Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.58 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
DNEL value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
264.47 mg/m³
Explanation for the modification of the dose descriptor starting point:
Only an oral repeat-dose data is available. The oral NOAEL was converted to an inhalation NOAEC according to REACH guidance.
AF for dose response relationship:
1
Justification:
REACH guidance 8.4.3.1
AF for differences in duration of exposure:
2
Justification:
REACH guidance 8.4.3.1 - sub chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
REACH guidance 8.4.3.1 - AF included in route-to-route conversion
AF for other interspecies differences:
2.5
Justification:
REACH guidance 8.4.3.1
AF for intraspecies differences:
5
Justification:
REACH guidance 8.4.3.3
AF for the quality of the whole database:
1
Justification:
REACH guidance 8.4.3.1
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Extrapolation assumes 50% dermal absorption based on molecular weight of 146.23, vapor pressure of 15 Pa @ 20 °C, water solubility of 2.8 g/l, log Pow of 2.9.
AF for dose response relationship:
1
Justification:
REACH guidance 8.4.3.1
AF for differences in duration of exposure:
2
Justification:
REACH guidance 8.4.3.1 - sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
REACH guidance 8.4.3.1
AF for other interspecies differences:
2.5
Justification:
REACH guidance 8.4.3.1
AF for intraspecies differences:
5
Justification:
REACH guidance 8.4.3.1
AF for the quality of the whole database:
1
Justification:
REACH guidance 8.4.3.1
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Discussion of DNELs for 1,1,3,3-tetramethylbutyl hydroperoxide, CAS 5809-08-5

 

A 28-day repeat dose study is available. The registered substance was administered to rats at 100, 300 and 600 mg/kg/day by gavage.

 

Within the context of this study it was not possible to establish a No Observed Adverse

Effect Level (NOAEL) for the oral administration of 1,1,3,3-tetramethylbutyl hydroperoxide (CAS 5809-08-5) to the rat. However for a human health hazard assessment, 100 mg/kg/day was considered the NOAEL. This is justified as the effects noted at 100 mg/kg/day were not considered relevant to humans and/or were not considered adverse.

 

At 100 mg/kg/day the report noted a decrease in hemoglobin and erythrocyte count, an increase in neutrophils and kidney weight (males only), kidney changes (associated with hyaline droplets and granular casts) and local irritation of the non-glandular stomach.

 

The changes in hemoglobin and erythrocyte count, although statistically significant were slight, only ~5% lower than controls and the majority of erythrocyte individual values were within the historical control range. In addition, at 100 mg/kg/day, there was no increase in reticulocyte count indicating the reduction was not recognized as anemia (i.e. lack of compensation).

 

At all dosages, mean neutrophil counts for both sexes were higher than control, but these values showed no consistent dosage relationship. While individual values for all treated animals exceeded the historical control range so did four of the five individual control values and no corresponding statistically significant increase in total leucocyte count was observed. This increased number in neutrophils probably represent an adaptive response to microscopic liver, kidney and stomach changes apparent for animals on this study. At 100 mg/kg/day, irritation of the non-glandular stomach was reported which could account for the change in neutrophil count.

 

The registered substance is irritating to skin and eyes. Therefore, irritation of the non-glandular stomach is not unexpected following repeated oral administration. As irritation is a local effect, it was not considered for calculation of systemic DNELs. In the absence of any equivalent to the non-glandular region of the stomach for the rat in humans this finding may have limited relevance in the assessment of human health.

 

For males at all dosages, test item-related hyaline nephropathy was apparent. The increase in hyaline droplets was considered to be the result of an increase in the renal content of alpha-2μ -globulin (α2μ-g) in proximal convoluted renal tubules. This globulin is of hepatic origin, regulated by androgen hormones, the rate of synthesis declines during aging, and only younger male rats which produce large amounts of α2μ-g are susceptible to development of associated tubular kidney finding. These kidney findings are considered to be adverse in the susceptible young mature male rats used in this study but they are considered not to be predictive for a risk to humans.

 

A 90-day repeat dose study is available. The registered substance was administered to rats at 30, 150 and 450 mg/kg/day by gavage. Followed by a 28 day treatment free period in sub-groups of animals previously dosed at 450 mg/kg bw/day.

 

The NOEL from this study is 30 mg/kg bw/day. There were no effects of treatment for females that received 30 mg/kg bw/day (low dose group) and the findings observed for males at this dosage appeared to be associated with hydrocarbon nephropathy associated with α2-microglobulin. This condition, while adverse to the male rat, is deemed not to be a hazard to human health as this is principally a rodent only phenomenon, as described above.

 

Also in this study local effects on the stomach were seen at 150 and 450 mg/kg bw/day, as written abovethis finding may have limited relevance in the assessment of human health.

 

At 150 mg/kg bw/day, adaptive effects in the liver were seen and nephropathy as described above in males. Further, statistically significant reductions for hemoglobin, red blood cell count (RBC),

haematocrit and mean cell hemoglobin concentration were apparent for males but all values were within the historical control range. Females at this dosage showed statistically significant increase for mean cell volume and mean cell hemoglobin and also decreased higher mean cell hemoglobin concentration (MCHC) but the majority of individual values were within the historical control range. These findings were similar to anemia present for both sexes at 450 mg/kg bw/day but, at this lower dosage, there was no clear effect of spleen histopathology. In the absence of such effect, and with individual erythrocyte values being generally within the normal range, these findings were considered not to represent an adverse effect at this dosage.

 

At 450 mg/kg bw/day several significant treatment findings were apparent for both sexes during the study. Males showed lower body weight gain and marginally lower food intake. They also had a slightly lower food conversion. The overall activity in males was lower. In both sexesstatistically significant reductions for hemoglobin, red blood cell count (RBC) and hematocrit and increases in mean cell volume (MCV), mean cell hemoglobin (MCH) and a reduction in mean cell hemoglobin concentration (MCHC), significant increase in circulating neutrophils. In females higher platelets counts attained statistical significance at this dose level. Males showed slight but statistically significant increase in blood urea levels, increase in plasma glucose levels, protein and significant increase in inorganic phosphorus and lower sodium levels.

Both sexes statistically significant increases in absolute and body weight relative liver weights and centrilobular hypertrophy was seen. A significant increase in absolute and relative adrenal weights were identified in both sexes accompanied by zona fasciculata hypertrophy. Significant increases in absolute and relative spleen weights were identified in both sexes with increased hematopoiesis, increased hemosiderin. One male showed an enlarged spleen and one female showed discoloration of the spleen. In both sexes statistically significant increases in absolute and body weight relative kidney weights were observed. In males this was seen together with hyaline droplets with associated pathological changes). In the thymus atrophy was present males and females. Hypertrophy of the follicular cells in the thyroid was present in 5 of 10 females.

Although some of these findings were clearly adaptive in nature or of little relevance to man, the extent of findings for both sexes was considered to preclude this dosage from being considered as a NOAEL for the purposes of human risk assessment.

 

Therefore, based on the above, 150 mg/kg/day was considered the NOAEL for human DNEL calculations.

  

Systemic Dermal DNEL Worker

A systemic NOAEL of 150 mg/kg/day is based on the 90-day oral rat gavage study (OECD 408).

 

Oral absorption rat — oral/dermal absorption human: Assume 50% dermal absorption based on molecular weight of 146.23, log Pow of 2.9, water solubility of 2.8 g/l and vapor pressure of 0.015 kPa at 20 °C. Dermal absorption should be expected due to the low molecular weight and water solubility and partition coefficient.

= 150 mg/kg bw/day/0.5

= 300 mg/kg bw/day dermal dose descriptor

Correction for interspecies differences (apply factor for allometric scaling 4 for rat x 2.5 for additional factors):10

= 300 mg/kg bw/day / 10

= 30 mg/kg bw/day

Correction for intraspecies differences: 5

= 30 mg/kg bw/day / 5

= 6 mg/kg bw/day

Correction for duration between 90-day sub-chronic to chronic: 2

= 6 mg/kg bw/day / 2

= 3 mg/kg bw/day

Correction for dose-response: 1

= 3 mg/kg bw/day / 1

= 3 mg/kg bw/day

Correction of whole database: 1 due to quality of study

= 3 mg/kg bw/day / 1

= 3 mg/kg bw/day (DNEL dermal-worker-systemic)

based on an overall AF of 100

  

Systemic Inhalation DNEL Workers

 

Corrected inhalation NOAEC from oral NOAEL

 

oral NOAEL x (1/sRVrat)x(ABSoral-rat/ABSinh-human)xs(RVhuman/wRV)

 

ABSoral-rat/ABSinh-human is 100/100 = 1.0

Due to the low volatility and high water solubility, the respiratory absorption and oral absorption were considered equal. 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.”

 

= 150 mg/kg bw/day x (1/0.38m3/kg bw/day) x (1.0) x (6.7m3/10m3)

= 264.47 mg/m3 inhalation dose descriptor

 

[: Absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]

 

Additional correction for interspecies differences: 2.5

= 264.47 mg/m3/2.5 

= 105.79 mg/m3

Correction for intraspecies differences: 5

= 105.79 mg/m3/ 5 

= 21.16 mg/m3

Correction for duration between sub-acute to chronic: 2

= 21.16 mg/m3/ 2 

= 10.58 mg/m3

Correction for dose-response: 1

= 10.58 mg/m3/ 1

= 10.58 mg/m3

Correction of whole database: 1 due to quality of study

= 10.58 mg/m3/ 1

= 10.58 mg/m3(DNELinhalation-worker-systemic)

based on an overall AF of 25

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

There are no consumer uses of this substance. Human exposure, via the environment, is unlikely. According to REACH guidance (R.8.1.2.3) , only DNELs for relevant populations must be calculated.