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N-Isopropylhydroxylamine: Assessment of Toxicokinetic Properties


CAS number


Chemical name

N-Isopropylhydroxylamine; HYDROGUARD™ I-15 Hydroxylamine; IPHA I-15 Hydroxylamine; CHAINGUARD™ I-15 Hydroxylamine; IPHA

Molecular structure

Molecular formula


Molecular weight


Water solubility

1 x 105mg/L at 25oC (estimated by EPIWEB version 4.10); 22% at 27°C) [1]

Vapour pressure

0.24 mm Hg at 20°C [1]; 2.78 mm Hg at 25oC (estimated by EPIWEB version 4.10)

Log Kow

0.15 (estimated by KOAWIN version 1.68)

Log Koa

6.11 (estimated by KOAWIN version 1.10)


The pure N-Isopropylhydroxylamine (IPHA) is a white crystalline flake; however, it is sold as a 15% solution in water [2]. The aqueous solution is colourless with a slight amine odour [2]. IPHA is marketed as a free-radical scavenger and uses in acrylonitrile-butadiene rubber and styrene-butadiene rubber manufacturing under the trade name CHAINGUARDTMI-15 Hydroxylamine. It is also used as an oxygen scavenger and metal passivator to control corrosion in boilers and marketed with the trade name HYDROGUARDTM I-15 Hydroxylamine [2]. IPHA may also be used in other applications, such as photographic processing, “popcorn” polymer inhibition, monomer stabilization, reducing agent, dye affinity aid; ORE recovery (chelator) and as a synthetic building block [1]. The estimated rate constant of oral absorption of IPHA through human gastrointestinal tract (jejunum) is 0.014 min-1by ACD/ADME Suite version 5.0 (Advanced Chemistry development, Toronto, ON, Canada). This low rate of oral absorption is consistent with the pKa (6.16) of the basic (pH of 15% aqueous solution = 10.6) compound. Most of IPHA will remain ionized in human jejunum which has a pH of 6.5, lowering oral absorption. Even with the slow rate of oral absorption, the overall amount of absorption is estimated to be 99% (ACD/ADME Suite). It has also been estimated to have a moderate volume of distribution of 1.1 L/kg in human, consistent with the low log Kow for this compound. Similarly, plasma protein binding of IPHA is estimated to be ~52% in humans by ACD/ADME Suite. No toxicological information for IPHA is found for comparison with the rate of absorption and acute toxicity.

The steady-state dermal permeability coefficient of aqueous IPHA through human epidermis has been estimated to be 7.42 x 10-4cm/h by Dermwin version 2.01 (EPI Suite version 4.0). On the basis of this data, negligible penetration of dermally applied IPHA is expected. However, no dermal toxicity data are available for comparison.


Due to its basic nature (pH = 10.6 of 15% aqueous solution [1]), non-lipophilicity (log Kow= 0.15) and moderate plasma protein binding (~52%), a moderate volume of distribution (1.1 L/kg) is estimated for IPHA in humans by ACD/ADME Suite.


Due to moderate plasma protein binding and low volume of distribution, IPHA is expected to have very low bioaccumulation potential.


No data on the metabolism of IPHA in rat or other species has been reported. As shown in the chemical structure, IHPA contains the two moieties of isopropyl and hydroxyamine. Therefore, it’s metabolism will be predicted based on the metabolism of both isopropyl and hydroxyamine. The isopropyl group can be metabolized to by cytochrome P450 via hydroxylation, this will lead to the hydroxylated IPHA metabolite. The hydroxyamine group is expected to be metabolically stable, and will not be further metabolized by cytochrome P450 or other Phase I or II enzymes,in vivoorin vitro. Based on these rationale, the potential metabolite of IPHA will be hydroxylated isopropylhydroxyamine.


Both IPHA and the hydroxylated isopropylhydroxyamine metabolite are water-soluble; therefore, would be expected to excreted primarily in urine.


  1. ANGUS Chemical Company Technical Data Sheet (2000). IPHA I-15 – TDS 46.
  2. Dow Chemical Company (2008). Product Safety Assessment: N-Isopropylhydroxylamine (IPHA). QSAR Estimation of Dermal Penetration for IPHA




This analysis estimated a relative dermal absorption of 3.5% to 7.4% of the applied dose for an aqueous solution of N-isopropylhydroxylamine (IPHA), CAS No. 5080-22-8.  A literature search of several databases did not find experimental dermal absorption results for IPHA. QSARs were used to estimate the skin permeability coefficient and which was then extrapolated to a relative dermal absorption. Although one analog of IPHA was found, it did not have experimental dermal absorption results so read across could not be applied.




An evaluation of the potential human dermal absorption was conducted for IPHA in order to refine the DNEL derivation for the ANGUS Chemical registration of IPHA for REACH. The previous DNEL analysis conservatively assumed 100% relative dermal absorption.


Chemical properties

Molecular Formula: C3H9NO

Molecular Weight: 75.11

Vapor Pressure: 0.24 mm Hg at 25°C (in 15% aqueous)

The USEPA EPISuite ™ ( predicted the following values: 

Log Kow (KOWWIN v1.67 estimate): 0.15

Water Solubility at 25 deg C (mg/L): 100,000 (= 10%)


The Dow Product Safety Assessment for IPHA says "Prolonged skin contact may cause slight irritation with local redness, but is unlikely to result in absorption of harmful amounts." This may be because product is alkaline; it has a pH of 10.6.


Literature search


It is preferred to use experimental dermal absorption results in an exposure assessment. A literature search of several databases did not find experimental dermal absorption or penetration results for IPHA. The following data bases were searched:

1.           EDETOX (2008)

2.           Flynn from CEFIC (2001) report

3.           Wilschut (1995)

4.           Magnusson (2004)

5.           Fasano (2007)

6.           EPA (1992)


Read-across method


The read-across (or analogue) approach is simply described as using the skin permeability of one chemical to make a prediction of the skin permeability for another chemical which is considered to be similar. The hypothesis is similar chemicals should have similar properties. One analog of IPHA was found (N-Isopropyl hydroxylamine CAS 50632-53-6) using ChemIDplus®, a chemical dictionary and structure database (NLM, 2012), but it did not have experimental dermal absorption results so the read-across approach could not be applied.


REACH stepwise approach


This analysis applied the logic presented by the European Chemicals Agency (2008) for a stepwise approach for use of non-testing data in REACH to evaluate dermal penetration of a chemical substance.


1.           Physical state. The substance is in aqueous solution under the use conditions; liquids are taken up more readily than dry particulates.

2.           Exposure. IPHA is used in 15% aqueous solutions in HYDROGUARD™ and CHAINGUARD™ , these products are for industrial use in water-treatment operations and polymer reaction-control applications. It was suggested that transferring the chemical from a product container into a process tank would present the highest exposure potential; other tasks would expose the worker to more dilute solutions. 

3.           Physical and chemical properties. IPHA has a molecular weight of 75. Molecular weight is an indicator of the molecule volume and the penetration rate of a molecule into the skin is inversely proportional to its volume. One would not expect the molecular weight of IPHA to significantly limit is dermal penetration. 

4.           Octanol/water partition coefficient, Kow. The estimated log Kow for IPHA is 0.15 and it is classified as lipophobic. The Kow, is the ratio of the chemical concentration in octanol to its concentration in water, with octanol acting as a model for the lipids (fats) in an organism. A log Kow value below 0 will limit penetration into the stratum corneum and limit dermal absorption. A high log Kow value corresponds to a highly lipophilic chemical which will tend to partition into the skin lipids rather than the aqueous matrix. 

5.           Vapor pressure. If a substance has a significant vapor pressure it may evaporate before it has time to penetrate the skin or the skin penetration may be significantly reduced. The vapor pressure for IPHA was reported as 0.26 mm Hg at 20°C (15% aqueous IPHA in CHAINGUARD™ ) and evaporation may reduce the dermal load and possibly limit the dermal penetration.

6.           Lag time. This is the experimentally determined duration for the substance to penetrate the skin and be measured in the receptor fluid in the test cell. A long lag time may be due to the stratum corneum providing a barrier which prevents substance penetration. A long lag time may also be due to the substance penetrating slowly or formation of a skin residue. The calculations using the skin permeability coefficient assume the substance immediately penetrates the skin and do not consider the lag time in uptake. The USEPA DERMWIN v2.01 predicted tau as 0.281 hr, tau is lag time in update; it predicted t*as 0.674 hr, t* is time to steady state penetration. 

7.           Water solubility. This limits the substance concentration in an aqueous solution. Substances which are soluble tend to penetrate the skin well. Substances with a high water solubility may be too hydrophilic to cross the stratum corneum. IPHA has a high predicted water solubility and it is hydrophilic.

8.           Water dissociation. Substances which dissociate (ionize) in water do not tend to penetrate the skin well. IPHA does not ionize.


Therefore, using the REACH stepwise approach one would expect the low log Kow and the hydrophilic nature of IPHA to limit its dermal penetration. Evaporation may reduce the dermal load and possibly limit the dermal penetration.


QSAR method


A QSAR uses mathematics to relate the biological activity of a substance to its physicochemical and structural properties. A QSAR can be used to estimate skin permeability. Two general (e.g. not chemical family specific) QSARs were applied: USEPA EPISuite™ DERMWIN v2.01 and Magnusson et al. (2004).


DERMWIN v2.01 predicted a skin permeability coefficient of 7.4 x 10-4 cm/hr (see below) for IPHA. This value was used to estimate a relative dermal absorption of 7.4% of the applied dose for an aqueous solution of IPHA for one hour contact time consistent with worker exposure. It was assumed the skin cleaned afterwards (calculations not shown).


The Magnusson QSAR predicted a maximum dermal flux of 4.7E-06 mol/cm2 -hr. This value was used to estimate a relative dermal absorption of 3.5% of the applied dose for an aqueous solution of IPHA for one hour contact time assuming the skin cleaned afterwards (calculations not shown).


Skin residue


REACH guidance states one major regulatory issue is a QSAR does not predict or address the fate of the skin residue, the substance mass which is absorbed into the skin but does not penetrate into the blood stream. Based on the hydrophilic nature of IPHA one would not expect it to have large accumulation in the stratum corneum. 




Based on the available information, the predicted relative dermal absorption of aqueous solution of IPHA ranged from 3.5% to 7.4% for one hour contact time. The stepwise approach indicated the low log Kow and the hydrophilic nature of IPHA may limit its dermal penetration. Evaporation may also reduce the dermal load and possibly limit its dermal penetration.





1.           National Library of Medicine (NLM), ChemIDplus®;; 2012.

2.           European Chemicals Agency, Stepwise Approach on Page 31, Chapter R.6: QSARs and grouping of chemicals, Guidance for the implementation of REACH, European Chemicals Agency, May 2008.

3.           B. M. Magnusson, Y. G. Anissimov, S. E. Cross, and M. S. Roberts. Molecular Size as the Main Determinant of Solute Maximum Flux Across the Skin. J Invest Dermatol 122:993–999, 2004.





Table 1. USEPA EPISuite™ DERMWIN v2.01 QSAR results.  


                 Kp (est): 0.000742 cm/hr

CAS No.: 005080-22-8


MOL FOR: C3 H9 N1 O1

MOL WT : 75.11

------------------------------ Dermwin v2.01 ----------------------------------

Log Kow (estimated) : 0.15

Log Kow (experimental): not available


GENERAL Equation:  log Kp = -2.80 + 0.66 log Kow - 0.0056 MW

   Kp (predicted): 7.42e-004 cm/hr


Dermally Absorbed Dose per Event for Organic Compounds - Water Contact:

  Water Conc (mg/cm3): 1e+002 (estimated by program)

  Fraction Absorbed : 1.0000


  DA(event): 8.28e-002 mg/cm2-event (using eqn 3.2 & 3.3)

                  (tau = 0.281 hr, t* = 0.674 hr)


Dermally Absorbed Dose (70 kg Adult) - Water Contact:

  DAD: 8.75e+000 mg/kg-day (using eqn 3.1)