcage in suspended cages. Bedding was placed beneath the cages and changed at least three timeslweek. Fresh Purina Rabbit Chow (Diet #5321) was provided daily. Water was available libitum.
The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12 hour lightidark cycle and was kept clean and vermin free.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
The test article was kept in contact with the skin for three (3) minutes and scored for erythema and edema one hour following patch removal. Since the 3 minute exposure did not produce a definitive effect, two additional rabbits were added to the study. All three animals were dosed at site #2 for an exposure period of 1 hour and at site #3 for a four hour exposure. Each site was scored for erythema and edema one hour following patch removal, at 24, 48 and 72 hours and again on days 7 and 14.
Observation period:
Animals were observed for systemic signs at each dermal scoring interval.
Number of animals:
3
Details on study design:
Initially, one rabbit was placed in a restraining stock and site #1 was dosed with 0.5 ml of the test article.
The test article was used as received, dosed by volume (0.5 mllsite) and placed on the clipped site undera 2.5 x 2.5 cm 4 ply surgical gauze patch. A plastic covering was held over the dose site in a semiocclusive manner for the three minute exposure period. Residual test article was removed from the test site by gentle washing with distilled water at the end of the exposure period, prior to scoring for dermal reactions. The site was scored for skin reactions, including ulceration and necrosis, at 1 hour following patch removal.
Since no evidence of a corrosive effect was observed at the three minute exposure, two additional animals were added to the study. All three animals were dosed with 0.5 ml of the test article at site #2 for an exposure period of one hour and at site #3 for an exposure period of four hours. The dosing procedure was the same as that used for site #1. The torso of each rabbit was loosely wrapped with a semi-occlusive dressing which was secured with non-irritating tape to aid in retaining the test patches in position and to retard evaporation of volatile substances. The patches from site #2 were removed at one hour post-dose and those from site #3 were removed at 4 hours post-dose. Residual test article was removed from the test site by gentle washing with water at the end of the exposure period, prior to scoring for dermal reactions. Care was taken to avoid cross-contamination of the dose sites.
Sites #2 and #3 of all animals were scored at 1 hour following patch removal, at 24,48 and 72 hours and again on days 7 and 14. Erythema and edema were scored according to the Draize scoring code, below.
Additional signs were described.
Erythema & Eschar
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4
Edema
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-defined by definite raising) 2
Moderate edema (raised approximately 1.0 mm) 3
Severe edema (raised more than 1.0 mm, extending beyond the area of exposure) 4
Site # 1 was located dorsally at the shoulder level. Sites #2 and # 3 were located dorsally at the hip
level. The general health of the animals was monitored at each observation time. Body weights were recorded pretest and at termination of the study.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
animal reclipped
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 1 hour
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
7 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
14 d
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritant / corrosive response data:
3 minute exposure: There was no erythema or edema.
1 hour exposure: There was no erythema or edema.
4 hour exposure: There was no erythema or edema.
Other effects:
Svstemic Observations: Two animals had diarrhea and soiling of the anogenital area. The remaining animal appeared normal during the observation period. Body weight changes were normal.
Interpretation of results:
GHS criteria not met
Conclusions:
The modified Primary Irritation Index is 0. The test substance is not corrosive to rabbit skin.
Executive summary:

The purpose of this study was to determine if the test article causes irreversible damage when applied to therabbit skin.Initially, one healthy New Zealand White rabbit was placed in a restrainer and dosed with NE 1060. Thetest article (0.5 ml) was placed on the intact skin of the back (Site1).The test article was kept in contactwith the skin for three (3) minutes and scored for erythema and edema one hour following patch removal.Sincethe 3 minute exposure did not produce a definitive effect, two additional rabbits were added to thestudy. All three animals were dosed at Site 2 for an exposure period of 1 hour and at Site 3 for a four hour exposure. Each site was scored for erythema and edema one hour following patch removal, at 24,48, and72 hours and again on Days 7 and 14. Animals were observed for systemic signs at each dermal scoringinterval. A modified primary irritation index was calculated. Body weights were recorded pretest and attermination.3 minute exposure: There was no erythema or edema.1hour exposure: There was no erythema or edema.4 hour exposure: There was no erythema or edema.Systemic observations: Two animals had diarrhea and soiling of the anogenital area. The remaining animalappeared normal during the observation period. Body weight changes were normal.

Based on the presence of approximately 10% of 1,3-bis[3-(dimethylamino)propyl]urea.(bisDMAPAU) in the test item, and according to the attached read-acorss justification this result is also deemed valid for 1,3-bis[3-(dimethylamino)propyl]urea (bisDMAPU).

bisDMAPAU is classified as Corrosive Cat 1C.


Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The test item was a mixture of the reaction products (1-(3-(Dimethylamino)propyl)urea (CAS 31506-43-1, EC 401-950-2, monoDMAPAU) )and 1,3-bis[3-(dimethylamino)propyl]urea (CAS 52338-87-1, EC 257-861-2, bisDMAPAU), and urea in diproylene glycol.

Both source (1-(3-(Dimethylamino)propyl)urea (CAS 31506-43-1, EC 401-950-2) )and target 1,3-bis[3-(dimethylamino)propyl]urea (CAS 52338-87-1, EC 257-861-2) substances are based on the reaction product of dimethylaminopropylamine (DMAPA) and urea.
The main product of this reaction is the singly-substituted urea product, (3-(dimethylamino)propyl) urea (or mono-DMAPAU)
However, an unavoidable side-reaction is the formation of the doubly-substituted product, 1,3-bis[3-(dimethylamino)propyl]urea, which is formed by the disproportionation of mono-DMAPAU.
The test item will contain approximately 10% of 1,3-bis[3-(dimethylamino)propyl]urea.
Read-across is also claimed based on structural similarity and properties of both reaction products. Justification attached.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
This study was designed to comply with the standards set forth in OECD Guidelines For Testing Chemicals, Number 405, adopted February 24, 1987.
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
Source : Air Products and Chemicals, Inc.
Date Received : 12/17/99
Label Identity : NE 1060
Storage : Room temperature and humidity.
Description : Clear liquid
Sample Preparation : The test article was used as received.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
New Zealand White rabbits were received from Ace Animals, Boyertown, PA on 12/21/99 and quarantined for at least five days. Only animals in apparent good health were made available for study assignment. Prior to being selected for this study, both eyes of each animal were examined according to the Draize technique for any evidence of irritation or abnormalities of the cornea, iris and/or conjunctiva. A Mini-MagliteB flashlight equipped with a high intensity bulb was used to aid in the examination. Three rabbits (males), free from evidence of ocular irritation or abnormalities, were assigned to this study.

The animals were born the weeks of 10/10 through 10/24/99. The pretest body weight was 2.1 kg. The animals were identified by cage notation and a uniquely numbered metal eartag. The animals were housed llcage in suspended cages. Bedding was placed beneath the cages and changed at least three timeslweek. Fresh Purina Rabbit Chow (Diet #5321) was provided daily. Water was available ad libitum. The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12 hour lightldark cycle and was kept clean and vermin free.
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
The test article (0.1 ml) was placed by syringe into the conjunctival sac which was formed by gently pulling the lower eyelid away from the eye.
Duration of treatment / exposure:
After instillation, the lids were held together for approximately one second to insure adequate distribution of the test article.
Observation period (in vivo):
Using a Mini-Maglit- flashlight equipped with a high intensity bulb, the treated eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1,24,48, and 72 hours post dose and on day 7. Ocular reactions were graded according to the numerical Draize technique. Additional signs were described.
Duration of post- treatment incubation (in vitro):
The eyes were examined and scored by the Draize technique at 1,24,48 and 72 hours post dose and on day 7
Number of animals or in vitro replicates:
Three rabbits (males), free from evidence of ocular irritation or abnormalities, were assigned to this study.
Details on study design:
Test Animals
New Zealand White rabbits were received from Ace Animals, Boyertown, PA on 12/21/99 and
quarantined for at least five days. Only animals in apparent good health were made available for study assignment. Prior to being selected for this study, both eyes of each animal were examined according to the Draize technique for any evidence of irritation or abnormalities of the cornea, iris and/or conjunctiva. A Mini-MagliteB flashlight equipped with a high intensity bulb was used to aid in the examination. Three rabbits (males), free from evidence of ocular irritation or abnormalities, were assigned to this study.
The animals were born the weeks of 10/10 through 10/24/99. The pretest body weight was 2.1 kg. The animals were identified by cage notation and a uniquely numbered metal eartag. The animals were housed llcage in suspended cages. Bedding was placed beneath the cages and changed at least three timeslweek. Fresh Purina Rabbit Chow (Diet #5321) was provided daily. Water was available ad libitum. The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12 hour lightldark cycle and was kept clean and vermin free.

Dosing
One eye of each rabbit was dosed. The contralateral eye sewed as a control. The test article (0.1 ml) was placed by syringe into the conjunctival sac which was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together for approximately one second to insure adequate distribution of the test article.

Type and Frequency of Observations
Using a Mini-Maglit- flashlight equipped with a high intensity bulb, the treated eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1,24,48, and 72 hours post dose and on day 7. Ocular reactions were graded according to the numerical Draize technique. Additional signs were described.
Body weights were recorded pretest.
The general health of the animals was monitored at each observation time.

Analysis of Data
The primary eye irritation score for each rabbit was calculated from the weighted Draize scale.
Eve irritation is the production of reversible changes in the eye following application of the test article to the anterior surface of the eye.
Eve corrosion is the production of irreversible tissue damage to the eye following application of the test article to the anterior surface of the eye.

Retention of Data
The raw data is filed at MB Research by project number. The final report is filed at MB Research by sponsor name and MB project number.
The test article will be returned to the sponsor following submission of the report.
Amendment to the Protocol
There were no amendments to the protocol
Irritation parameter:
cornea opacity score
Basis:
animal: #1,#2, #3
Time point:
7 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal: #1,#2, #3
Time point:
7 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal: #1,#2, #3
Time point:
7 d
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritant / corrosive response data:
Corneal opacity, iritis and conjunctival irritation persisted through day 7.
Other effects:
Systemic Observations: One instance of soiling of the anogenital area was noted during the observation period.
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Corneal opacity, iritis and conjunctival irritation persisted through day 7. One instance of soiling of the anogenital area was noted during the observation period.
NE 1060 is corrosive to the rabbit eye.
Based on the presence of approximately 10% of 1,3-bis[3-(dimethylamino)propyl]urea.(bisDMAPAU) in the test item, and according to the attached read-across justification this result is also deemed valid for 1,3-bis[3-(dimethylamino)propyl]urea (bisDMAPU).
bisDMAPAU is classified for serious eye damage - Eye cat 1.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Additional information

Justification for classification or non-classification