1,1',1''-nitrilotripropan-2-ol

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to test guidelines and in accordance with GLP.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

2007

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Principles of method if other than guideline:

This study was conducted to determine the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA). Groups of 4 female Fischer 344 rats received a dermal application of 19.5 mg/ kg 14C-DIPA in acetone to an area of 1 cm2 on the back and covered with a bandage. Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,1'-iminodipropan-2-ol

EC Number:

203-820-9

EC Name:

1,1'-iminodipropan-2-ol

Cas Number:

110-97-4

Molecular formula:

C6H15NO2

IUPAC Name:

1-(2-hydroxypropylamino)propan-2-ol

Test material form:

solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
A
- Name of test material: 14C-labeled DIPA [(U-14C) 1,10-iminodi-2-propanol]
- Source of test material: Amersharm (Arlington Heights, IL)
B
- Name of test material: Non-radiolabeled DIPA and monoisopropanolamine (MIPA)
- Source of test material: The Dow Chemical Company (Midland,MI)
- Purity: >99%

RADIOLABELLING INFORMATION (if applicable)
A
- Radiochemical purity: >99.5%
- Specific activity: 75 lCi/mg

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, NY)
- Age at study initiation: 10 weeks
- Weight at study initiation: 148–162 g
- Housing: two per cage
- Individual metabolism cages: yes/no
- Diet: Purina Certified Rodent Chow #5002 (Ralston Purina Co.,) ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2°C
- Humidity (%): 40–60 %
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

occlusive

Vehicle:

acetone

Duration of exposure:

48 h

Doses:

- Actual doses calculated as follows: 19.5 mg/kg bw;
A Teflon template with 1 cm2 opening was used to define the area and as a guide to apply the dose solution. After the application of the entire dose, template was
removed and analyzed for radioactivity which was used to correct the actual dose applied to each animal.
- Dose radioactivity: ~19 µCi of radioactivity per rat

No. of animals per group:

4

Control animals:

no

Details on study design:

TEST SITE
- Preparation of test site: shaved
- Area of exposure: 1 cm2
- Type of cover / wrap if used: 4 cm2 piece of Teflon and secured in place with Conform adhesive bandages


SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes: each rat was fitted with a rodent jacket


SAMPLE COLLECTION
- Collection of blood: 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h post-dosing
- Collection of urine and faeces: 6, 12, 24 and 48 h post-dosing (urine); feces: at 12 h intervals
- Collection of expired air: 12 h intervals


ANALYSIS
- Method type(s) for identification: Liquid scintillation counting

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Total recovery:

- Total recovery: 69.2 ± 17.0%
- Results adjusted for incomplete recovery of the applied dose:
The absolute systemic dermal bioavailability (dose corrected AUCdermal/AUCi.v.) of 2% was calculated by the intravenous experimental results.

Percutaneous absorption

Time point:

48 h

Dose:

19.5 mg/kg bw

Parameter:

percentage

Absorption:

ca. 20 %

Remarks on result:

other: Total recovery: 69%, of which 26% was recovered from protective appliances and 24% from the surface of the dosed skin.

Any other information on results incl. tables

Table 1: Recovery of the radioactivity from the appliances used to protect the dosing site skin, tissues and excreta following dermal application of 19.5 mg/kg 14C-DIPA to female Fisher 344 rats.

 

Samples	% of applied dose
	Mean	SD
Protective appliances^a	25.73	11.17
Dose site skin	23.73	4.45
Remote skin	3.53	3.52
Liver	0.14	0.05
Kidney	0.14	0.06
Fat^b	<0.01	–
Carcass	1.1	0.38
Urine	12.04	4.01
Feces	0.18	0.08
14CO2	0.19	0.02
Charcoal trap	0.05	0.05
Final cage wash	2.33	1.53
Total recovery	69.16	17.03

 SD, standard deviation (n= 4).

a Protective appliance include Teflon patch, bandage, template and jacket.

b Amount of radioactivity in fat was <0.01% of the applied dose.

Table 2: Concentration of radioactivity in plasma and red blood cells (RBC) of female Fischer 344 rats applied dermally with 19.5 mg¹⁴C-DIPA/kg body weight

Time (h)	lgequivalent 14C-DIPA/g
	Plasma	RBC
0.5	1.12 ± 0.76	0.98±0.70
1	0.14 ± 0.04	0.15 ± 0.10
2	0.31 ± 0.44	0.47 ± –^a
4	0.04 ± 0.01	0.07±0.02
6	0.05 ± 0.02	0.10 ± –
12	0.07 ± 0.02	0.13 ± 0.04
24	0.14 ± 0.06	0.16 ± 0.07
36	0.14 ± 0.05	0.13 ± 0.04
48	0.13 ± 0.07	0.14 ± –

Mean ± standard deviation (n= 4).

aSamples collected from 2 out of 4 rats did not have sufficient radio- activity to quantify.

Applicant's summary and conclusion

Conclusions:

The total recovery of the dermally applied dose was 69.2 ± 17.0%. The recovery of the applied radioactivity from 3 out of 4 rats was between 71% and 80%; recovery in one of the rats was only 48%. Most of the administered radioactivity was recovered from the protective appliances (Teflon patch, template, bandage, and jacket) accounting for 25.7 ± 11.2% and from the surface of the dosed skin (23.7 ± 4.5%). At the end of the study (48 h post-application), 3.5 ± 3.5% of the dose was found in skin remote from the site of the dosing with levels in 2 of 4 rats 0.5% and the other 2 between 5% and 8% of the dose.
Concentration of 14C-DIPA-derived radioactivity was 0.1% in liver and kidney and 0.01% in fat. A total of 1.1 ± 0.4% of the applied dose was found in carcass. The dermally applied DIPA was not volatile or metabolized to CO2; 0.2% of the dosed radioactivity was trapped in charcoal or monoethanolamine:1-methoxy-2-propanol solution. A total of 14.6% of the applied radioactivity was found in excreta (urine + feces + final cage wash).
Consistent with the intravenous data, urine was the major route for the excretion of 14C-DIPA constituting 99% of the total excretion (urine + final cage wash + feces), fecal elimination of 14C-DIPA was 0.2% or 1.2% of the total radioactivity recovered in excreta.

Executive summary:

In a combined dermal and intravenous study, the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA), an alcohol amine used in a number of industrial and personal care products, was determined.

Groups of 4 female Fischer 344 rats received either a single bolus i.v. dose of 19.0 mg/kg 14C-DIPA in water or a dermal application of 19.5 mg/ kg 14C-DIPA in acetone to an area of 1 cm2 on the back and covered with a bandage.

Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA).

Following dermal application, 20% of the dose was absorbed in 48 h with the steady-state penetration rate of 0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine at a relatively constant rate due to the presence of large amount of the 14C-DIPA at the application site. Fecal elimination was <0.2% of the dose. The absorbed DIPA did not accumulate in tissues; only 0.1% of the administered dose was found in liver and kidney. The absolute systemic dermal bioavailability (dose corrected AUCdermal/AUCi.v.) of 14C-DIPA was 12%.

The ADME of DIPA contrasts that of its diethanol analogue, diethanolamine, which displays a broad spectrum of toxicity in rats and mice. Toxicologically significant concentrations of DIPA are unlikely to be achieved in the systemic circulation and/or tissues as a result of repeated dermal application of products containing DIPA due to slow absorption from the skin, rapid unchanged elimination in urine, and majority of the products contain 61% DIPA.

It has to be mentioned that an overprediction of the absorption through the skin due to several dermal applications with acetone produced a worse-case scenario in the dermal application part presented in the study.