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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

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: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report date:
2009

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
GLP compliance:
yes
Test type:
up-and-down procedure

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol
EC Number:
701-173-1
Molecular formula:
C14 H10 NO (C15 H12 N2 O2 R)n NCO where R = C4 H8 O2 and C4 H8 O3 and C3 H6 O2, n=0-2
IUPAC Name:
1,1'-methylenebis(4-isocyanatobenzene) and its oligomeric reaction products with butane-1,3-diol, 2,2'-oxydiethanol and propane-1,2-diol
Details on test material:
Identification: Suprasec 2015
Lot/Batch No.: RZBX317
Physical Description: Clear colorless liquid
Composition/Purity: Reaction mass of 1,2-Propanediol, polymer with 1,1'-methylenebis[isocyanatobenzene] and 1,3-Butanediol, polymer with 1-isocyanato-2-[(4-isocyanatophenyl)methyl]benzene and 1,1'-methylenebis[4-isocyanatobenzene] and 4,4'-Methylenediphenyl diisocyanate, oligomeric reaction products with 2,2'-oxydiethanol and 2,4'-diisocyanatodiphenylmethane and 4,4'-methylenediphenyl diisocyanate and o-(p-isocyanatobenzyl)phenyl isocyanate
NCO value: 26.44 %A
Stability The test article was expected to be stable under standard laboratory conditions, under nitrogen blanket and protected from moisture, for the duration of testing.
Storage Conditions: Room temperature (10-30ºC), under nitrogen and protected from moisture

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Age Range: 9 to 11 weeks at start of dosing; records of dates of birth for animals used in this study are retained in the Calvert archives.
Body Weight Range: 179 to 206 grams
Animal Source: Harlan
Experimental History: Purpose-bred and experimentally naïve at the outset of the study.
Identification: Ear tag and cage card.
Housing: Animals were group housed by sex upon receipt and individually housed upon assignment to study in compliance with the National Research Council “Guide for the Care and Use of Laboratory Animals”. Calvert is a USDA registered and fully AAALAC accredited facility. The room in which the animals were kept was documented in the study records. No other species were kept in the same room.
Lighting: 12 hours light/12 hours dark
Room Temperature: 17.8 to 25.6°C
Relative Humidity: 16 to 78%
Food: All animals had access to Harlan Teklad Rodent Diet (certified) as per Calvert SOP. Animals were fasted overnight prior to dose administration. Food was returned to the animals ~30 minutes after dosing. The lot number(s) and specifications of each lot used are archived at Calvert. No contaminants were known to be present in the certified diet at levels that would be expected to interfere with the results of this study. Analysis of the diet was limited to that performed by the manufacturer, records of which are maintained in the Calvert archives.
Water: Tap water was available ad libitum, to each animal via an automatic watering device. The water is routinely analyzed for contaminants as per Calvert SOP’s. No contaminants were known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis are maintained in the Calvert archives.
Acclimation: Study animals were acclimated to their housing for a minimum of 5 days prior to dosing.
Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: 2 Jun 2009 To: 6 Jul 2009

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Jeffsol - Propylene Carbonate - NF
Details on oral exposure:
VEHICLE
The 175 mg/kg dose level was prepared at 35 mg/ml and dosed at 5 ml/kg (dose volume). The 550, 2000 and 5000 mg/kg levels were dosed as received at 0.45, 1.6 or 4.05 ml/kg, respectively. The 175 mg of test article was brought to a volume of 5 ml with the vehicle. Each preparation was made daily on the day of dosing. The stock bottle was inverted several times prior to dispensing. The 175 mg/kg formulation was described as a clear liquid. The test article stock bottle was purged with nitrogen after use.

The vehicle, Jeffsol - Propylene Carbonate - NF, was used to prevent hydrolysis of the test substance.

Doses:
175, 550, 2000 and 5000 mg/kg
No. of animals per sex per dose:
Dose No. of
Treatment (mg/kg) Sex Rats
175 F 1
550 F 1
2000 F 1
5000 F 3
Control animals:
no
Details on study design:
The first animal was dosed at an initial dose level of 175 mg/kg. Since this animal survived, the second animal received a higher dose (550 mg/kg) and the third received the test article at 2000 mg/kg. One animal followed by two additional animals were dosed at 5000 mg/kg. The dose for each successive animal was adjusted up or down, depending on the previous result. The test continued based on the fixed time interval outcomes of all the animals up to that point and until one of the stopping criteria was first met. There were three possible stopping criteria.
• 3 consecutive animals survive at the limit dose;
• 5 reversals occur in any 6 consecutive animals test;
• or at least 4 animals have followed the first reversal and the specific likelihood-ratios exceed the critical value
Dose progression and stopping criteria was calculated using a dedicated software program [Acute Oral Toxicity (Guideline 425) Statistical Program, Version 1.0] provided by the EPA.
Statistics:
The design of this study was such that statistical analysis was not necessary.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: Practically nontoxic
Mortality:
Mortality was not observed in any of the animals dosed at 175, 550, 2000 or 5000 mg/kg of the test article.
Clinical signs:
other: All animals appeared normal throughout the study at dose levels of 175, 550, 2000 and 5000 mg/kg.
Gross pathology:
Terminal necropsy revealed no visible lesions in any of the animals at dose levels of 175, 550 2000 or 5000 mg/kg.

Any other information on results incl. tables

Animal ID#

Observation Period (Day)

Treatment
175 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

3276F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

 

Animal ID#

Observation Period (Day)

Treatment
550 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

3277F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

 

Animal ID#

Observation Period (Day)

Treatment
2000 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

3278F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

Animal ID#

Observation Period (Day)

Treatment
5000 mg/kg

Day 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

30 Min

4 Hr

3279F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

3280F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

3281F

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

AN

 

All animals appeared normal prior to dosing     AN = Appears normal     

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
Based on the results of this study, the oral LD50 for the test substance in rats was estimated to be greater than 5000 mg/kg.
Executive summary:
The purpose of this study was to assess the toxicity of the test article following a single oral dose to the rat. The results of the study are believed to be of value in predicting the likely toxicity in man by the oral route.

Initially, one female Sprague Dawley rat was dosed at 175 mg/kg. No mortality was observed at 175 mg/kg and dosing continued in another female at 550 mg/kg. Dosing continued in an additional female at 2000 mg/kg as per protocol guidelines and then in one female at 5000 mg/kg. Based on these results two additional females were dosed at 5000 mg/kg. A total of 6 females were dosed. Mortality checks were made once daily. Clinical observations were recorded prior to dosing, as well at 30 minutes, 4 hours post-dose, and daily thereafter through Day 15. Body weights were recorded on the day of dosing (Day 1), and on Days 8 and 15. All rats were euthanized by CO2asphyxiation and necropsied on Day 15. For doses of 175, 550, 2000 or 5000 mg/kg, no mortality was observed. All animals appeared normal throughout the study at 175, 550, 2000 and 5000 mg/kg. No biologically significant effect was seen on body weights on Days 8 and 15. Terminal necropsy revealed no visible lesions in any of the animals at 175, 550, 2000 and 5000 mg/kg.