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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: expert statement
Executive summary:

Direct toxicokinetic data are not available on the test item. Certain physico-chemical properties suggest potential absorption at a limited level. The two repeated dose oral administration studies resulted in some microscopic changes in liver and kidney in rats treated with 50 or 120 mg/kg bw/day. Recovery was evident after treatment was stopped. These biological effects provide qualitative evidence that in rats at least, intestinal absorption, and subsequent tissue distribution, cellular uptake and biological effects of the test item or its metabolites take place.

Description of key information

There is no specific requirement to generate TK information in REACH. (R.7.12.1). There are no adequate studies that specifically address toxicokinetics (i.e. absorption, metabolism, distribution and elimination).  However, physical-chemical properties were used to estimate absorption via oral, dermal and inhalation exposures. Animal data from repeated dose studies provide some evidence of absorption and distribution based on certain biological effects observed. The 90-day repeated dose oral administration study in rats resulted in microscopic liver changes (bile duct hyperplasia associated with inflammatory cell infiltration and pigment deposits in bile ducts) and some non-adverse kidney changes (hyaline droplets) in males treated with 120 mg/kg bw/day and adaptive liver changes (hypertrophy) in females treated with 120 mg/kg bw/day. Recovery was evident after treatment was stopped. Liver effects were also seen in another rat study of shorter duration (OECD 422). These biological effects provide qualitative evidence that in rats atleast, intestinal absorption, and subsequent tissue distribution, cellular uptake and bilogical effects take place.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
25
Absorption rate - inhalation (%):
100

Additional information

Toxicokinetics Summary

There is no specific requirement to generate toxicokinetic information in REACH. (R.7.12.1).

 

A. There is no specific requirement to generate toxicokinetic information in REACH. (R.7.12.1). There are no adequate studies that completely address toxicokinetics (i.e. absorption, metabolism, distribution and elimination) of the test substance, 1,2,4,5,7,8-Hexoxonane, 3,6,9-trimethyl-, 3,6,9-tris(Ethyl and Propyl) derivatives,CAS# 1613243 -54 -1. Available physicochemical properties are as follows:

MW

WS (Water Solubility)

Log P

Vapor Pressure

systemic toxicity

Average: 273 (range: 264-306)

19.6 mg/L @ 20 oC

6

66 Pa @ 25 oC

Yes, oral (OECD 408 and 422)

Oral Absorption: There is no quantitative information on the oral absorption of this peroxide. While the water solubility would not favor absorption, a repeat dose study (OECD 422) indicates systemic effects (microscopic changes in liver and heart) providing an evidence that some of the administered test item was absorbed when administered orally.

Dermal Absorption: Per ECHA Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance for dermal absorption:

MW: <100 favors absorption; > 500 does not

WS: 1-100 mg/L absorption is low to moderate

Log P: 1-4 favors absorption, > 4 penetration is limited by rate of transfer between stratum corneum and epidermis

VP: vapors with < 100 Pa are likely to be well absorbed and the amount absorbed dermally may be more than 10% of the amount that would be absorbed by inhalation.

Based on the above guidance and physical-chemical properties, dermal absorption of the test substance is estimated to be ~25% of oral absorption.

Inhalation Absorption: Per ECHA Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance for inhalation absorption:

VP: substances with VPs < 0.5 KPA have low volatility

Log P: > 4 favors micellular solubilization if poor WS (1 mg/L or less)

WS: low WS enhance penetration to lower respiratory tract.

Animal data from repeated dose studies provide some evidence of absorption and distribution based on certain biological effects observed. The 90-day repeated dose oral administration study in rats resulted in microscopic liver changes (bile duct hyperplasia associated with inflammatory cell infiltration and pigment deposits in bile ducts) and some non-adverse kidney changes (hyaline droplets) in males treated with 120 mg/kg bw/day and adaptive liver changes (hypertrophy) in females treated with 120 mg/kg bw/day. Recovery was evident after treatment was stopped. Liver effects were also seen in another rat study of shorter duration (OECD 422). These biological effects provide qualitative evidence that in rats atleast, intestinal absorption, and subsequent tissue distribution, cellular uptake and bilogical effects take place.

B. Supporting evidence: Available information on 1,2,4,5,7,8 -Hexoxonane, 3,6,9 -triethyl-3,6,9 -trimethyl-(CAS# 24748 -23 -0), a cyclic peroxy ketone, which is a major constituentof the test substance (CAS# 1613243 -54 -1) is provided below.:

 

MW

Water Solubility

Log P

Vapor Pressure

Surface Tension

Systemic toxicity

264

13.1 mg/L

(slightly soluble)

4.84

4.1 Pa (0.0041 KPa)

Log10 Koc 3.16

Yes, oral 90-day

No studies are available on the toxicokinetics, metabolism and distribution of this substance. The pure peroxide is not commercially available. 

 

Oral Absorption:There is no information on the oral absorption of this peroxide. While the water solubility would not favor absorption, repeat dose studies indicate systemic effects (liver, kidney and blood).

In a hydrolysis study, OECD 111, under the physiologically relevant conditions of pH 1.2, 37.0 ± 0.5 °C, the mean half-life of the test item was determined to be 0.23 hours (14 minutes), with a rate constant of 8.41 x 10-4s-1.

Dermal Absorption:Per ECHA Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance for dermal absorption:

MW: <100 favors absorption; > 500 does not

WS: 1-100 mg/L absorption is low to moderate

Log P: > 4 penetration is limited by rate of transfer between stratum corneum and epidermis

VP: vapors with < 100 Pa are likely to be well absorbed and the amount absorbeddermally may be morethan 10% of the amount that would be absorbed by inhalation.

Inhalation Absorption :Per ECHA Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance for inhalation absorption:

VP: substances with VPs < 0.5 KPA have low volatility

Log P: > 4 favors micellular solubilization if poor WS (1 mg/L or less)

WS: low WS enhance penetration to lower respiratory tract.

 

Based on the above guidance and physical-chemical properties, dermal absorption of the registered substance is estimated to be low compared to oral absorption.