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Description of key information

Specific data are not available on the toxicokinetics, metabolism and distribution of the test substance,1,1,3,3-tetramethylbutyl hydroperoxide (CAS# 5809-08-5). The physico-chemical information shown below may be useful to understand the potential for the absorption of the test item. The test item is not biodegradable; however, there is evidence for the absorption/distribution of the test material based on oral, inhalation and dermal studies in rats and a positive dermal sensitization study in mice.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Specific data are not available on the toxicokinetics, metabolism and distribution of the test substance,1,1,3,3-tetramethylbutyl hydroperoxide (CAS# 5809-08-5). The physico-chemical information shown below may be useful to understand the potential for the absorption of the test item. The test item is not biodegradable; however, there is evidence for the absorption/distribution of the test material based on oral, inhalation and dermal studies in rats and a positive dermal sensitization study in mice.

Molecular weight

146.23 g/mol

physical state at 20 °C

liquid

Water Solubility

2.8 g/L (OECD 105)

Log Pow

2.9 (OECD 117)

Vapor Pressure

15 Pa at 20oC (ASTM C1782-08)

Skin irritation

Severely irritating

 

 

Oral Absorption

 

Evidence of absorption and distribution of the test item can be inferred from the availablein vivo studies in rat (oral). The following systemic effects were noted in a 28-day oral gavage study in rats:

 

·        absolute and body weight relative liver weights were increased for both sexes At 300 and 600 mg/kg bw/day;

 

·        absolute and body weight relative kidney weights were increased for males at 100 and 300 mg/kg bw/day and both sexes at 600 mg/kg bw/day;

 

·        absolute and body weight relative spleen weights were increased for females at 300 mg/kg bw/day and both sexes at 600 mg/kg bw/day; and

 

·        absolute and body weight relative adrenal weights were increased for males at 100, 300 and 600 mg/kg bw/day.

 

Histological findings in this study were:

 

·        liver: centrilobular hepatocellular hypertrophy in both sexes at 300 and 600 mg/kg bw/day with associated glycogen depletion for males;

 

·        thyroid: minimal diffuse follicular cell hypertrophy for females at 600 mg/kg bw/day;

·        spleen: increased in severity for extramedullary hematopoiesis for both sexes at 300 and 600 mg/kg bw/day;

 

·        kidneys: nephropathy, characterized by tubular degeneration/regeneration in renal proximal tubules for males at 100, 300 and 600 mg/kg bw/day, with an associated increased severity in tubular hyaline droplets, often with granular casts in tubules of the inner cortex;

 

·        stomach: hyperkeratosis of the non-glandular region in both sexes at 100, 300 and 600 mg/kg bw/day, with diffuse squamous hyperplasia and submucosal inflammation also present at 300 and 600 mg/kg bw/day. Minimal to moderate vesicle formation in the keratin layer was observed at 600 mg/kg bw/day; and

 

·        adrenals: slightly increased incidence and severity for diffuse fatty change in the zona fasciculata of the adrenal cortices for males at 600 mg/kg bw/day.

 

Forestomach mucosal necrosis was recorded in males (100 mg/kg/day) and both sexes (300 and 1000 mg/kg/day). In the forestomach, hyperkeratosis/parakeratosis, and other microscopic changes were also observed. These were considered to be local injuries caused by repeated oral gavage of the test substance that resulted in subsequent adverse reactions. Increased severity of hyaline droplets in the renal proximal tubules of the kidneys (males, 1000 mg/kg/day) was considered to be due to a protein specific to male rats, similar to alpha-2 microglobulin, and generally derived from hyperfunction of the liver. Although this is considered to be an adverse finding in rats, this protein has no counterpart in humans and is therefore of no toxicological relevance. The no-observed-effect-level (NOEL) and the no-observed-adverse-effect-level (NOAEL) for 1,1,3,3-tetramethylbutyl hydroperoxide was considered to be below 100 mg/kg/day, the lowest dose tested in this study.

 

These results were considered as the evidence of absorption of the test substance (at a dose as low as 100 mg/kg/day) from the gastrointestinal tract of the rat, and distribution into internal organs at sufficient concentrations, of either the test substance or its potential metabolite(s), causing microscopic effects at tissue / cellular levels in a generally dose-dependent manner. However, this information does not provide quantitative data as to how much of the substance was absorbed.

 

Dermal Absorption

Some evidence of absorption and distribution of the test item can be inferred from a dermal sensitization study in mice. The test item is severely irritating to rat skin, but since the substance has been identified as a skin sensitizer in guinea pigs, some uptake must have occurred to cause a positive immune system effect, which is a systemic response. Based on the physical properties (molecular weight; water solubility and log Pow of 2.9), the test substance is expected to have penetrate the skin to some degree. The dermal absorption rate was assumed to be 50% for long term systemic DNEL calculations.

 

Absorption through Inhalation

The vapor pressure (15 Pa at 20oC) of the test item is low. Therefore, inhalation is not expected to be a major route of exposure / absorption. In an acute inhalation study with rats, some clinical signs of toxicity were noted.

Due to the low volatility and high water solubility, the respiratory absorption and oral absorption were considered equal for DNEL calculation. Guidance on requirements and chemical safety assessment Ch. R.7c pg 159 state that,“Vapors of very hydrophilic substances may be retained within the mucus. For absorption of deposited material similar criteria as for GI absorption apply.”

 

The test substance is not biodegradable. No specific information is available on the metabolism or elimination of the test substance.