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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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):
75
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
132.24 mg/m³
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL of 150 mg/kg/day from a 28 -day repeat dose oral study with rats was used. Assuming an oral /inhalation

absorption of 0.5 a dose descriptor of 132.26 mg/m3 was derived as the starting point. This study was was used for DNEL derivation as it is the only repeated dose study and the study is of good quality (GLP, OECD guideline).

AF for dose response relationship:
1
Justification:
based on REACH guidance
AF for differences in duration of exposure:
6
Justification:
based on REACH guidance: subacute to chronic
Justification:
Not applicable for inhalation DNEL, per REACH guidance
AF for other interspecies differences:
2.5
Justification:
based on REACH guidance
AF for intraspecies differences:
5
Justification:
based on REACH guidance
AF for the quality of the whole database:
1
Justification:
based on REACH guidance
AF for remaining uncertainties:
1
Justification:
based on REACH guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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):
300
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL of 150 mg/kg/day from a 28 -day repeat dose oral study in rats was used. Assuming a dermal absorption of 50% a dose descriptor of 300 mg/kg/day was derived as the starting point.This study was was used for DNEL derivation as it is the only repeated dose study and as it is a study of good quality (GLP, OECD guideline).

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL Calculations for 3,3,5,7,7-pentamethyl-1,2,4-trioxepane

WS

g/L, in water (measured)

5.54 at 20.1oC

Log Pow

 (OECD 117)

   2.4 at 22oC

VP

Pa (measured)

 274 at 20oC

Skin/eye irritation

(measured) 

Non irritant

Skin sensitization 

 

Non-sensitizer 

NOAEL, oral, rat 

Mg/kg bw/day

150 

 Although the oral LD50 is 300 - 2000 mg/kg and classified for acute toxicity (Cat 4), the LD50 for dermal and inhalation routes are high and are not classified. The latter route-specific data were not appropriate to calculate short term Worker DNELs. Hydrophilic substances, by dissolving in the mucus lining of the respiratory tract are effectively removed from the air in the upper respiratory tract. Occupational exposure, if any, may only be by dermal or inhalation exposures. Therefore two long-term DNELs are calculated for workers - inhalation and dermal.

.

The OECD TG 407 study is selected for DNEL derivation as it is the only repeated dose study available and is a study of good quality (GLP, OECD guideline). The following treatment related microscopic findings were observed: (1) Bile duct proliferation of minimal or slight degree (2/5 males and 2/5 females at 150 mg/kg/day, 4/5 males and 4/5 females at 450 mg/kg/day); (2) Diffuse midzonal/centrilobular hypertrophy of the liver at minimal or slight degree (4/5 males at 450 mg/kg/day); (3) Increased severity of cortical hyaline droplets in the kidneys to slight or moderate degree (4/5 males at 150 mg/kg/day and 5/5/ males at 450 mg/kg/day); (4) Very slight increase in the severity of splenic hemopoiesis (primarily erythropoiesis) to a moderate degree (1/5 males at 450 mg/kg/day). The bile duct effects observed at 150 mg/kg/day were not indicative of clear organ dysfunction and were not regarded to be adverse in toxicological terms. Reduced red blood cell counts, hemoglobin level, and hematocrit level in females at 150 and 450 mg/kg/day were seen, but reticulocytosis was seen only at the high dose. Liver weight of males and females at 450 mg/kg/day were increased, while liver to body weight ratios were increased in males and females at 150 and 450 mg/kg/day. There were no increases in the enzymes indicative of liver pathology. The liver changes were considered as typical adaptive changes to xenobiotics. A slightly increased kidney to body weight ratio was measured for males at 450 mg/kg/day. The kidney microscopic observation (hyaline droplets formation) is a well-known species (rat) and gender (male) specific finding with certain chemicals. This finding, although adverse in male rats, is irrelevant for human hazard assessment. Deaths at 450 mg/kg/day were considered treatment-related, and as such considered to be clear evidence for an adverse effect of the test substance at this dose level.  Therefore, from the results presented in this report, a definitive systemic No Observed Adverse Effect Level (NOAEL) for Pentamethyl-trioxepane of 150 mg/kg/day was established.

DNEL inhalation-systemic-workerfor 3,3,5,7,7-pentamethyl-1,2,4-trioxepane:                                                                          

Corrected inhalatoary NOAEC: Oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (sRVhuman/wRV)

Correction for inhalation and oral absorption rates: Assume ABSoral-rat/ABSinh-human is 50/100 = 0.5 based on phys-chem properties and Endpoint Specific Guidance chapters 8 and 7c (R.7.12).

Conversion into an inhalatory rat NOAEC: dividing by 0.38 m3/kg (8-hour respiratory volume in the rat)

Correction for activity driven differences in respiratory volume in workers compared to individuals at rest: (6.7 m3/10 m3) [ABS: absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume]                                                       

Corrected NOAEC = 150 mg/kg/day x (1/0.38 m3/kg/day) x (0.5) x 6.7 m3/10m3 = 132.24 mg/m3 (Dose descriptor)                

Applying remaining assessment factors in accordance with Endpoint Specific Guidance Chapter 8:                                    

Correction for interspecies differences: 2.5                                                                                                                                    

132.24 mg/m3/2.5 = 52.9 mg/m3                                                                                                                                                  

Correction for intraspecies differences:5                                                                                                                                       

52.9 mg/m3 /5 = 10.58 mg/m3                                                                                                                                                     

Correction for duration between subacute to chronic: 6                                                                                                                 

10.58 mg/m3/6 = 1.76 mg/m3                                                                                                                                                     

Correction for dose-response:1                                                                                                                                              

1.76 mg/m3/1 = 1.76 mg/m3                                                                                                                                                

Correction for whole database: 1 due to quality of study                                                                                                                

1.76 mg/m3/1 = 1.76 mg/m3                                                                                                                                               

Total AF = 75                                                                                                                                                       

1.76 mg/m3, DNEL inhalation-systemic-worker

                                                          

DNEL dermal-systemic-workerfor 3,3,5,7,7-pentamethyl-1,2,4-trioxepane: 

Correction for dermal and oral absorption rates of 3,3,5,7,7-pentamethyl-1,2,4-trioxepane (based on Guidance on information requirements and chemical safety assessment, Chapter R 7.12): Dermal absorption is assumed to be low for several reasons. 1. highly soluble in water (5.54 g/L); and 2. the experimental log Kow is 2.4. Most importantly, the substance is not a skin irritant, and a non-sensitizer to the skin. Therefore, low skin absorption is expected based on these biological behaviors and may be reasonably assumed to be 50% (correction factor= 0.5). No data is available on absorption by oral route. It is therefore assumed that oral absorption factor is 100 %.                                  

Oral NOAEL (150 mg/kg/day) / 0.5 = 300 mg/kg/day = dermal dose descriptor.                                                                            

Applying assessment factors in accordance with Endpoint Specific Guidance Chapters 8 and 7.c:                                                       

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

300 mg/kg/day/10 = 30  mg/kg/d                                                                                            

Correction for intraspecies difference: 5                                                                                                                                        

30 mg/kg/day/5 = 6 mg/kg/d

Correction for duration between sub-acute to chronic: 6                                                                                                                

6 mg/kg/day/6 = 1 mg/kg/d                                                                                                                                                         

Correction for dose-response: 1 due to NOAEL                                                                                              

6 mg/kg/day/1 = 6 mg/kg/d                                                                                                                                               

Correction for whole database: 1 due to quality of study                                                                                                                

6 mg/kg/day/1 = 6 mg/kg/d                                                                                                                                                         

Total AF = 300                                                                                                                                            

1 mg/kg/day, DNEL Dermal-worker-systemic                                                                                                                             

 

General population is not exposed to the substance by inhalation, dermal or oral exposure. The discharge of the substance in the environment (water, air) is extremely low. Therefore no inhalation and no dermal DNEL is derived for general population.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population